The Role of PharmEcovigilance in Reducing the Environmental Footprint of Pharmaceuticals

EPA Science Inventory

The prescribing and usage of medications have ramifications extending far beyond conventional medical care. The pharmaceutical and healthcare industries have an environmental footprint because the active pharmaceutical ingredients (APIs) can enter the environment as contaminants ...

Paper analytical devices for fast field screening of beta lactam antibiotics and antituberculosis pharmaceuticals.

PubMed

Weaver, Abigail A; Reiser, Hannah; Barstis, Toni; Benvenuti, Michael; Ghosh, Debarati; Hunckler, Michael; Joy, Brittney; Koenig, Leah; Raddell, Kellie; Lieberman, Marya

2013-07-02

Reports of low-quality pharmaceuticals have been on the rise in the past decade, with the greatest prevalence of substandard medicines in developing countries, where lapses in manufacturing quality control or breaches in the supply chain allow substandard medicines to reach the marketplace. Here, we describe inexpensive test cards for fast field screening of pharmaceutical dosage forms containing beta lactam antibiotics or combinations of the four first-line antituberculosis (TB) drugs. The devices detect the active pharmaceutical ingredients (APIs) ampicillin, amoxicillin, rifampicin, isoniazid, ethambutol, and pyrazinamide and also screen for substitute pharmaceuticals, such as acetaminophen and chloroquine that may be found in counterfeit pharmaceuticals. The tests can detect binders and fillers such as chalk, talc, and starch not revealed by traditional chromatographic methods. These paper devices contain 12 lanes, separated by hydrophobic barriers, with different reagents deposited in the lanes. The user rubs some of the solid pharmaceutical across the lanes and dips the edge of the paper into water. As water climbs up the lanes by capillary action, it triggers a library of different chemical tests and a timer to indicate when the tests are completed. The reactions in each lane generate colors to form a "color bar code" which can be analyzed visually by comparison with standard outcomes. Although quantification of the APIs is poor compared with conventional analytical methods, the sensitivity and selectivity for the analytes is high enough to pick out suspicious formulations containing no API or a substitute API as well as formulations containing APIs that have been "cut" with inactive ingredients.

Paper analytical devices for fast field screening of beta lactam antibiotics and anti-tuberculosis pharmaceuticals

PubMed Central

Weaver, Abigail A.; Reiser, Hannah; Barstis, Toni; Benvenuti, Michael; Ghosh, Debarati; Hunckler, Michael; Joy, Brittney; Koenig, Leah; Raddell, Kellie; Lieberman, Marya

2013-01-01

Reports of low quality pharmaceuticals have been on the rise in the last decade with the greatest prevalence of substandard medicines in developing countries, where lapses in manufacturing quality control or breaches in the supply chain allow substandard medicines to reach the marketplace. Here, we describe inexpensive test cards for fast field screening of pharmaceutical dosage forms containing beta lactam antibiotics or combinations of the four first-line antituberculosis (TB) drugs. The devices detect the active pharmaceutical ingredients (APIs) ampicillin, amoxicillin, rifampicin, isoniazid, ethambutol, and pyrazinamide, and also screen for substitute pharmaceuticals such as acetaminophen and chloroquine that may be found in counterfeit pharmaceuticals. The tests can detect binders and fillers like chalk, talc, and starch not revealed by traditional chromatographic methods. These paper devices contain twelve lanes, separated by hydrophobic barriers, with different reagents deposited in the lanes. The user rubs some of the solid pharmaceutical across the lanes and dips the edge of the paper into water. As water climbs up the lanes by capillary action, it triggers a library of different chemical tests and a timer to indicate when the tests are completed. The reactions in each lane generate colors to form a “color bar code” which can be analyzed visually by comparison to standard outcomes. While quantification of the APIs is poor compared to conventional analytical methods, the sensitivity and selectivity for the analytes is high enough to pick out suspicious formulations containing no API or a substitute API, as well as formulations containing APIs that have been “cut” with inactive ingredients. PMID:23725012

The role of cocrystals in pharmaceutical science.

PubMed

Shan, Ning; Zaworotko, Michael J

2008-05-01

Pharmaceutical cocrystals, a subset of a long known but little-studied class of compounds, represent an emerging class of crystal forms in the context of pharmaceutical science. They are attractive to pharmaceutical scientists because they can significantly diversify the number of crystal forms that exist for a particular active pharmaceutical ingredient (API), and they can lead to improvements in physical properties of clinical relevance. In this article we address pharmaceutical cocrystals from the perspective of design (crystal engineering) and present a series of case studies that demonstrate how they can enhance the solubility, bioavailability, and/or stability of API crystal forms.

Life cycle analysis within pharmaceutical process optimization and intensification: case study of active pharmaceutical ingredient production.

PubMed

Ott, Denise; Kralisch, Dana; Denčić, Ivana; Hessel, Volker; Laribi, Yosra; Perrichon, Philippe D; Berguerand, Charline; Kiwi-Minsker, Lioubov; Loeb, Patrick

2014-12-01

As the demand for new drugs is rising, the pharmaceutical industry faces the quest of shortening development time, and thus, reducing the time to market. Environmental aspects typically still play a minor role within the early phase of process development. Nevertheless, it is highly promising to rethink, redesign, and optimize process strategies as early as possible in active pharmaceutical ingredient (API) process development, rather than later at the stage of already established processes. The study presented herein deals with a holistic life-cycle-based process optimization and intensification of a pharmaceutical production process targeting a low-volume, high-value API. Striving for process intensification by transfer from batch to continuous processing, as well as an alternative catalytic system, different process options are evaluated with regard to their environmental impact to identify bottlenecks and improvement potentials for further process development activities. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peculiar surface behavior of some ionic liquids based on active pharmaceutical ingredients

NASA Astrophysics Data System (ADS)

Restolho, José; Mata, José Luis; Saramago, Benilde

2011-02-01

The ionic liquids based on biologically active cations and anions, commonly designated by ionic liquids based on active pharmaceutical ingredients (ILs-APIs), are interesting compounds for use in pharmaceutical applications. Lidocaine docusate, ranitidine docusate, and didecyldimethylammonium ibuprofen are examples of promising ILs-APIs that were recently synthesized. They were submitted to biological testing and calorimetric measurements, but nothing is known about their surface properties. In this work, we measured the surface tension and the contact angles on both hydrophilic and hydrophobic surfaces in a temperature range as wide as possible. Based on the wettability data, the polarity fractions were estimated using the Fowkes theory. The peculiar surface behavior observed was tentatively attributed to the presence of mesophases.

Green Pharmacy & PharmEcovigilance: Prescribing and the Planet

EPA Science Inventory

Active pharmaceutical ingredients (APIs) are well documented as ubiquitous contaminants in the environment, especially in surface waters. Although their primary source is excretion and bathing, a secondary route by which many APIs enter the environment is disposal of unwanted, le...

Leveraging a large scale mammalian pharmacological dataset to prioritize potential environmental hazard of pharmaceuticals

EPA Science Inventory

The potential for pharmaceuticals in the environment to cause adverse ecological effects is of increasing concern. Given the thousands of active pharmaceutical ingredients (APIs) which can enter the aquatic environment through various means, a current challenge in aquatic toxicol...

The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development.

PubMed

Dobo, Krista L; Greene, Nigel; Cyr, Michelle O; Caron, Stéphane; Ku, Warren W

2006-04-01

Starting materials and intermediates used to synthesize pharmaceuticals are reactive in nature and may be present as impurities in the active pharmaceutical ingredient (API) used for preclinical safety studies and clinical trials. Furthermore, starting materials and intermediates may be known or suspected mutagens and/or carcinogens. Therefore, during drug development due diligence need be applied from two perspectives (1) to understand potential mutagenic and carcinogenic risks associated with compounds used for synthesis and (2) to understand the capability of synthetic processes to control genotoxic impurities in the API. Recently, a task force comprised of experts from pharmaceutical industry proposed guidance, with recommendations for classification, testing, qualification and assessing risk of genotoxic impurities. In our experience the proposed structure-based classification, has differentiated 75% of starting materials and intermediates as mutagenic and non-mutagenic with high concordance (92%) when compared with Ames results. Structure-based assessment has been used to identify genotoxic hazards, and prompted evaluation of fate of genotoxic impurities in API. These two assessments (safety and chemistry) culminate in identification of genotoxic impurities known or suspected to exceed acceptable levels in API, thereby triggering actions needed to assure appropriate control and measurement methods are in place. Hypothetical case studies are presented demonstrating this multi-disciplinary approach.

FOCUS AREA 4 BACKGROUND PAPER: AQUATIC ECOTOXICITY ASSESSMENT

EPA Science Inventory

In parallel with a growing literature on the presence of Active Pharmaceutical Ingredients (APIs) in effluents and surface waters, recent years have witnessed a steady increase in published studies on the ecotoxicity of APIs to aquatic organisms. Against this background, key issu...

Development and validation of an ICP-MS method for the determination of elemental impurities in TP-6076 active pharmaceutical ingredient (API) according to USP 〈232〉/〈233〉.

PubMed

Chahrour, Osama; Malone, John; Collins, Mark; Salmon, Vrushali; Greenan, Catherine; Bombardier, Amy; Ma, Zhongze; Dunwoody, Nick

2017-10-25

The new guidelines of the United States pharmacopeia (USP), European pharmacopeia (EP) and international conference on harmonization (ICH) regulating elemental impurities limits in pharmaceuticals signify the end of unspecific analysis of metals as outlined in USP 〈231〉. The new guidelines specify both daily doses and concentration/limits of elemental impurities in pharmaceutical final products, active pharmaceutical ingredients (API) and excipients. In chapter USP 〈233〉 method implementation, validation and quality control during the analytical process are described. We herein report the use of a stabilising matrix that overcomes low spike recovery problem encountered with Os and allows the determination of all USP required elemental impurities (As, Cd, Hg, Pb, V, Cr, Ni, Mo, Cu, Pt, Pd, Ru, Rh, Os and Ir) in a single analysis. The matrix was used in the validation of a method to determine elemental impurities in TP-6076 active pharmaceutical ingredient (API) by ICP-MS according to the procedures defined in USP〈233〉 and to GMP requirements. This validation will support the regulatory submission of TP-6076 which is a novel tetracycline analogue effective against the most urgent multidrug-resistant gram-negative bacteria. Evaluation of TP-6076 in IND-enabling toxicology studies has led to the initiation of a phase 1 clinical trial. Copyright © 2017 Elsevier B.V. All rights reserved.

On the role of API in determining porosity, pore structure and bulk modulus of the skeletal material in pharmaceutical tablets formed with MCC as sole excipient.

PubMed

Ridgway, Cathy; Bawuah, Prince; Markl, Daniel; Zeitler, J Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik; Gane, Patrick

2017-06-30

The physical properties and mechanical integrity of pharmaceutical tablets are of major importance when loading with active pharmaceutical ingredient(s) (API) in order to ensure ease of processing, control of dosage and stability during transportation and handling prior to patient consumption. The interaction between API and excipient, acting as functional extender and binder, however, is little understood in this context. The API indomethacin is combined in this study with microcrystalline cellulose (MCC) at increasing loading levels. Tablets from the defined API/MCC ratios are made under conditions of controlled porosity and tablet thickness, resulting from different compression conditions, and thus compaction levels. Mercury intrusion porosimetry is used to establish the accessible pore volume, pore size distribution and, adopting the observed region of elastic intrusion-extrusion at high pressure, an elastic bulk modulus of the skeletal material is recorded. Porosity values are compared to previously published values derived from terahertz (THz) refractive index data obtained from exactly the same tablet sample sets. It is shown that the elastic bulk modulus is dependent on API wt% loading under constant tablet preparation conditions delivering equal dimensions and porosity. The findings are considered of novel value in respect to establishing consistency of tablet production and optimisation of physical properties. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs.

PubMed

Karagianni, Anna; Malamatari, Maria; Kachrimanis, Kyriakos

2018-01-25

Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development.

BEYOND THE MEDICINE CABINET: AN ANALYSIS OF WHERE AND WHY MEDICATIONS ACCUMULATE

EPA Science Inventory

Active pharmaceutical ingredients (APIs) from medications can enter the environment as trace contaminants, at individual concentrations generally below a part per billion (μg/L). APIs enter the environment primarily via the discharge of raw and treated sewage. Residues of unmet...

Presence of active pharmaceutical ingredients in the continuum of surface and ground water used in drinking water production.

PubMed

Ahkola, Heidi; Tuominen, Sirkku; Karlsson, Sanja; Perkola, Noora; Huttula, Timo; Saraperä, Sami; Artimo, Aki; Korpiharju, Taina; Äystö, Lauri; Fjäder, Päivi; Assmuth, Timo; Rosendahl, Kirsi; Nysten, Taina

2017-12-01

Anthropogenic chemicals in surface water and groundwater cause concern especially when the water is used in drinking water production. Due to their continuous release or spill-over at waste water treatment plants, active pharmaceutical ingredients (APIs) are constantly present in aquatic environment and despite their low concentrations, APIs can still cause effects on the organisms. In the present study, Chemcatcher passive sampling was applied in surface water, surface water intake site, and groundwater observation wells to estimate whether the selected APIs are able to end up in drinking water supply through an artificial groundwater recharge system. The API concentrations measured in conventional wastewater, surface water, and groundwater grab samples were assessed with the results obtained with passive samplers. Out of the 25 APIs studied with passive sampling, four were observed in groundwater and 21 in surface water. This suggests that many anthropogenic APIs released to waste water proceed downstream and can be detectable in groundwater recharge. Chemcatcher passive samplers have previously been used in monitoring several harmful chemicals in surface and wastewaters, but the path of chemicals to groundwater has not been studied. This study provides novel information on the suitability of the Chemcatcher passive samplers for detecting APIs in groundwater wells.

77 FR 60124 - Draft Guidance for Industry on Initial Completeness Assessments for Type II Active Pharmaceutical...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-02

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-1010] Draft Guidance for Industry on Initial Completeness Assessments for Type II Active Pharmaceutical... certain drug master files, namely, Type II active pharmaceutical ingredient (API) drug master files (DMFs...

Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs

PubMed Central

Karagianni, Anna; Kachrimanis, Kyriakos

2018-01-01

Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development. PMID:29370068

Introduction to Studies in Granular Mixing

ERIC Educational Resources Information Center

Llusa, Marcos; Muzzio, Fernando

2008-01-01

This article describes a hands-on educational activity designed to introduce students (or industrial employees) in the pharmaceutical arena to some of the most common problems in the mixing of solids: Active Pharmaceutical Ingredient (API) and lubricant (i.e. magnesium stearate) homogenization, characterization of segregation tendencies, and…

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals.

PubMed

Healy, Anne Marie; Worku, Zelalem Ayenew; Kumar, Dinesh; Madi, Atif M

2017-08-01

Active pharmaceutical ingredients (APIs) may exist in various solid forms, which can lead to differences in the intermolecular interactions, affecting the internal energy and enthalpy, and the degree of disorder, affecting the entropy. Differences in solid forms often lead to differences in thermodynamic parameters and physicochemical properties for example solubility, dissolution rate, stability and mechanical properties of APIs and excipients. Hence, solid forms of APIs play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights and developing suitable manufacturing methods. In this review, the fundamental characteristics and trends observed for pharmaceutical hydrates, solvates and amorphous forms are presented, with special emphasis, due to their relative abundance, on pharmaceutical hydrates with single and two-component (i.e. cocrystal) host molecules. Copyright © 2017 Elsevier B.V. All rights reserved.

Raw material variability of an active pharmaceutical ingredient and its relevance for processability in secondary continuous pharmaceutical manufacturing.

PubMed

Stauffer, F; Vanhoorne, V; Pilcer, G; Chavez, P-F; Rome, S; Schubert, M A; Aerts, L; De Beer, T

2018-06-01

Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability. Copyright © 2018 Elsevier B.V. All rights reserved.

Characterization of solid polymer dispersions of active pharmaceutical ingredients by 19F MAS NMR and factor analysis

NASA Astrophysics Data System (ADS)

Urbanova, Martina; Brus, Jiri; Sedenkova, Ivana; Policianova, Olivia; Kobera, Libor

In this contribution the ability of 19F MAS NMR spectroscopy to probe structural variability of poorly water-soluble drugs formulated as solid dispersions in polymer matrices is discussed. The application potentiality of the proposed approach is demonstrated on a moderately sized active pharmaceutical ingredient (API, Atorvastatin) exhibiting extensive polymorphism. In this respect, a range of model systems with the API incorporated in the matrix of polvinylpyrrolidone (PVP) was prepared. The extent of mixing of both components was determined by T1(1H) and T1ρ(1H) relaxation experiments, and it was found that the API forms nanosized domains. Subsequently it was found out that the polymer matrix induces two kinds of changes in 19F MAS NMR spectra. At first, this is a high-frequency shift reaching 2-3 ppm which is independent on molecular structure of the API and which results from the long-range polarization of the electron cloud around 19F nucleus induced by electrostatic fields of the polymer matrix. At second, this is broadening of the signals and formation of shoulders reflecting changes in molecular arrangement of the API. To avoid misleading in the interpretation of the recorded 19F MAS NMR spectra, because both the contributions act simultaneously, we applied chemometric approach based on multivariate analysis. It is demonstrated that factor analysis of the recorded spectra can separate both these spectral contributions, and the subtle structural differences in the molecular arrangement of the API in the nanosized domains can be traced. In this way 19F MAS NMR spectra of both pure APIs and APIs in solid dispersions can be directly compared. The proposed strategy thus provides a powerful tool for the analysis of new formulations of fluorinated pharmaceutical substances in polymer matrices.

Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges.

PubMed

Cerreia Vioglio, Paolo; Chierotti, Michele R; Gobetto, Roberto

2017-08-01

In recent years many efforts have been devoted to the screening and the study of new solid-state forms of old active pharmaceutical ingredients (APIs) with salification or co-crystallization processes, thus modulating final properties without changing the pharmacological nature. Salts, hydrates/solvates, and cocrystals are the common solid-state forms employed. They offer the intriguing possibility of exploring different pharmaceutical properties for a single API in the quest of enhancing the final drug product. New synthetic strategies and advanced characterization techniques have been recently proposed in this hot topic for pharmaceutical companies. This paper reviews the recent progresses in the field particularly focusing on the characterization challenges encountered when the nature of the solid-state form must be determined. The aim of this article is to offer the state-of-the-art on this subject in order to develop new insights and to promote cooperative efforts in the fascinating field of API salt and cocrystal forms. Copyright © 2017 Elsevier B.V. All rights reserved.

Sorption of active pharmaceutical ingredients in untreated wastewater effluent and effect of dilution in freshwater: Implications for an "impact zone" environmental risk assessment approach.

PubMed

Bagnis, Simone; Fitzsimons, Mark; Snape, Jason; Tappin, Alan; Comber, Sean

2018-05-15

Evidence of ecotoxicological effects of active pharmaceuticals ingredients (APIs) has increased research into their environmental fate. In low and low-middle income countries (LLMICs) the main source of APIs to surface waters is from discharge of untreated wastewater. Consequently, concentrations of APIs can be relatively high in the "impact zone" downstream of a discharge point. Little is known about the fate of APIs in these impact zones. In this laboratory scale investigation, the effect of successive dilution of synthetic untreated wastewater (dilution factor 1 to 10) on the distribution of APIs was studied. The sorption was consistent with the chemical properties of each compound: charge, lipophilicity, and structure. Dilution increased desorption of the basic and neutral APIs (up to 27.7%) and correlated with their lipophilicity (R 2 >0.980); the positive charge was of secondary importance. Anions did not significantly desorb (<10% loss). Increased concentrations of dissolved organic matter at dilutions of 8 and 10 times that of untreated wastewater coincided with lower dissolved API concentrations. The data showed a clear trend in the desorption process of APIs that may lead to higher exposure risk than anticipated. Therefore, it is suggested that these aspects should be accounted for in the development of dedicated environmental risk assessment approach for APIs in riverine impact zones of LLMICs countries. Copyright © 2017 Elsevier B.V. All rights reserved.

Analysis of ecologically relevant pharmaceuticals in wastewater and surface water using selective solid phase extraction and UPLC/MS/MS

EPA Science Inventory

A rapid and sensitive method has been developed for the analysis of 48 human prescription active pharmaceutical ingredients (APIs) and 6 metabolites of interest, utilizing selective solid-phase extraction (SPE) and ultra performance liquid chromatography in combination with tripl...

In-line UV spectroscopy for the quantification of low-dose active ingredients during the manufacturing of pharmaceutical semi-solid and liquid formulations.

PubMed

Bostijn, N; Hellings, M; Van Der Veen, M; Vervaet, C; De Beer, T

2018-07-12

UltraViolet (UV) spectroscopy was evaluated as an innovative Process Analytical Technology (PAT) - tool for the in-line and real-time quantitative determination of low-dosed active pharmaceutical ingredients (APIs) in a semi-solid (gel) and a liquid (suspension) pharmaceutical formulation during their batch production process. The performance of this new PAT-tool (i.e., UV spectroscopy) was compared with an already more established PAT-method based on Raman spectroscopy. In-line UV measurements were carried out with an immersion probe while for the Raman measurements a non-contact PhAT probe was used. For both studied formulations, an in-line API quantification model was developed and validated per spectroscopic technique. The known API concentrations (Y) were correlated with the corresponding in-line collected preprocessed spectra (X) through a Partial Least Squares (PLS) regression. Each developed quantification method was validated by calculating the accuracy profile on the basis of the validation experiments. Furthermore, the measurement uncertainty was determined based on the data generated for the determination of the accuracy profiles. From the accuracy profile of the UV- and Raman-based quantification method for the gel, it was concluded that at the target API concentration of 2% (w/w), 95 out of 100 future routine measurements given by the Raman method will not deviate more than 10% (relative error) from the true API concentration, whereas for the UV method the acceptance limits of 10% were exceeded. For the liquid formulation, the Raman method was not able to quantify the API in the low-dosed suspension (0.09% (w/w) API). In contrast, the in-line UV method was able to adequately quantify the API in the suspension. This study demonstrated that UV spectroscopy can be adopted as a novel in-line PAT-technique for low-dose quantification purposes in pharmaceutical processes. Important is that none of the two spectroscopic techniques was superior to the other for both formulations: the Raman method was more accurate in quantifying the API in the gel (2% (w/w) API), while the UV method performed better for API quantification in the suspension (0.09% (w/w) API). Copyright © 2018 Elsevier B.V. All rights reserved.

New solid-state chemistry technologies to bring better drugs to market: knowledge-based decision making.

PubMed

Park, Aeri; Chyall, Leonard J; Dunlap, Jeanette; Schertz, Christine; Jonaitis, David; Stahly, Barbara C; Bates, Simon; Shipplett, Rex; Childs, Scott

2007-01-01

Modern drug development demands constant deployment of more effective technologies to mitigate the high cost of bringing new drugs to market. In addition to cost savings, new technologies can improve all aspects of pharmaceutical development. New technologies developed at SSCI, Inc. include solid form development of an active pharmaceutical ingredients. (APIs) are PatternMatch software and capillary-based crystallisation techniques that not only allow for fast and effective solid form screening, but also extract maximum property information from the routine screening data that is generally available. These new technologies offer knowledge-based decision making during solid form development of APIs and result in more developable API solid forms.

X-ray powder diffractometry of intact film coated tablets--an approach to monitor the physical form of the active pharmaceutical ingredient during processing and storage.

PubMed

Yamada, Hiroyuki; Suryanarayanan, Raj

2007-08-01

The antiviral compound, 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl)ester (MCC-478), can exist in several anhydrous polymorphic forms and also as a hemihydrate. The XRD patterns of the tablets, containing each form of the active pharmaceutical ingredient (API), revealed at least one peak unique to each form. A semiquantitative microdiffractometric method was developed to nondestructively characterize the physical form of the API in intact film-coated tablets. This was accomplished even though the weight fraction of the API was <0.2 and that of mannitol, a highly crystalline excipient, was approximately 0.6. The method was used to determine the effect of aqueous film-coating process on the physical form of the API. The final dosage form was also monitored following storage at 40 degrees C/75% RH for 6 months. There was no phase transformation of the API either due to the film-coating process or following accelerated storage. This technique has potential utility not only for process control during manufacture, but also for the quality control of the final product. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.

National rivers and streams assessment survey: evaluating the extent of selected human prescription pharmaceuticals in United States surface waters

EPA Science Inventory

The Ecological Exposure Research Division (EERD) has prioritized a list of the most prescribed active pharmaceutical ingredients (API) in the U.S. based on the potential of their wastewater residues to cause biological effects. A method using selective solid phase extraction and...

A systematic reactor design approach for the synthesis of active pharmaceutical ingredients.

PubMed

Emenike, Victor N; Schenkendorf, René; Krewer, Ulrike

2018-05-01

Today's highly competitive pharmaceutical industry is in dire need of an accelerated transition from the drug development phase to the drug production phase. At the heart of this transition are chemical reactors that facilitate the synthesis of active pharmaceutical ingredients (APIs) and whose design can affect subsequent processing steps. Inspired by this challenge, we present a model-based approach for systematic reactor design. The proposed concept is based on the elementary process functions (EPF) methodology to select an optimal reactor configuration from existing state-of-the-art reactor types or can possibly lead to the design of novel reactors. As a conceptual study, this work summarizes the essential steps in adapting the EPF approach to optimal reactor design problems in the field of API syntheses. Practically, the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene was analyzed as a case study of pharmaceutical relevance. Here, a small-scale tubular coil reactor with controlled heating was identified as the optimal set-up reducing the residence time by 33% in comparison to literature values. Copyright © 2017 Elsevier B.V. All rights reserved.

Quality investigation of hydroxyprogesterone caproate active pharmaceutical ingredient and injection

PubMed Central

Chollet, John L.; Jozwiakowski, Michael J.

2012-01-01

The purpose of this study was to investigate the quality of hydroxyprogesterone caproate (HPC) active pharmaceutical ingredient (API) sources that may be used by compounding pharmacies, compared to the FDA-approved source of the API; and to investigate the quality of HPC injection samples obtained from compounding pharmacies in the US, compared to the FDA-approved product (Makena®). Samples of API were obtained from every source confirmed to be an original manufacturer of the drug for human use, which were all companies in China that were not registered with FDA. Eight of the ten API samples (80%) did not meet the impurity specifications required by FDA for the API used in the approved product. One API sample was found to not be HPC at all; additional laboratory testing showed that it was glucose. Thirty samples of HPC injection obtained from com pounding pharmacies throughout the US were also tested, and eight of these samples (27%) failed to meet the potency requirement listed in the USP monograph for HPC injection and/or the HPLC assay. Sixteen of the thirty injection samples (53%) exceeded the impurity limit setforthe FDA-approved drug product. These results confirm the inconsistency of compounded HPC Injections and suggest that the risk-benefit ratio of using an unapproved compounded preparation, when an FDA-approved drug product is available, is not favorable. PMID:22329865

In-line Raman spectroscopic monitoring and feedback control of a continuous twin-screw pharmaceutical powder blending and tableting process.

PubMed

Nagy, Brigitta; Farkas, Attila; Gyürkés, Martin; Komaromy-Hiller, Szofia; Démuth, Balázs; Szabó, Bence; Nusser, Dávid; Borbás, Enikő; Marosi, György; Nagy, Zsombor Kristóf

2017-09-15

The integration of Process Analytical Technology (PAT) initiative into the continuous production of pharmaceuticals is indispensable for reliable production. The present paper reports the implementation of in-line Raman spectroscopy in a continuous blending and tableting process of a three-component model pharmaceutical system, containing caffeine as model active pharmaceutical ingredient (API), glucose as model excipient and magnesium stearate as lubricant. The real-time analysis of API content, blend homogeneity, and tablet content uniformity was performed using a Partial Least Squares (PLS) quantitative method. The in-line Raman spectroscopic monitoring showed that the continuous blender was capable of producing blends with high homogeneity, and technological malfunctions can be detected by the proposed PAT method. The Raman spectroscopy-based feedback control of the API feeder was also established, creating a 'Process Analytically Controlled Technology' (PACT), which guarantees the required API content in the produced blend. This is, to the best of the authors' knowledge, the first ever application of Raman-spectroscopy in continuous blending and the first Raman-based feedback control in the formulation technology of solid pharmaceuticals. Copyright © 2017 Elsevier B.V. All rights reserved.

Ionic liquids in drug delivery.

PubMed

Shamshina, Julia L; Barber, Patrick S; Rogers, Robin D

2013-10-01

To overcome potential problems with solid-state APIs, such as polymorphism, solubility and bioavailability, pure liquid salt (ionic liquid) forms of active pharmaceutical ingredients (API-ILs) are considered here as a design strategy. After a critical review of the current literature, the recent development of the API-ILs strategy is presented, with a particular focus on the liquefaction of drugs. A variety of IL tools for control over the liquid salt state of matter are discussed including choice of counterion to produce an IL from a given API; the concept of oligomeric ions that enables liquefaction of solid ILs by changing the stoichiometry or complexity of the ions; formation of 'liquid co-crystals' where hydrogen bonding is the driving force in the liquefaction of a neutral acid-base complex; combining an IL strategy with the prodrug strategy to improve the delivery of solid APIs; using ILs as delivery agents via trapping a drug in a micelle and finally ILs designed with tunable hydrophilic-lipophilic balance that matches the structural requirements needed to solubilize poorly water-soluble APIs. The authors believe that API-IL approaches may save failed lead candidates, extend the patent life of current APIs, lead to new delivery options or even new pharmaceutical action. They encourage the pharmaceutical industry to invest more research into the API-IL platform as it could lead to fast-tracked approval based on similarities to the APIs already approved.

Development and validation of a fast static headspace GC method for determination of residual solvents in permethrin.

PubMed

Tian, Jingzhi; Rustum, Abu

2016-09-05

A fast static headspace gas chromatography (HS-GC) method was developed to separate all residual solvents present in commercial active pharmaceutical ingredient (API) batches of permethrin. A total of six residual solvents namely 2-methylpentane, 3-methylpentane, methylcyclopentane, n-hexane, cyclohexane and toluene were found in typical commercial batches of permethrin; and three of them are not in the list of ICH solvents. All six residual solvents were baseline separated in five minutes by the new method presented in this paper. The method was successfully validated as per International Conference on Harmonisation (ICH) guidelines. Evaluation of this method was conducted to separate 26 commonly used solvents in the manufacturing of various APIs, key intermediates of APIs and pharmaceutical excipients. The results of the evaluation demonstrated that this method can also be used as a general method to determine residual solvents in various APIs, intermediates and excipients that are used in pharmaceutical products. Copyright © 2016 Elsevier B.V. All rights reserved.

Forced degradation and impurity profiling: recent trends in analytical perspectives.

PubMed

Jain, Deepti; Basniwal, Pawan Kumar

2013-12-01

This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities profiling of pharmaceuticals including active pharmaceutical ingredient (API) as well as drug products during 2008-2012. These recent trends in forced degradation and impurity profiling were discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated techniques for the identification and quantification of thresholds of impurities and degradants in different pharmaceutical matrices. © 2013 Elsevier B.V. All rights reserved.

Integrative Advanced Oxidation and Biofiltration for Treating Pharmaceuticals in Wastewater.

PubMed

Lester, Yaal; Aga, Diana S; Love, Nancy G; Singh, Randolph R; Morrissey, Ian; Linden, Karl G

2016-11-01

  Advanced oxidation of active pharmaceutical ingredients (APIs) in wastewater produces transformation products (TPs) that are often more biodegradable than the parent compounds. Secondary effluent from a wastewater treatment plant was treated using UV-based advanced oxidation (LPUV/H2O2 and MPUV/NO3) followed by biological aerated filtration (BAF), and different APIs and their transformation products were monitored. The advanced oxidation processes degraded the APIs by 55-87% (LPUV/H2O2) and 58-95% (MPUV/NO3), while minor loss of APIs was achieved in the downstream BAF system. Eleven TPs were detected following oxidation of carbamazepine (5) and iopromide (6); three key TPs were biodegraded in the BAF system. The other TPs remained relatively constant in the BAF. The decrease in UV absorbance (UVA254) of the effluent in the BAF system was linearly correlated to the degradation of the APIs (for the MPUV/NO3-BAF), and can be applied to monitor the biotransformation of APIs in biological-based systems.

77 FR 30027 - Manufacturer of Controlled Substances; Notice of Application; Austin Pharma, LLC.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-21

... Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture bulk active pharmaceutical ingredients (APIs) for distribution to its customers. In reference to drug code 7360 (Marihuana...

Concerns about the safety of obesity agents from a manufacturing perspective.

PubMed

Kanfer, Isadore

2008-07-01

Salt derivatives of active pharmaceutical ingredients (API), such as hydrochloride and mesylate salts, are frequently used during drug product development. Compared with the underivatized API, salt derivatives are often associated with beneficial properties, including improved solubility and better absorption. Although the obesity agent sibutramine was initially approved as the hydrochloride salt, it has also been formulated as a mesylate salt (sibutramine mesylate). In order to qualify as interchangeable, generic products generally must be both pharmaceutically equivalent and bioequivalent to an approved reference product. Because generic versions of hydrochloride salt formulations that have been reformulated as mesylate salts are not pharmaceutically equivalent to the approved reference products, they would not be interchangeable, even if bioequivalent. The safety of APIs and drug products manufactured outside the United States in non-Food and Drug Administration-regulated facilities are of concern, particularly agents that may contain harmful impurities, such as obesity products formulated as mesylate salts.

Fluxes of 13 selected pharmaceuticals in the water cycle of Stockholm, Sweden.

PubMed

Wahlberg, C; Björlenius, B; Paxéus, N

2011-01-01

Mass flows of 13 pharmaceutical active ingredients (APIS) found in drinking water were studied in the water cycle of Stockholm. Data were collected by analyzing samples of surface water, raw water and drinking water as well as influents, effluents and sludges from waste water treatment plants (WWTPs) in Stockholm area. A mass balance was performed, based on sold amounts of pharmaceuticals and the measured concentrations in water and sludge. The selected APls were all present in WWTP effluents and the removal rates for many of them were poor. Mass balance calculations showed that the three studied WWTPs in Stockholm release considerable amounts of the selected APIs into the Baltic Sea while the portions ending up in WWTP sludge were significantly lower. The levels of APIs found in drinking water are low at present, but may increase in the future unless the releases from WWTPs in the catchment of Lake Mälären are mitigated.

Multicomponent chemical imaging of pharmaceutical solid dosage forms with broadband CARS microscopy.

PubMed

Hartshorn, Christopher M; Lee, Young Jong; Camp, Charles H; Liu, Zhen; Heddleston, John; Canfield, Nicole; Rhodes, Timothy A; Hight Walker, Angela R; Marsac, Patrick J; Cicerone, Marcus T

2013-09-03

We compare a coherent Raman imaging modality, broadband coherent anti-Stokes Raman scattering (BCARS) microscopy, with spontaneous Raman microscopy for quantitative and qualitative assessment of multicomponent pharmaceuticals. Indomethacin was used as a model active pharmaceutical ingredient (API) and was analyzed in a tabulated solid dosage form, embedded within commonly used excipients. In comparison with wide-field spontaneous Raman chemical imaging, BCARS acquired images 10× faster, at higher spatiochemical resolution and with spectra of much higher SNR, eliminating the need for multivariate methods to identify chemical components. The significant increase in spatiochemical resolution allowed identification of an unanticipated API phase that was missed by the spontaneous wide-field method and bulk Raman spectroscopy. We confirmed the presence of the unanticipated API phase using confocal spontaneous Raman, which provided spatiochemical resolution similar to BCARS but at 100× slower acquisition times.

Improved properties of fine active pharmaceutical ingredient powder blends and tablets at high drug loading via dry particle coating.

PubMed

Kunnath, Kuriakose; Huang, Zhonghui; Chen, Liang; Zheng, Kai; Davé, Rajesh

2018-05-30

It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting. Copyright © 2018 Elsevier B.V. All rights reserved.

Suspensions as a Valuable Alternative to Extemporaneously Compounded Capsules.

PubMed

Dijkers, Eli; Nanhekhan, Valerie; Thorissen, Astrid; Polonini, Hudson

2017-01-01

The objective of this study was to determine the variation in content of 74 different active pharmaceutical ingredients (APIs) and compare it with what is known in the literature for the content uniformity of extemporaneous prepared capsules. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography, via a stability-indicating method. Samples for all active pharmaceutical ingredients were taken throughout a 90-day period and the content was determined. In total, 5,190 different samples were analyzed for 74 different active pharmaceutical ingredients at room (15°C to 25°C) or controlled refrigerated temperature (2°C to 8°C). Each of these datasets was analyzed according to the United States Pharmacopeia Content Uniformity monograph, corrected for the sample number. The mean acceptance values were well within specifications. In addition, all suspensions complied with the criteria defined by the British Pharmacopoeia monograph for Content Uniformity of Liquid Dispersions for both room and controlled refrigerated temperature. In previous studies, it was found that a routine weight variation check is often not sufficient for quality assurance of extemporaneous prepared capsules. Compounded oral liquids show little variation in content for 74 different active pharmaceutical ingredients; therefore, compounded oral liquids are a suitable alternative when compounding individualized medications for patients. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

A Tape Method for Fast Characterization and Identification of Active Pharmaceutical Ingredients in the 2-18 THz Spectral Range

NASA Astrophysics Data System (ADS)

Kissi, Eric Ofosu; Bawuah, Prince; Silfsten, Pertti; Peiponen, Kai-Erik

2015-03-01

In order to find counterfeit drugs quickly and reliably, we have developed `tape method' a transmission spectroscopic terahertz (THz) measurement technique and compared it with a standard attenuated total reflection (ATR) THz spectroscopic measurement. We used well-known training samples, which include commercial paracetamol and aspirin tablets to check the validity of these two measurement techniques. In this study, the spectral features of some active pharmaceutical ingredients (APIs), such as aspirin and paracetamol are characterized for identification purpose. This work covers a wide THz spectral range namely, 2-18 THz. This proposed simple but novel technique, the tape method, was used for characterizing API and identifying their presence in their dosage forms. By comparing the spectra of the APIs to their dosage forms (powder samples), all distinct fingerprints present in the APIs are also present in their respective dosage forms. The positions of the spectral features obtained with the ATR techniques were akin to that obtained from the tape method. The ATR and the tape method therefore, complement each other. The presence of distinct fingerprints in this spectral range has highlighted the possibility of developing fast THz sensors for the screening of pharmaceuticals. It is worth noting that, the ATR method is applicable to flat faced tablets whereas the tape method is suitable for powders in general (e.g. curved surface tablets that require milling before measurement). Finally, we have demonstrated that ATR techniques can be used to screen counterfeit antimalarial tablets.

Detection of Xeljanz enantiomers in diethyl amine active pharmaceutical ingredients and tablets.

PubMed

Wang, Na-Na; Zhang, Dao-Lin; Jiang, Xin-Hui

2015-03-01

A high-performance liquid chromatography (HPLC) method was established to detect Xeljanz enantiomers in active pharmaceutical ingredients (APIs) and tablets. The separation was achieved on a Chiralpak IC column using a mobile phase of hexane-ethanol-diethylamine (65:35:0.1, v/v). The detection wavelength was 289 nm. The peak areas and the enantiomer concentrations in the range of 0.15-2.25 μg•mL(-1) were in high linearity, with correlation coefficients higher than 0.999. The recoveries were 86.44% at the concentrations of 7.5, 18.75, and 37.5 μg•mL(-1) . The limit of detection (LOD) and limit of quantification (LOQ) were 0.042 and 0.14 μg•mL(-1) , respectively. This HPLC method is suitable for detecting the enantiomers of Xeljanz in its APIs and tablets. © 2014 Wiley Periodicals, Inc.

Rapid Determination of Trace Palladium in Active Pharmaceutical Ingredients by Magnetic Solid-Phase Extraction and Flame Atomic Absorption Spectrometry

NASA Astrophysics Data System (ADS)

Yin, Q. H.; Zhu, D. M.; Yang, D. Z.; Hu, Q. F.; Yang, Y. L.

2018-01-01

Clutaraldehyde cross-linked magnetic chitosan nanoparticles were synthesized and used as an adsorbent for the dispersive solid-phase extraction of palladium in active pharmaceutical ingredients (APIs) prior to analysis by a flame atomic absorption spectrophotometer. FT-IR, X-ray diffraction, and TEM were used to characterize the adsorbent. Various parameters of experimental performance, such as adsorbent amount, pH, adsorption time, desorption solutions, coexisting ions, and adsorbent reusability, were investigated and optimized. Under the optimized conditions, good linearity was achieved in the 5.0-500 μg/L concentration range, with correlation coefficients of 0.9989. The limit of detection is 2.8 μg/L and the recoveries of spiked samples ranged from 91.7 to 97.6%. It was confirmed that the GMCNs nanocomposite was a promising adsorbing material for extraction and preconcentration of Pd in APIs.

Hot-stage microscopy for determination of API particles in a formulated tablet.

PubMed

Simek, Michal; Grünwaldová, Veronika; Kratochvíl, Bohumil

2014-01-01

Although methods exist to readily determine the particle size distribution (PSD) of an active pharmaceutical ingredient (API) before its formulation into a final product, the primary challenge is to develop a method to determine the PSD of APIs in a finished tablet. To address the limitations of existing PSD methods, we used hot-stage microscopy to observe tablet disintegration during temperature change and, thus, reveal the API particles in a tablet. Both mechanical and liquid disintegration were evaluated after we had identified optimum milling time for mechanical disintegration and optimum volume of water for liquid disintegration. In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs. Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs. Good agreement was obtained, thereby confirming the robustness of our methodology. The availability of such a method equips pharmaceutical scientists with an in vitro assessment method that will more reliably determine the PSD of active substances in finished tablets.

Improving the API dissolution rate during pharmaceutical hot-melt extrusion I: Effect of the API particle size, and the co-rotating, twin-screw extruder screw configuration on the API dissolution rate.

PubMed

Li, Meng; Gogos, Costas G; Ioannidis, Nicolas

2015-01-15

The dissolution rate of the active pharmaceutical ingredients in pharmaceutical hot-melt extrusion is the most critical elementary step during the extrusion of amorphous solid solutions - total dissolution has to be achieved within the short residence time in the extruder. Dissolution and dissolution rates are affected by process, material and equipment variables. In this work, we examine the effect of one of the material variables and one of the equipment variables, namely, the API particle size and extruder screw configuration on the API dissolution rate, in a co-rotating, twin-screw extruder. By rapidly removing the extruder screws from the barrel after achieving a steady state, we collected samples along the length of the extruder screws that were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) to determine the amount of undissolved API. Analyses of samples indicate that reduction of particle size of the API and appropriate selection of screw design can markedly improve the dissolution rate of the API during extrusion. In addition, angle of repose measurements and light microscopy images show that the reduction of particle size of the API can improve the flowability of the physical mixture feed and the adhesiveness between its components, respectively, through dry coating of the polymer particles by the API particles. Copyright © 2014. Published by Elsevier B.V.

Concentrations of prioritized pharmaceuticals in effluents from 50 large wastewater treatment plants in the US and implications for risk estimation.

PubMed

Kostich, Mitchell S; Batt, Angela L; Lazorchak, James M

2014-01-01

We measured concentrations of 56 active pharmaceutical ingredients (APIs) in effluent samples from 50 large wastewater treatment plants across the US. Hydrochlorothiazide was found in every sample. Metoprolol, atenolol, and carbamazepine were found in over 90% of the samples. Valsartan had the highest concentration (5300 ng/L), and also had the highest average concentration (1600 ng/L) across all 50 samples. Estimates of potential risks to healthy human adults were greatest for six anti-hypertensive APIs (lisinopril, hydrochlorothiazide, valsartan, atenolol, enalaprilat, and metoprolol), but nevertheless suggest risks of exposure to individual APIs as well as their mixtures are generally very low. Estimates of potential risks to aquatic life were also low for most APIs, but suggest more detailed study of potential ecological impacts from four analytes (sertraline, propranolol, desmethylsertraline, and valsartan). Published by Elsevier Ltd.

Terahertz absorption spectra of commonly used antimalarial drugs

NASA Astrophysics Data System (ADS)

Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

2018-06-01

Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

Terahertz absorption spectra of commonly used antimalarial drugs

NASA Astrophysics Data System (ADS)

Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

2018-03-01

Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

Modeling of quantitative relationships between physicochemical properties of active pharmaceutical ingredients and tensile strength of tablets using a boosted tree.

PubMed

Hayashi, Yoshihiro; Oishi, Takuya; Shirotori, Kaede; Marumo, Yuki; Kosugi, Atsushi; Kumada, Shungo; Hirai, Daijiro; Takayama, Kozo; Onuki, Yoshinori

2018-07-01

The aim of this study was to explore the potential of boosted tree (BT) to develop a correlation model between active pharmaceutical ingredient (API) characteristics and a tensile strength (TS) of tablets as critical quality attributes. First, we evaluated 81 kinds of API characteristics, such as particle size distribution, bulk density, tapped density, Hausner ratio, moisture content, elastic recovery, molecular weight, and partition coefficient. Next, we prepared tablets containing 50% API, 49% microcrystalline cellulose, and 1% magnesium stearate using direct compression at 6, 8, and 10 kN, and measured TS. Then, we applied BT to our dataset to develop a correlation model. Finally, the constructed BT model was validated using k-fold cross-validation. Results showed that the BT model achieved high-performance statistics, whereas multiple regression analysis resulted in poor estimations. Sensitivity analysis of the BT model revealed that diameter of powder particles at the 10th percentile of the cumulative percentage size distribution was the most crucial factor for TS. In addition, the influences of moisture content, partition coefficients, and modal diameter were appreciably meaningful factors. This study demonstrates that BT model could provide comprehensive understanding of the latent structure underlying APIs and TS of tablets.

Drugs and the Environment: Stewardship and Sustainability

EPA Science Inventory

This report represents the first-ever comprehensive examination of the broad scope of issues surrounding the topic of disposal of unwanted, unneeded, leftover medications from consumer use and the countless ways in which the introduction of active pharmaceutical ingredients (API...

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey.

PubMed

Fortunak, Joseph M; de Souza, Rodrigo O M A; Kulkarni, Amol A; King, Christopher L; Ellison, Tiffany; Miranda, Leandro S M

2014-01-01

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey

PubMed Central

Fortunak, Joseph M; de Souza, Rodrigo OMA; Kulkarni, Amol A; King, Christopher L; Ellison, Tiffany; Miranda, Leandro SM

2015-01-01

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President’s Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent. PMID:25310430

Temporal and spatial behavior of pharmaceuticals in ...

EPA Pesticide Factsheets

The behavior of active pharmaceutical ingredients (APIs) in urban estuaries is not well understood. In this study, 15 high volume usage APIs were measured over a one year period throughout Narragansett Bay, RI, USA to determine factors controlling their concentration and distribution. Dissolved APIs ranged in concentration from not detected to 310 ng/L, with numerous APIs present at all sites and sampling periods. Eight APIs were present in suspended particulate material, ranging in concentration from <1 ng/g to 44 ng/g. Partitioning coefficients (Kds) were determined for APIs present in both the dissolved and particulate phases, with their range and variability remaining relatively constant during the study. Organic carbon normalization reduced the observed variability of several APIs to a small extent; however, other factors appear to play a role in controlling partitioning behavior. The continuous discharge of wastewater treatment plant effluents into upper Narragansett Bay resulted in sustained levels of APIs, resulting in a zone of “pseudo-persistence.” For most of the APIs, there was a strong relationship with salinity, indicating conservative behavior within the estuary. Short flushing times in Narragansett Bay coupled with APIs present primarily in the dissolved phase suggests that most APIs will be diluted and transported out of the estuary, with only small amounts of several compounds removed to and sequestered in sediments. This study ide

Raman Spectroscopy of Cocrystals

NASA Astrophysics Data System (ADS)

Rooney, Frank; Reardon, Paul; Ochoa, Romulo; Abourahma, Heba; Marti, Marcus; Dimeo, Rachel

2010-02-01

Cocrystals are a class of compounds that consist of two or more molecules that are held together by hydrogen bonding. Pharmaceutical cocrystals are those that contain an active pharmaceutical ingredient (API) as one of the components. Pharmaceutical cocrystals are of particular interest and have gained a lot of attention in recent years because they offer the ability to modify the physical properties of the API, like solubility and bioavailability, without altering the chemical structure of the API. The APIs that we targeted for our studies are theophylline (Tp) and indomethacin (Ind). These compounds have been mixed with complementary coformers (cocrystal former) that include acetamide (AcONH2), melamine (MLM), nicotinic acid (Nic-COOH), 4-cyanopyridine (4-CNPy) and 4-aminopyridine (4-NH2Py). Raman spectroscopy has been used to characterize these cocrystals. Spectra of the cocrystals were compared to those of the coformers to analyze for peak shifts, specifically those corresponding to hydrogen bonding. A 0.5 m CCD Spex spectrometer was used, in a micro-Raman setup, for spectral analysis. An Argon ion Coherent laser at 514.5 nm was used as the excitation source. )

Prioritizing human pharmaceuticals for ecological risks in the freshwater environment of Korea.

PubMed

Ji, Kyunghee; Han, Eun Jeong; Back, Sunhyoung; Park, Jeongim; Ryu, Jisung; Choi, Kyungho

2016-04-01

Pharmaceutical residues are potential threats to aquatic ecosystems. Because more than 3000 active pharmaceutical ingredients (APIs) are in use, identifying high-priority pharmaceuticals is important for developing appropriate management options. Priority pharmaceuticals may vary by geographical region, because their occurrence levels can be influenced by demographic, societal, and regional characteristics. In the present study, the authors prioritized human pharmaceuticals of potential ecological risk in the Korean water environment, based on amount of use, biological activity, and regional hydrologic characteristics. For this purpose, the authors estimated the amounts of annual production of 695 human APIs in Korea. Then derived predicted environmental concentrations, using 2 approaches, to develop an initial candidate list of target pharmaceuticals. Major antineoplastic drugs and hormones were added in the initial candidate list regardless of their production amount because of their high biological activity potential. The predicted no effect concentrations were derived for those pharmaceuticals based on ecotoxicity information available in the literature or by model prediction. Priority lists of human pharmaceuticals were developed based on ecological risks and availability of relevant information. Those priority APIs identified include acetaminophen, clarithromycin, ciprofloxacin, ofloxacin, metformin, and norethisterone. Many of these pharmaceuticals have been neither adequately monitored nor assessed for risks in Korea. Further efforts are needed to improve these lists and to develop management decisions for these compounds in Korean water. © 2015 SETAC.

The significance of different health institutions and their respective contributions of active pharmaceutical ingredients to wastewater.

PubMed

Herrmann, Manuel; Olsson, Oliver; Fiehn, Rainer; Herrel, Markus; Kümmerer, Klaus

2015-12-01

Active pharmaceutical ingredients (APIs) have been frequently found in the environment. It is, however, still not quite clear who is mainly responsible for API emissions. Hospitals have been considered to be the main contributing point sources for wastewater (WW) discharge of APIs. However, recent studies have shown that the contribution of hospitals to the input of APIs into the aquatic environment is quite low. Due to demographic change and the increase of psychiatric diseases, health institutions (HIs) such as psychiatric hospitals and nursing homes are likely to be important sources as well, but no data is available in this respect. This study aims to assess the impact of HIs and to provide a methodology to measure their respective contributions. Drawing on pharmaceutical consumption data for the years 2010, 2011, and 2012, this study identified API usage patterns for a psychiatric hospital (146 beds), a nursing home (286 inhabitants), and a general hospital (741 beds), the latter of which comprises three separate locations. All the HIs are located in two sub-regions of a county district with about 400,000 citizens in southwestern Germany. A selection of neurological drugs was quantified in the sewer of these facilities to evaluate the correlation between consumption and emission. The API contribution of HIs was assessed by comparing the specific consumption in the facilities with the consumption in households, expressed as the emission potential (IEP). The study shows that the usage patterns of APIs in the psychiatric hospital and the nursing home were different from the general hospital. Neurological drugs such as anticonvulsants, psycholeptics, and psychoanaleptics were mainly consumed in the psychiatric hospital and the nursing home (74% and 65%, respectively). Predicted and average measured concentrations in the effluent of the investigated HIs differed mostly by less than one order of magnitude. Therefore, the consumption-based approach is a useful method to assess usage patterns of APIs in HIs and to predict their respective contributions to WW. The national contribution of HIs on total WW discharge of APIs compared to households was very low. Only the results for the sedative clomethiazole in general hospitals as well as the antidepressant moclobemide and the antipsychotic quetiapine for the nursing homes were found to deserve some attention. The regional comparison showed that in sub-regions with a comparably higher density of HIs, the allocated facilities could be seen as point sources emitting particular APIs. However, in general, the bulk of the consumed pharmaceuticals to WW discharge has to be attributed to households. Copyright © 2015 Elsevier Ltd. All rights reserved.

Environmental footprint of pharmaceuticals: the significance of factors beyond direct excretion to sewers.

PubMed

Daughton, Christian G; Ruhoy, Ilene S

2009-12-01

The combined excretion of active pharmaceutical ingredients (APIs) via urine and feces is considered the primary route by which APIs from human pharmaceuticals enter the environment. Disposal of unwanted, leftover medications by flushing into sewers has been considered a secondary route-one that does not contribute substantially to overall environmental loadings. The present study presents the first comprehensive examination of secondary routes of API release to the environment and for direct but unintentional human exposure. These include bathing, washing, and laundering, all of which release APIs remaining on the skin from the use of high-content dermal applications or from excretion to the skin via sweating, and disposal of unused and partially used high-content devices. Also discussed are the health hazards associated with: partially used devices, medication disposal practices of consumers, and interpersonal dermal transfer of API residues. Understanding these secondary routes is important from the perspective of pollution prevention, because actions can be designed more easily for reducing the environmental impact of APIs compared with the route of direct excretion (via urine and feces), for reducing the incidence of unintentional and purposeful poisonings of humans and pets, and for improving the quality and cost-effectiveness of health care. Overall, unintentional exposure to APIs for humans via these routes is possibly more important than exposure to trace residues recycled from the environment in drinking water or foods.

Chronic toxicity of an environmentally relevant mixture of pharmaceuticals to three aquatic organisms (alga, daphnid, and fish).

PubMed

Watanabe, Haruna; Tamura, Ikumi; Abe, Ryoko; Takanobu, Hitomi; Nakamura, Ataru; Suzuki, Toshinari; Hirose, Akihiko; Nishimura, Tetsuji; Tatarazako, Norihisa

2016-04-01

Principles of concentration addition and independent action have been used as effective tools to predict mixture toxicity based on individual component toxicity. The authors investigated the toxicity of a pharmaceutical mixture composed of the top 10 detected active pharmaceutical ingredients (APIs) in the Tama River (Tokyo, Japan) in a relevant concentration ratio. Both individual and mixture toxicities of the 10 APIs were evaluated by 3 short-term chronic toxicity tests using the alga Pseudokirchneriella subcapitata, the daphnid Ceriodaphnia dubia, and the zebrafish Danio rerio. With the exception of clarithromycin toxicity to alga, the no-observed-effect concentration of individual APIs for each test species was dramatically higher than the highest concentration of APIs found in the environment. The mixture of 10 APIs resulted in toxicity to alga, daphnid, and fish at 6.25 times, 100 times, and 15,000 times higher concentrations, respectively, than the environmental concentrations of individual APIs. Predictions by concentration addition and independent action were nearly identical for alga, as clarithromycin was the predominant toxicant in the mixture. Both predictions described the observed mixture toxicity to alga fairly well, whereas they slightly underestimated the observed mixture toxicity in the daphnid test. In the fish embryo test, the observed toxicity fell between the predicted toxicity by concentration addition and independent action. These results suggested that the toxicity of environmentally relevant pharmaceutical mixtures could be predicted by individual toxicity using either concentration addition or independent action. © 2015 SETAC.

Surface modification of acetaminophen particles by atomic layer deposition.

PubMed

Kääriäinen, Tommi O; Kemell, Marianna; Vehkamäki, Marko; Kääriäinen, Marja-Leena; Correia, Alexandra; Santos, Hélder A; Bimbo, Luis M; Hirvonen, Jouni; Hoppu, Pekka; George, Steven M; Cameron, David C; Ritala, Mikko; Leskelä, Markku

2017-06-15

Active pharmaceutical ingredients (APIs) are predominantly organic solid powders. Due to their bulk properties many APIs require processing to improve pharmaceutical formulation and manufacturing in the preparation for various drug dosage forms. Improved powder flow and protection of the APIs are often anticipated characteristics in pharmaceutical manufacturing. In this work, we have modified acetaminophen particles with atomic layer deposition (ALD) by conformal nanometer scale coatings in a one-step coating process. According to the results, ALD, utilizing common chemistries for Al 2 O 3 , TiO 2 and ZnO, is shown to be a promising coating method for solid pharmaceutical powders. Acetaminophen does not undergo degradation during the ALD coating process and maintains its stable polymorphic structure. Acetaminophen with nanometer scale ALD coatings shows slowed drug release. ALD TiO 2 coated acetaminophen particles show cytocompatibility whereas those coated with thicker ZnO coatings exhibit the most cytotoxicity among the ALD materials under study when assessed in vitro by their effect on intestinal Caco-2 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Comprehensive two-dimensional liquid chromatography separations of pharmaceutical samples using dual Fused-Core columns in the 2nd dimension.

PubMed

Alexander, Anthony J; Ma, Lianjia

2009-02-27

This paper focuses on the application of RPLC x RPLC to pharmaceutical analysis and addresses the specific problem of separating co-eluting impurities/degradation products that maybe "hidden" within the peak envelope of the active pharmaceutical ingredient (API) and thus may escape detection by conventional methods. A comprehensive two-dimensional liquid chromatograph (LC x LC) was constructed from commercially available HPLC equipment. This system utilizes two independently configurable 2nd dimension binary pumping systems to deliver independent flow rates, gradient profiles and mobile phase compositions to dual Fused-Core secondary columns. Very fast gradient separations (30s total cycle time) were achieved at ambient temperature without excessive backpressure and without compromising optimal 1st dimension sampling rates. The operation of the interface is demonstrated for the analysis of a 1mg/ml standard mixture containing 0.05% of a minor component. The practicality of using RPLC x RPLC for the analysis of actual co-eluting pharmaceutical degradation products, by exploiting pH-induced changes in selectivity, is also demonstrated using a three component mixture. This mixture (an API, an oxidation product of the API at 1.0%, w/w, and a photo degradant of the API at 0.5%, w/w) was used to assess the stability indicating nature of an established LC method for analysis of the API.

Potential ecological footprints of active pharmaceutical ingredients: an examination of risk factors in low-, middle- and high-income countries

PubMed Central

Kookana, Rai S.; Williams, Mike; Boxall, Alistair B. A.; Larsson, D. G. Joakim; Gaw, Sally; Choi, Kyungho; Yamamoto, Hiroshi; Thatikonda, Shashidhar; Zhu, Yong-Guan; Carriquiriborde, Pedro

2014-01-01

Active pharmaceutical ingredients (APIs) can enter the natural environment during manufacture, use and/or disposal, and consequently public concern about their potential adverse impacts in the environment is growing. Despite the bulk of the human population living in Asia and Africa (mostly in low- or middle-income countries), limited work relating to research, development and regulations on APIs in the environment have so far been conducted in these regions. Also, the API manufacturing sector is gradually shifting to countries with lower production costs. This paper focuses mainly on APIs for human consumption and highlights key differences between the low-, middle- and high-income countries, covering factors such as population and demographics, manufacture, prescriptions, treatment, disposal and reuse of waste and wastewater. The striking differences in populations (both human and animal), urbanization, sewer connectivity and other factors have revealed that the environmental compartments receiving the bulk of API residues differ markedly between low- and high-income countries. High sewer connectivity in developed countries allows capture and treatment of the waste stream (point-source). However, in many low- or middle-income countries, sewerage connectivity is generally low and in some areas waste is collected predominantly in septic systems. Consequently, the diffuse-source impact, such as on groundwater from leaking septic systems or on land due to disposal of raw sewage or septage, may be of greater concern. A screening level assessment of potential burdens of APIs in urban and rural environments of countries representing low- and middle-income as well as high-income has been made. Implications for ecological risks of APIs used by humans in lower income countries are discussed. PMID:25405973

An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137--a successful approach.

PubMed

Petzoldt, Christine; Bley, Oliver; Byard, Stephen J; Andert, Doris; Baumgartner, Bruno; Nagel, Norbert; Tappertzhofen, Christoph; Feth, Martin Philipp

2014-04-01

The so-called pharmaceutical solid chain, which encompasses drug substance micronisation to the final tablet production, at pilot plant scale is presented as a case study for a novel, highly potent, pharmaceutical compound: SAR114137. Various solid-state analytical methods, such as solid-state Nuclear Magnetic Resonance (ssNMR), Differential Scanning Calorimetry (DSC), Dynamic Water Vapour Sorption Gravimetry (DWVSG), hot-stage Raman spectroscopy and X-ray Powder Diffraction (XRPD) were applied and evaluated to characterise and quantify amorphous content during the course of the physical treatment of crystalline active pharmaceutical ingredient (API). DSC was successfully used to monitor the changes in amorphous content during micronisation of the API, as well as during stability studies. (19)F solid-state NMR was found to be the method of choice for the detection and quantification of low levels of amorphous API, even in the final drug product (DP), since compaction during tablet manufacture was identified as a further source for the formation of amorphous API. The application of different jet milling techniques was a critical factor with respect to amorphous content formation. In the present case, the change from spiral jet milling to loop jet milling led to a decrease in amorphous API content from 20-30 w/w% to nearly 0 w/w% respectively. The use of loop jet milling also improved the processability of the API. Stability investigations on both the milled API and the DP showed a marked tendency for recrystallisation of the amorphous API content on exposure to elevated levels of relative humidity. No significant impact of amorphous API on either the chemical stability or the dissolution rate of the API in drug formulation was observed. Therefore, the presence of amorphous content in the oral formulation was of no consequence for the clinical trial phases I and II. Copyright © 2013 Elsevier B.V. All rights reserved.

Binary polymorphic cocrystals: an update on the available literature in the Cambridge Structural Database, including a new polymorph of the pharmaceutical 1:1 cocrystal theophylline-3,4-dihydroxybenzoic acid.

PubMed

Mnguni, Malitsatsi J; Michael, Joseph P; Lemmerer, Andreas

2018-06-01

An analysis and classification of the 2925 neutral binary organic cocrystals in the Cambridge Structural Database is reported, focusing specifically on those both showing polymorphism and containing an active pharmaceutical ingredient (API). The search was confined to molecules having only C, H, N, O, S and halogens atoms. It was found that 400 out of 2925 cocrystals can be classified as pharmaceutical cocrystals, containing at least one API, and that of those, 56 can be classified as being polymorphic cocrystals. In general, the total number of polymorphic cocrystal systems of any type stands at 125. In addition, a new polymorph of the pharmaceutical cocrystal theophylline-3,4-dihydroxybenzoic acid (1/1), C 7 H 8 N 4 O 2 ·C 7 H 6 O 4 , is reported.

Dropwise additive manufacturing of pharmaceutical products for solvent-based dosage forms.

PubMed

Hirshfield, Laura; Giridhar, Arun; Taylor, Lynne S; Harris, Michael T; Reklaitis, Gintaras V

2014-02-01

In recent years, the US Food and Drug Administration has encouraged pharmaceutical companies to develop more innovative and efficient manufacturing methods with improved online monitoring and control. Mini-manufacturing of medicine is one such method enabling the creation of individualized product forms for each patient. This work presents dropwise additive manufacturing of pharmaceutical products (DAMPP), an automated, controlled mini-manufacturing method that deposits active pharmaceutical ingredients (APIs) directly onto edible substrates using drop-on-demand (DoD) inkjet printing technology. The use of DoD technology allows for precise control over the material properties, drug solid state form, drop size, and drop dynamics and can be beneficial in the creation of high-potency drug forms, combination drugs with multiple APIs or individualized medicine products tailored to a specific patient. In this work, DAMPP was used to create dosage forms from solvent-based formulations consisting of API, polymer, and solvent carrier. The forms were then analyzed to determine the reproducibility of creating an on-target dosage form, the morphology of the API of the final form and the dissolution behavior of the drug over time. DAMPP is found to be a viable alternative to traditional mass-manufacturing methods for solvent-based oral dosage forms. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs.

PubMed

Bergström, Christel A S; Holm, René; Jørgensen, Søren Astrup; Andersson, Sara B E; Artursson, Per; Beato, Stefania; Borde, Anders; Box, Karl; Brewster, Marcus; Dressman, Jennifer; Feng, Kung-I; Halbert, Gavin; Kostewicz, Edmund; McAllister, Mark; Muenster, Uwe; Thinnes, Julian; Taylor, Robert; Mullertz, Anette

2014-06-16

Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. Copyright © 2013 Elsevier B.V. All rights reserved.

Active pharmaceutical ingredient (API) production involving continuous processes--a process system engineering (PSE)-assisted design framework.

PubMed

Cervera-Padrell, Albert E; Skovby, Tommy; Kiil, Søren; Gani, Rafiqul; Gernaey, Krist V

2012-10-01

A systematic framework is proposed for the design of continuous pharmaceutical manufacturing processes. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and fermentation-based products. The method exploits the synergic combination of continuous flow technologies (e.g., microfluidic techniques) and process systems engineering (PSE) methods and tools for faster process design and increased process understanding throughout the whole drug product and process development cycle. The design framework structures the many different and challenging design problems (e.g., solvent selection, reactor design, and design of separation and purification operations), driving the user from the initial drug discovery steps--where process knowledge is very limited--toward the detailed design and analysis. Examples from the literature of PSE methods and tools applied to pharmaceutical process design and novel pharmaceutical production technologies are provided along the text, assisting in the accumulation and interpretation of process knowledge. Different criteria are suggested for the selection of batch and continuous processes so that the whole design results in low capital and operational costs as well as low environmental footprint. The design framework has been applied to the retrofit of an existing batch-wise process used by H. Lundbeck A/S to produce an API: zuclopenthixol. Some of its batch operations were successfully converted into continuous mode, obtaining higher yields that allowed a significant simplification of the whole process. The material and environmental footprint of the process--evaluated through the process mass intensity index, that is, kg of material used per kg of product--was reduced to half of its initial value, with potential for further reduction. The case-study includes reaction steps typically used by the pharmaceutical industry featuring different characteristic reaction times, as well as L-L separation and distillation-based solvent exchange steps, and thus constitutes a good example of how the design framework can be useful to efficiently design novel or already existing API manufacturing processes taking advantage of continuous processes. Copyright © 2012 Elsevier B.V. All rights reserved.

Relationships between response surfaces for tablet characteristics of placebo and API-containing tablets manufactured by direct compression method.

PubMed

Hayashi, Yoshihiro; Tsuji, Takahiro; Shirotori, Kaede; Oishi, Takuya; Kosugi, Atsushi; Kumada, Shungo; Hirai, Daijiro; Takayama, Kozo; Onuki, Yoshinori

2017-10-30

In this study, we evaluated the correlation between the response surfaces for the tablet characteristics of placebo and active pharmaceutical ingredient (API)-containing tablets. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Ten tablet formulations were prepared. The tensile strength (TS) and disintegration time (DT) of tablets were measured as tablet characteristics. The response surfaces for TS and DT were estimated using a nonlinear response surface method incorporating multivariate spline interpolation, and were then compared with those of placebo tablets. A correlation was clearly observed for TS and DT of all APIs, although the value of the response surfaces for TS and DT was highly dependent on the type of API used. Based on this knowledge, the response surfaces for TS and DT of API-containing tablets were predicted from only two and four formulations using regression expression and placebo tablet data, respectively. The results from the evaluation of prediction accuracy showed that this method accurately predicted TS and DT, suggesting that it could construct a reliable response surface for TS and DT with a small number of samples. This technique assists in the effective estimation of the relationships between design variables and pharmaceutical responses during pharmaceutical development. Copyright © 2017 Elsevier B.V. All rights reserved.

Multicomponent Pharmaceutical Cocrystals: A Novel Approach for Combination Therapy.

PubMed

Fatima, Zeeshan; Srivastava, Dipti; Kaur, Chanchal Deep

2018-03-05

Cocrystallization is a technique for modifying the physicochemical and pharmacokinetic properties of an active pharmaceutical ingredient (API) embodying the concept of supramolecular synthon. Most of the examples cited in the literature are of cocrystals formed between an API and a coformer chosen from the generally recognized as safe (GRAS) substance list, however, few examples exist where a cocrystal consists of two or more APIs. These cocrystals are commonly known as multi API, multi drug or drug- drug cocrystals. The formation of such cocrystals is feasible by virtue of non covalent interactions between the APIs, which help them in retaining their biologic activity. In addition, drug- drug cocrystals also offer the potential solution to the limitations such as solubility, stability differences and chemical interaction between the APIs which is often faced during the traditional combination therapy. Cocrystallization of two or more APIs can be employed for delivery of combination drugs for the better and efficacious management of many complex disorders where existing monotherapies do not furnish the desired therapeutic effect. This review on the existing drug-drug cocrystals is to gain insight for better designing of multi API cocrystals with improved physicochemical and pharmacokinetic profile and its application in multiple target therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Method for the determination of Pd-catalyst residues in active pharmaceutical ingredients by means of high-energy polarized-beam energy dispersive X-ray fluorescence.

PubMed

Marguí, E; Van Meel, K; Van Grieken, R; Buendía, A; Fontàs, C; Hidalgo, M; Queralt, I

2009-02-15

In medicinal chemistry, Pd is perhaps the most-widely utilized precious metal, as catalyst in reactions which represent key transformations toward the synthesis of new active pharmaceutical ingredients (APIs). The disadvantage of this metal-catalyzed chemistry is that expensive and toxic metal residues are invariably left bound to the desired product. Thus, stringent regulatory guidelines exist for the amount of residual Pd that a drug candidate is allowed to contain. In this work, a rapid and simple method for the determination of Pd in API samples by high-energy polarized-beam energy dispersive X-ray fluorescence spectrometry has been developed and validated according to the specification limits of current legislation (10 mg kg(-1) Pd) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH guidelines). Sample and calibration standards preparation includes a first step of homogenization and then, in a second step, the pressing of the powdered material into pellets without any chemical treatment. The use of several synthetic calibration standards made of cellulose to simulate the API matrix appears to be an effective means to obtain reliable calibration curves with a good spread of data points over the working range. With the use of the best measuring conditions, the limit of detection (0.11 mg kg(-1) Pd) as well as the limit of quantitation (0.37 mg kg(-1) Pd) achieved meet rigorous requirements. The repeatability of the XRF measurement appeared to be less than 2%, while the precision of the whole method was around 7%. Trueness was evaluated by analyzing spiked API samples at the level of the specification limit and calculating the recovery factor, which was better than 95%. To study the applicability of the developed methodology for the intended purpose, three batches of the studied API were analyzed for their Pd content, and the attained results were comparable to those obtained by the daily routine method (acid digestion plus atomic spectroscopy) used in most pharmaceutical laboratories.

Pharmaceutical Cocrystals and Their Physicochemical Properties

PubMed Central

2009-01-01

Over the last 20 years, the number of publications outlining the advances in design strategies, growing techniques, and characterization of cocrystals has continued to increase significantly within the crystal engineering field. However, only within the last decade have cocrystals found their place in pharmaceuticals, primarily due to their ability to alter physicochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API) and thus, possibly, the bioactivity. This review article will highlight and discuss the advances made over the last 10 years pertaining to physical and chemical property improvements through pharmaceutical cocrystalline materials and, hopefully, draw closer the fields of crystal engineering and pharmaceutical sciences. PMID:19503732

An integrated approach for prioritizing pharmaceuticals found in the environment for risk assessment, monitoring and advanced research.

PubMed

Caldwell, Daniel J; Mastrocco, Frank; Margiotta-Casaluci, Luigi; Brooks, Bryan W

2014-11-01

Numerous active pharmaceutical ingredients (APIs), approved prior to enactment of detailed environmental risk assessment (ERA) guidance in the EU in 2006, have been detected in surface waters as a result of advancements in analytical technologies. Without adequate knowledge of the potential hazards these APIs may pose, assessing their environmental risk is challenging. As it would be impractical to commence hazard characterization and ERA en masse, several approaches to prioritizing substances for further attention have been published. Here, through the combination of three presentations given at a recent conference, "Pharmaceuticals in the Environment, Is there a problem?" (Nîmes, France, June 2013) we review several of these approaches, identify salient components, and present available techniques and tools that could facilitate a pragmatic, scientifically sound approach to prioritizing APIs for advanced study or ERA and, where warranted, fill critical data gaps through targeted, intelligent testing. We further present a modest proposal to facilitate future prioritization efforts and advanced research studies that incorporates mammalian pharmacology data (e.g., adverse outcomes pathways and the fish plasma model) and modeled exposure data based on pharmaceutical use. Copyright © 2014 Elsevier Ltd. All rights reserved.

Quality assessment of pharmaceutical tablet samples using Fourier transform near infrared spectroscopy and multivariate analysis

NASA Astrophysics Data System (ADS)

Kandpal, Lalit Mohan; Tewari, Jagdish; Gopinathan, Nishanth; Stolee, Jessica; Strong, Rick; Boulas, Pierre; Cho, Byoung-Kwan

2017-09-01

Determination of the content uniformity, assessed by the amount of an active pharmaceutical ingredient (API), and hardness of pharmaceutical materials is important for achieving a high-quality formulation and to ensure the intended therapeutic effects of the end-product. In this work, Fourier transform near infrared (FT-NIR) spectroscopy was used to determine the content uniformity and hardness of a pharmaceutical mini-tablet and standard tablet samples. Tablet samples were scanned using an FT-NIR instrument and tablet spectra were collected at wavelengths of 1000-2500 nm. Furthermore, multivariate analysis was applied to extract the relationship between the FT-NIR spectra and the measured parameters. The results of FT-NIR spectroscopy for API and hardness prediction were as precise as the reference high-performance liquid chromatography and mechanical hardness tests. For the prediction of mini-tablet API content, the highest coefficient of determination for the prediction (R2p) was found to be 0.99 with a standard error of prediction (SEP) of 0.72 mg. Moreover, the standard tablet hardness measurement had a R2p value of 0.91 with an SEP of 0.25 kg. These results suggest that FT-NIR spectroscopy is an alternative and accurate nondestructive measurement tool for the detection of the chemical and physical properties of pharmaceutical samples.

Main Reasons for Registration Application Refusal of Generic and Similar Pharmaceutical Drug Products by the Brazilian Health Regulatory Agency (ANVISA).

PubMed

do Carmo, Ana Cerúlia Moraes; Piras, Stefânia Schimaneski; Rocha, Nayrton Flávio Moura; Gratieri, Tais

2017-01-01

Objective . The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods . A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results . Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion . Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products.

Pharmaceutical cocrystals, salts and polymorphs: Advanced characterization techniques.

PubMed

Pindelska, Edyta; Sokal, Agnieszka; Kolodziejski, Waclaw

2017-08-01

The main goal of a novel drug development is to obtain it with optimal physiochemical, pharmaceutical and biological properties. Pharmaceutical companies and scientists modify active pharmaceutical ingredients (APIs), which often are cocrystals, salts or carefully selected polymorphs, to improve the properties of a parent drug. To find the best form of a drug, various advanced characterization methods should be used. In this review, we have described such analytical methods, dedicated to solid drug forms. Thus, diffraction, spectroscopic, thermal and also pharmaceutical characterization methods are discussed. They all are necessary to study a solid API in its intrinsic complexity from bulk down to the molecular level, gain information on its structure, properties, purity and possible transformations, and make the characterization efficient, comprehensive and complete. Furthermore, these methods can be used to monitor and investigate physical processes, involved in the drug development, in situ and in real time. The main aim of this paper is to gather information on the current advancements in the analytical methods and highlight their pharmaceutical relevance. Copyright © 2017 Elsevier B.V. All rights reserved.

Main Reasons for Registration Application Refusal of Generic and Similar Pharmaceutical Drug Products by the Brazilian Health Regulatory Agency (ANVISA)

PubMed Central

do Carmo, Ana Cerúlia Moraes; Piras, Stefânia Schimaneski; Rocha, Nayrton Flávio Moura

2017-01-01

Objective. The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods. A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results. Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion. Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products. PMID:28280742

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing.

PubMed

Burcham, Christopher L; Florence, Alastair J; Johnson, Martin D

2018-06-07

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

Influence of Coformer Stoichiometric Ratio on Pharmaceutical Cocrystal Dissolution: Three Cocrystals of Carbamazepine/4-Aminobenzoic Acid.

PubMed

Li, Zi; Matzger, Adam J

2016-03-07

Cocrystallization is a technique to optimize solid forms that shows great potential to improve the solubility of active pharmaceutical ingredients (APIs). In some systems, an API can form cocrystals in multiple stoichiometries with the same coformer. However, it remains unclear how coformer stoichiometry influences solubility. This paper investigates the pharmaceutical:coformer pair carbamazepine (CBZ)/p-aminobenzoic acid (PABA); both CBZ/PABA 1:1 and 2:1 cocrystals are known, and a novel 4:1 CBZ/PABA cocrystal is reported here. The 4:1 cocrystal is structurally characterized, and phase stability data suggest that it is a thermodynamically unstable form. Dissolution experiments show that there is no correlation between the cocrystal stoichiometry and dissolution rate in this system. On the other hand, with the relatively weak intermolecular interactions, metastable forms can be beneficial to dissolution rate, which suggests that more effort should be devoted to cocrystal production with kinetic growth methods.

Pharmaceuticals in water, fish and osprey nestlings in Delaware River and Bay

USGS Publications Warehouse

Bean, Thomas G.; Rattner, Barnett A.; Lazarus, Rebecca S.; Day, Daniel D.; Burket, S. Rebekah; Brooks, Bryan W.; Haddad, Samuel P.; Bowerman, William W.

2018-01-01

Exposure of wildlife to Active Pharmaceutical Ingredients (APIs) is likely to occur but studies of risk are limited. One exposure pathway that has received attention is trophic transfer of APIs in a water-fish-osprey food chain. Samples of water, fish plasma and osprey plasma were collected from Delaware River and Bay, and analyzed for 21 APIs. Only 2 of 21 analytes exceeded method detection limits in osprey plasma (acetaminophen and diclofenac) with plasma levels typically 2–3 orders of magnitude below human therapeutic concentrations (HTC). We built upon a screening level model used to predict osprey exposure to APIs in Chesapeake Bay and evaluated whether exposure levels could have been predicted in Delaware Bay had we just measured concentrations in water or fish. Use of surface water and BCFs did not predict API concentrations in fish well, likely due to fish movement patterns, and partitioning and bioaccumulation uncertainties associated with these ionizable chemicals. Input of highest measured API concentration in fish plasma combined with pharmacokinetic data accurately predicted that diclofenac and acetaminophen would be the APIs most likely detected in osprey plasma. For the majority of APIs modeled, levels were not predicted to exceed 1 ng/mL or method detection limits in osprey plasma. Based on the target analytes examined, there is little evidence that APIs represent a significant risk to ospreys nesting in Delaware Bay. If an API is present in fish orders of magnitude below HTC, sampling of fish-eating birds is unlikely to be necessary. However, several human pharmaceuticals accumulated in fish plasma within a recommended safety factor for HTC. It is now important to expand the scope of diet-based API exposure modeling to include alternative exposure pathways (e.g., uptake from landfills, dumps and wastewater treatment plants) and geographic locations (developing countries) where API contamination of the environment may represent greater risk.

Uptake of human pharmaceuticals in bull sharks (Carcharhinus leucas) inhabiting a wastewater-impacted river.

PubMed

Gelsleichter, James; Szabo, Nancy J

2013-07-01

The presence of human pharmaceuticals in sewage-impacted ecosystems is a growing concern that poses health risks to aquatic wildlife. Despite this, few studies have investigated the uptake of active pharmaceutical ingredients (APIs) in aquatic organisms. In this study, the uptake of 9 APIs from human drugs was examined and compared in neonate bull sharks (Carcharhinus leucas) residing in pristine (Myakka River) and wastewater-impacted (Caloosahatchee River) tributaries of Florida's Charlotte Harbor estuary. The synthetic estrogen used in human contraceptives (17α-ethynylestradiol) and 6 of the selective serotonin/norepinephrine reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine) used in human antidepressants were observed at detectable and, in some cases, quantifiable levels in plasma of Caloosahatchee River sharks. Comparatively, only venlafaxine was detected in the plasma of a single Myakka River shark at a level below the limit of quantitation. These results suggest that sharks residing in wastewater-impacted habitats accumulate APIs, a factor that may pose special risks to C. leucas since it is one of few shark species to regularly occupy freshwater systems. Further research is needed to determine if the low levels of API uptake observed in Caloosahatchee River bull sharks pose health risks to these animals. Copyright © 2013 Elsevier B.V. All rights reserved.

New forms of old drugs: improving without changing.

PubMed

Domingos, Sofia; André, Vânia; Quaresma, Sílvia; Martins, Inês C B; Minas da Piedade, M Fátima; Duarte, Maria Teresa

2015-06-01

In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given. This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. We want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physico-chemical properties, such as solubility, thermal stability, shelf life, dissolution rate and compressibility. API-ionic liquids (ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-organic frameworks (BioMOFs) will also be addressed. © 2015 Royal Pharmaceutical Society.

Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations.

PubMed

Visser, J Carolina; Woerdenbag, Herman J; Crediet, Stefan; Gerrits, Edwin; Lesschen, Marjan A; Hinrichs, Wouter L J; Breitkreutz, Jörg; Frijlink, Henderik W

2015-01-15

Orodispersible films (ODFs) are promising drug delivery systems for customized small scale pharmacy preparations. The aim of the present study was to develop a versatile casting solution suitable for the extemporaneous production of ODFs to which active pharmaceutical ingredients (APIs) can be added. Different combinations of film forming agents and other excipients and different casting heights were tested for their suitability for production of ODFs. The best suitable casting solution contained hypromellose, carbomer, glycerol, disodium EDTA and trometamol. This casting solution was used to prepare ODFs containing water-soluble APIs (enalapril maleate and prednisolone disodium phosphate) and a poorly water-soluble API (diazepam) for which ethanol 96% was used as co-solvent.The water-soluble APIs as well as ethanol influenced the viscosity of the casting solution, mechanical properties and disintegration time of the ODFs. All ODFs containing API met the requirements on uniformity of mass and uniformity of content set by the European Pharmacopoeia (2014) (Ph. Eur.) 8th edition. In conclusion, ODFs of good pharmaceutical quality can be prepared on small scale. Hereby opening the perspective of using ODFs for individualized pharmacotherapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Experimental study of tensile strength of pharmaceutical tablets: effect of the diluent nature and compression pressure

NASA Astrophysics Data System (ADS)

Juban, Audrey; Briançon, Stéphanie; Puel, François; Hoc, Thierry; Nouguier-Lehon, Cécile

2017-06-01

In the pharmaceutical field, tablets are the most common dosage form for oral administration in the world. Among different manufacturing processes, direct compression is widely used because of its economics interest and it is a process which avoids the steps of wet granulation and drying processes. Tablets are composed of at least two ingredients: an active pharmaceutical ingredient (API) which is mixed with a diluent. The nature of the powders and the processing conditions are crucial for the properties of the blend and, consequently, strongly influence the mechanical characteristics of tablets. Moreover, tablets have to present a suitable mechanical strength to avoid crumbling or breaking when handling, while ensuring an appropriate disintegration after administration. Accordingly, this mechanical property is an essential parameter to consider. Experimental results showed that proportion of the diluent, fragmentary (DCPA) or plastic (MCC), had a large influence on the tensile strength evolution with API content as well as the compression load applied during tableting process. From these results a model was developed in order to predict the tensile strength of binary tablets by knowing the compression pressure. The validity of this model was demonstrated for the two studied systems and a comparison was made with two existing models.

35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirsh, David A.; Rossini, Aaron J.; Emsley, Lyndon

In this paper, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. 35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and 1H– 35Cl broadband adiabatic inversion crossmore » polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline 35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced 1H– 13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.« less

35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients

DOE PAGES

Hirsh, David A.; Rossini, Aaron J.; Emsley, Lyndon; ...

2016-08-24

In this paper, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. 35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and 1H– 35Cl broadband adiabatic inversion crossmore » polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline 35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced 1H– 13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.« less

Determination of sorption of seventy-five pharmaceuticals in sewage sludge.

PubMed

Hörsing, Maritha; Ledin, Anna; Grabic, Roman; Fick, Jerker; Tysklind, Mats; la Cour Jansen, Jes; Andersen, Henrik R

2011-10-01

Sorption of 75 active pharmaceutical ingredients (APIs) to three different types of sludge (primary sludge, secondary sludge with short and long sludge age respectively) were investigated. To obtain the sorption isotherms batch studies with the APIs mixture were performed in four nominal concentrations to water containing 1 g of sludge. The range of APIs concentrations was between ng L(-1) to μg L(-1) which are found in the wastewater effluents. Isotherms were obtained for approximately 45 of the APIs, providing distribution coefficients for linear (Kd), Freundlich (Kf) and Langmuir (KL) isotherms. Kd, Kf and KL ranging between 7.1×10(4) and 3.8×10(7), 1.1×10(-2) and 6.1×10(4) and 9.2×10(-3) and 1.1 L kg(-1), respectively. The obtained coefficients were applied to estimate the fraction of APIs in the water phase (see Abstract Graphic). For 37 of the 75 APIs, the predicted presence in the liquid phase was estimated to >80%. 24 APIs were estimated to be present in the liquid phase between 20 and 80%, and 14 APIs were found to have <20% presence in the liquid phase, i.e. high affinity towards sludge. Furthermore, the effect of pH at values 6, 7 and 8 was evaluated using one way ANOVA-test. A significant difference in Kds due to pH changes were found for 6 of the APIs (variation 10-20%). Copyright © 2011 Elsevier Ltd. All rights reserved.

Development and validation of an LC-UV method for the quantification and purity determination of the novel anticancer agent C1311 and its pharmaceutical dosage form.

PubMed

den Brok, Monique W J; Nuijen, Bastiaan; Hillebrand, Michel J X; Grieshaber, Charles K; Harvey, Michael D; Beijnen, Jos H

2005-09-01

C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. The pharmaceutical development of C1311 necessitated the availability of an assay for the quantification and purity determination of C1311 active pharmaceutical ingredient (API) and its pharmaceutical dosage form. A reversed-phase liquid chromatographic method (RP-LC) with ultraviolet (UV) detection was developed, consisting of separation on a C18 column with phosphate buffer (60 mM; pH 3 with 1 M citric acid)-acetonitrile-triethylamine (83:17:0.05, v/v/v) as the mobile phase and UV-detection at 280 nm. The method was found to be linear over a concentration range of 2.50-100 microg/mL, precise and accurate. Accelerated stress testing showed degradation products, which were well separated from the parent compound, confirming its stability-indicating capacity. Moreover, the use of LC-MS and on-line photo diode array detection enabled us to propose structures for four degradation products. Two of these products were also found as impurities in the API and more abundantly in an impure lot of API.

Considering ionic state in modeling sorption of pharmaceuticals to sewage sludge.

PubMed

Rybacka, Aleksandra; Andersson, Patrik L

2016-12-01

Information on the partitioning of chemicals between particulate matter and water in sewage treatment plants (STPs) can be used to predict their subsequent environmental fate. However, this information can be challenging to acquire, especially for pharmaceuticals that are frequently present in ionized forms. This study investigated the relationship between the ionization state of active pharmaceutical ingredients (APIs) and their partitioning between water and sludge in STPs. We also investigated the underlying mechanisms of sludge sorption by using chemical descriptors based on ionized structures, and evaluated the usefulness of these descriptors in quantitative structure-property relationship (QSPR) modeling. K D values were collected for 110 APIs, which were classified as neutral, positive, or negative at pH 7. The models with the highest performance had the R 2 Y and Q 2 values of above 0.75 and 0.65, respectively. We found that the dominant intermolecular forces governing the interactions of neutral and positively charged APIs with sludge are hydrophobic, pi-pi, and dipole-dipole interactions, whereas the interactions of negatively charged APIs with sludge were mainly governed by covalent bonding as well as ion-ion, ion-dipole, and dipole-dipole interactions; hydrophobicity-driven interactions were rather unimportant. Including charge-related descriptors improved the models' performance by 5-10%, underlining the importance of electrostatic interactions. The use of descriptors calculated for ionized structures did not improve the model statistics for positive and negative APIs, but slightly increased model performance for neutral APIs. We attribute this to a better description of neutral zwitterions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmaceutical Raw Material Identification Using Miniature Near-Infrared (MicroNIR) Spectroscopy and Supervised Pattern Recognition Using Support Vector Machine

PubMed Central

Hsiung, Chang; Pederson, Christopher G.; Zou, Peng; Smith, Valton; von Gunten, Marc; O’Brien, Nada A.

2016-01-01

Near-infrared spectroscopy as a rapid and non-destructive analytical technique offers great advantages for pharmaceutical raw material identification (RMID) to fulfill the quality and safety requirements in pharmaceutical industry. In this study, we demonstrated the use of portable miniature near-infrared (MicroNIR) spectrometers for NIR-based pharmaceutical RMID and solved two challenges in this area, model transferability and large-scale classification, with the aid of support vector machine (SVM) modeling. We used a set of 19 pharmaceutical compounds including various active pharmaceutical ingredients (APIs) and excipients and six MicroNIR spectrometers to test model transferability. For the test of large-scale classification, we used another set of 253 pharmaceutical compounds comprised of both chemically and physically different APIs and excipients. We compared SVM with conventional chemometric modeling techniques, including soft independent modeling of class analogy, partial least squares discriminant analysis, linear discriminant analysis, and quadratic discriminant analysis. Support vector machine modeling using a linear kernel, especially when combined with a hierarchical scheme, exhibited excellent performance in both model transferability and large-scale classification. Hence, ultra-compact, portable and robust MicroNIR spectrometers coupled with SVM modeling can make on-site and in situ pharmaceutical RMID for large-volume applications highly achievable. PMID:27029624

Engineered particles demonstrate improved flow properties at elevated drug loadings for direct compression manufacturing.

PubMed

Trementozzi, Andrea N; Leung, Cheuk-Yui; Osei-Yeboah, Frederick; Irdam, Erwin; Lin, Yiqing; MacPhee, J Michael; Boulas, Pierre; Karki, Shyam B; Zawaneh, Peter N

2017-05-15

Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D 50 =24μm) and particle engineered wet milled API (D 50 =70μm and 90μm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ff c <4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ff c >10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized. Copyright © 2017 Elsevier B.V. All rights reserved.

Required ozone doses for removing pharmaceuticals from wastewater effluents.

PubMed

Antoniou, Maria G; Hey, Gerly; Rodríguez Vega, Sergio; Spiliotopoulou, Aikaterini; Fick, Jerker; Tysklind, Mats; la Cour Jansen, Jes; Andersen, Henrik Rasmus

2013-07-01

The aim of the this study was to investigate the ozone dosage required to remove active pharmaceutical ingredients (APIs) from biologically treated wastewater of varying quality, originated from different raw wastewater and wastewater treatment processes. Secondary effluents from six Swedish wastewater treatment plants (WWTP) were spiked with 42 APIs (nominal concentration μg/L) and treated with different O₃ doses (0.5-12.0 mg/L ozone) in bench-scale experiments. In order to compare the sensitivity of APIs in each matrix, the specific dose of ozone required to achieve reduction by one decade of each investigated API (DDO₃) was determined for each effluent by fitting a first order equation to the remaining concentration of API at each applied ozone dose. Ozone dose requirements were found to vary significantly between effluents depending on their matrix characteristics. The specific ozone dose was then normalized to the dissolved organic carbon (DOC) of each effluent. The DDO₃/DOC ratios were comparable for each API between the effluents. 15 of the 42 investigated APIs could be classified as easily degradable (DDO₃/DOC ≤ 0.7), while 19 were moderately degradable (0.7 < DDO₃/DOC ≤ 1.4), and 8 were recalcitrant towards O₃-treatment (DDO₃/DOC >1.4). Furthermore, we predict that a reasonable estimate of the ozone dose required to remove any of the investigated APIs may be attained by multiplying the experimental average DDO₃/DOC obtained with the actual DOC of any effluent. Copyright © 2013 Elsevier B.V. All rights reserved.

Prioritization of pharmaceuticals for potential environmental hazard through leveraging a large-scale mammalian pharmacological dataset.

PubMed

Berninger, Jason P; LaLone, Carlie A; Villeneuve, Daniel L; Ankley, Gerald T

2016-04-01

The potential for pharmaceuticals in the environment to cause adverse ecological effects is of increasing concern. Given the thousands of active pharmaceutical ingredients (APIs) that can enter the aquatic environment through human and/or animal (e.g., livestock) waste, a current challenge in aquatic toxicology is identifying those that pose the greatest risk. Because empirical toxicity information for aquatic species is generally lacking for pharmaceuticals, an important data source for prioritization is that generated during the mammalian drug development process. Applying concepts of species read-across, mammalian pharmacokinetic data were used to systematically prioritize APIs by estimating their potential to cause adverse biological consequences to aquatic organisms, using fish as an example. Mammalian absorption, distribution, metabolism, and excretion (ADME) data (e.g., peak plasma concentration, apparent volume of distribution, clearance rate, and half-life) were collected and curated, creating the Mammalian Pharmacokinetic Prioritization For Aquatic Species Targeting (MaPPFAST) database representing 1070 APIs. From these data, a probabilistic model and scoring system were developed and evaluated. Individual APIs and therapeutic classes were ranked based on clearly defined read-across assumptions for translating mammalian-derived ADME parameters to estimate potential hazard in fish (i.e., greatest predicted hazard associated with lowest mammalian peak plasma concentrations, total clearance and highest volume of distribution, half-life). It is anticipated that the MaPPFAST database and the associated API prioritization approach will help guide research and/or inform ecological risk assessment. Published 2015 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.

[PICS: pharmaceutical inspection cooperation scheme].

PubMed

Morénas, J

2009-01-01

The pharmaceutical inspection cooperation scheme (PICS) is a structure containing 34 participating authorities located worldwide (October 2008). It has been created in 1995 on the basis of the pharmaceutical inspection convention (PIC) settled by the European free trade association (EFTA) in1970. This scheme has different goals as to be an international recognised body in the field of good manufacturing practices (GMP), for training inspectors (by the way of an annual seminar and experts circles related notably to active pharmaceutical ingredients [API], quality risk management, computerized systems, useful for the writing of inspection's aide-memoires). PICS is also leading to high standards for GMP inspectorates (through regular crossed audits) and being a room for exchanges on technical matters between inspectors but also between inspectors and pharmaceutical industry.

Pharmaceutical cocrystals: a novel approach for oral bioavailability enhancement of drugs.

PubMed

Chadha, Renu; Saini, Anupam; Arora, Poonam; Bhandari, Swati

2012-01-01

Solid dosage forms are by far the preferred drug delivery systems. However, these often face the problem of poor and erratic bioavailability during the drug development process. Numerous formulation strategies for drug delivery are currently under development, among which the solid forms such as polymorphs, solvates, salts, and cocrystals have been considered to be the most important for improving dissolution rate and bioavailability. Cocrystallization is a fairly new approach in pharmaceutical industry that can improve the solubility and, consequently, the bioactivity of the active pharmaceutical ingredient (API) without compromising its structural integrity. Pharmaceutical cocrystals have found their place in drug delivery, primarily due to their ability to produce alternative, viable solid forms when a more standard approach of salt and polymorph formation fails to deliver the desired objectives. Over the past few years, a number of papers have been published focusing on a broad range of subjects, from traditional crystal engineering to structure-property relationships of cocrystals. The present review, however, illustrates how the cocrystalline forms of APIs have improved their in vitro dissolution rate and in vivo bioavailability, often correlating well with their improved solubility as well.

Influence of Coformer Stoichiometric Ratio on Pharmaceutical Cocrystal Dissolution: Three Cocrystals of Carbamazepine/4-Aminobenzoic Acid

PubMed Central

Li, Zi; Matzger, Adam J.

2016-01-01

Cocrystallization is a technique to optimize solid forms that shows great potential to improve the solubility of active pharmaceutical ingredients (APIs). In some systems, an API can form cocrystals in multiple stoichiometries with the same coformer. However, it remains unclear how coformer stoichiometry influences solubility. This paper investigates the pharmaceutical:coformer pair carbamazepine (CBZ)/p-aminobenzoic acid (PABA); both CBZ/PABA 1:1 and 2:1 cocrystals are known, and a novel 4:1 CBZ/PABA cocrystal is reported here. The 4:1 cocrystal is structurally characterized, and phase stability data suggest that it is a thermodynamically unstable form. Dissolution experiments show that there is no correlation between the cocrystal stoichiometry and dissolution rate in this system. On the other hand, with the relatively weak intermolecular interactions, metastable forms can be beneficial to dissolution rate, which suggests that more effort should be devoted to cocrystal production with kinetic growth methods. PMID:26837376

Risks associated with the environmental release of pharmaceuticals on the U.S. Food and Drug Administration "flush list".

PubMed

Khan, Usman; Bloom, Raanan A; Nicell, James A; Laurenson, James P

2017-12-31

A select few prescription drugs can be especially harmful and, in some cases, fatal with just one dose when not used as prescribed. Therefore, the U. S. Food and Drug Administration (FDA) recommends that expired, unwanted, or otherwise unused portions of most of these drugs be disposed of quickly through a take-back program. If such an option is not readily available, FDA recommends that they be flushed down the sink or toilet. The goal of the current investigation was to evaluate the ecological and human-health risks associated with the environmental release of the 15 active pharmaceutical ingredients (APIs) currently on the FDA "flush list". The evaluation suggests that even when highly conservative assumptions are used-including that the entire API mass supplied for clinical use is flushed, all relevant sources in addition to clinical use of the API are considered, and no metabolic loss, environmental degradation, or dilution of wastewater effluents are used in estimating environmental concentrations-most of these APIs present a negligible eco-toxicological risk, both as individual compounds and as a mixture. For a few of these APIs, additional eco-toxicological data will need to be developed. Using similar conservative assumptions for human-health risks, all 15 APIs present negligible risk through ingestion of water and fish. Published by Elsevier B.V.

Pharmaceutical dust exposure at pharmacies using automatic dispensing machines: a preliminary study.

PubMed

Fent, Kenneth W; Durgam, Srinivas; Mueller, Charles

2014-01-01

Automatic dispensing machines (ADMs) used in pharmacies concentrate and dispense large volumes of pharmaceuticals, including uncoated tablets that can shed dust. We evaluated 43 employees' exposures to pharmaceutical dust at three pharmacies where ADMs were used. We used an optical particle counter to identify tasks that generated pharmaceutical dust. We collected 72 inhalable dust air samples in or near the employees' breathing zones. In addition to gravimetric analysis, our contract laboratory used internal methods involving liquid chromatography to analyze these samples for active pharmaceutical ingredients (APIs) and/or lactose, an inactive filler in tablets. We had to choose samples for these additional analyses because many methods used different extraction solvents. We selected 57 samples for analysis of lactose. We used real-time particle monitoring results, observations, and information from employees on the dustiness of pharmaceuticals to select 28 samples (including 13 samples that were analyzed for lactose) for analysis of specific APIs. Pharmaceutical dust was generated during a variety of tasks like emptying and refilling of ADM canisters. Using compressed air to clean canisters and manual count machines produced the overall highest peak number concentrations (19,000-580,000 particles/L) of smallest particles (count median aerodynamic diameter ≤ 2 μm). Employees who refilled, cleaned, or repaired ADM canisters, or hand filled prescriptions were exposed to higher median air concentrations of lactose (5.0-12 μg/m(3)) than employees who did other jobs (0.04-1.3 μg/m(3)), such as administrative/office work, labeling/packaging, and verifying prescriptions. We detected 10 APIs in air, including lisinopril, a drug prescribed for high blood pressure, levothyroxine, a drug prescribed for hypothyroidism, and methotrexate, a hazardous drug prescribed for cancer and other disorders. Three air concentrations of lisinopril (1.8-2.7 μg/m(3)) exceeded the lower bound of the manufacturer's hazard control band (1-10 μg/m(3)). All other API air concentrations were below applicable occupational exposure limits. Our findings indicate that some pharmacy employees are exposed to multiple APIs and that measures are needed to control those exposures.

Pharmaceutical cocrystals as an opportunity to modify drug properties: From the idea to application. A review.

PubMed

Sokal, Agnieszka; Pindelska, Edyta

2017-12-26

The properties of many drugs which have been available on the pharmaceutical market for a long time still need to be improved. Cocrystals are the solid state drug modification which can improve such properties as low solubility, stability and mechanical properties (e.g. compressibility). In this paper examples how to use cocrystals to modify properties of API (Active Pharmaceutical Ingredient) will be reported. Additionally, in this review the way from an idea of the new cocrystal to drug dosage form registration will be shortly described. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Transparency throughout the production chain--a way to reduce pollution from the manufacturing of pharmaceuticals?

PubMed

Joakim Larsson, D G; Fick, Jerker

2009-04-01

Recent findings have shown that wastewater from bulk drug production can be a source of very high environmental concentrations of drugs in certain locations. The release of active ingredients is often not specifically regulated, and thus rapid initiatives from the industries themselves are warranted. Possible ways to stimulate action include changes in local and international regulations, including the implementation of appropriate environmental standards within existing industry guidelines as well as demands from prescribers and consumers of medicines. The lack of readily available information regarding the origin of drugs and the environmental impact of the production, however, prevents consumers from making informed decisions. Here, we investigated the origin of active pharmaceutical ingredients (APIs) in 242 selected products on the Swedish market. By comparing registers from Sweden and India we found that the APIs in 71 products (31%) originated from Indian manufacturers sending their waste to a treatment plant where unprecedented amount of environmental pollution with broad-spectrum antibiotics and other drugs recently has been documented. We propose that increased transparency throughout the production chain would be one of several important steps to reducing pollution from the manufacturing of drugs.

The binding of orally dosed hydrophobic active pharmaceutical ingredients to casein micelles in milk.

PubMed

Cheema, M; Hristov, A N; Harte, F M

2017-11-01

Casein proteins (α S1 -, α S2 -, β- and κ-casein) account for 80% of the total protein content in bovine milk and form casein micelles (average diameter = 130 nm, approximately 10 15 micelles/mL). The affinity of native casein micelles with the 3 hydrophobic active pharmaceutical ingredients (API), meloxicam [351.4 g/mol; log P = 3.43; acid dissociation constant (pK a ) = 4.08], flunixin (296.2 g/mol; log P = 4.1; pK a = 5.82), and thiabendazole (201.2 g/mol; log P = 2.92; pK a = 4.64), was evaluated in bovine milk collected from dosed Holstein cows. Native casein micelles were separated from raw bovine milk by mild techniques such as ultracentrifugation, diafiltration, isoelectric point precipitation (pH 4.6), and size exclusion chromatography. Acetonitrile extraction of hydrophobic API was then done, followed by quantification using HPLC-UV. For the API or metabolites meloxicam, 5-hyroxy flunixin and 5-hydroxy thiabendazole, 31 ± 3.90, 31 ± 1.3, and 28 ± 0.5% of the content in milk was associated with casein micelles, respectively. Less than ∼5.0% of the recovered hydrophobic API were found in the milk fat fraction, and the remaining ∼65% were associated with the whey/serum fraction. A separate in vitro study showed that 66 ± 6.4% of meloxicam, 29 ± 0.58% of flunixin, 34 ± 0.21% of the metabolite 5-hyroxy flunixin, 50 ± 4.5% of thiabendazole, and 33 ± 3.8% of metabolite 5-hydroxy thiabendazole was found partitioned into casein micelles. Our study supports the hypothesis that casein micelles are native carriers for hydrophobic compounds in bovine milk. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Analysis of low active-pharmaceutical-ingredient signal drugs based on thin layer chromatography and surface-enhanced Raman spectroscopy.

PubMed

Li, Xiao; Chen, Hui; Zhu, Qingxia; Liu, Yan; Lu, Feng

2016-11-30

Active pharmaceutical ingredients (API) embedded in the excipients of the formula can usually be unravelled by normal Raman spectroscopy (NRS). However, more and more drugs with low API content and/or low Raman scattering coefficient were insensitive to NRS analysis, which was for the first time defined as Low API-Signal Drugs (LASIDs) in this paper. The NRS spectra of these LASIDs were similar to their dominant excipients' profiles, such as lactose, starch, microcrystalline cellulose (MCC), etc., and were classified into three types as such. 21 out of 100 kinds of drugs were screened as LASIDs and characterized further by Raman microscopic mapping. Accordingly, we proposed a tailored solution to the qualitation and quantitation problem of these LASIDs, using surface-enhanced Raman spectroscopic (SERS) detection on the thin layer chromatographic (TLC) plate both in situ and after-separation. Experimental conditions and parameters including TLC support matrix, SERS substrate, detection mode, similarity threshold, internal standard, etc., were optimized. All LASIDs were satisfactorily identified and the quantitation results agreed well with those of high performance liquid chromatography (HPLC). For some structural analogues of LASIDs, although they presented highly similar SERS spectra and were tough to distinguish even with Raman microscopic mapping, they could be successfully discriminated from each other by coupling SERS (with portable Raman spectrometer) with TLC. These results demonstrated that the proposed solution could be employed to detect the LASIDs with high accuracy and cost-effectiveness. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of 13C NMR cross-polarization inversion recovery experiments for the analysis of solid dosage forms.

PubMed

Pisklak, Dariusz Maciej; Zielińska-Pisklak, Monika; Szeleszczuk, Łukasz

2016-11-20

Solid-state nuclear magnetic resonance (ssNMR) is a powerful and unique method for analyzing solid forms of the active pharmaceutical ingredients (APIs) directly in their original formulations. Unfortunately, despite their wide range of application, the ssNMR experiments often suffer from low sensitivity and peaks overlapping between API and excipients. To overcome these limitations, the crosspolarization inversion recovery method was successfully used. The differences in the spin-lattice relaxation time constants for hydrogen atoms T1(H) between API and excipients were employed in order to separate and discriminate their peaks in ssNMR spectra as well as to increase the intensity of API signals in low-dose formulations. The versatility of this method was demonstrated by different examples, including the excipients mixture and commercial solid dosage forms (e.g. granules and tablets). Copyright © 2016 Elsevier B.V. All rights reserved.

In-line ATR-UV and Raman Spectroscopy for Monitoring API Dissolution Process During Liquid-Filled Soft-Gelatin Capsule Manufacturing.

PubMed

Wan, Boyong; Zordan, Christopher A; Lu, Xujin; McGeorge, Gary

2016-10-01

Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturing of liquid-filled soft-gelatin capsules (SGC). Attenuated total reflectance UV spectroscopy (ATR-UV) and Raman spectroscopy have been investigated for in-line monitoring of API dissolution during manufacturing of an SGC product. Calibration models have been developed with both techniques for in-line determination of API potency. Performance of both techniques was evaluated and compared. The ATR-UV methodology was found to be able to monitor the dissolution process and determine the endpoint, but was sensitive to temperature variations. The Raman technique was also capable of effectively monitoring the process and was more robust to the temperature variation and process perturbations by using an excipient peak for internal correction. Different data preprocessing methodologies were explored in an attempt to improve method performance.

78 FR 3900 - Generic Drug User Fee-Active Pharmaceutical Ingredient and Finished Dosage Form Facility Fee...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-17

... facility fee, we divide the $132,945,000 by the total number of facilities (758) which gives us a domestic... domestic API facility fee, we divide the $23,415,000 by the total number of facilities (885) which gives us..., Attention: Government Lockbox 979108, 1005 Convention Plaza, St. Louis, MO 63101. (Note: This U.S. Bank...

Analytical challenges in drug counterfeiting and falsification-The NMR approach.

PubMed

Holzgrabe, Ulrike; Malet-Martino, Myriam

2011-06-25

Counterfeiting of products is a global problem. As long as clothes, clocks, leather wear, etc. are faked there is no danger, but when it comes to drugs, counterfeiting can be life-threatening. In the last years sub-standard active pharmaceutical ingredients (APIs) were found more often even though the use of the quality-ensuring methods of international pharmacopoeias should have detected additional impurities and the low content of the API. Methods orthogonal to the separating methods used in the pharmacopoeias are necessary to find counterfeits. Beside Raman and NIR spectroscopies as well as powder X-ray analysis, NMR spectroscopy being a primary ratio method of measurement is highly suitable to identify and quantify a drug and its related substances as well as to recognize a drug of sub-standard quality. DOSY experiments are suitable to identify the ingredients of formulations and therefore to identify wrong and/or additional ingredients. This review gives an overview of the application of quantitative NMR spectroscopy and DOSY NMR in anticounterfeiting. Copyright © 2010 Elsevier B.V. All rights reserved.

Bitterness prediction in-silico: A step towards better drugs.

PubMed

Bahia, Malkeet Singh; Nissim, Ido; Niv, Masha Y

2018-02-05

Bitter taste is innately aversive and thought to protect against consuming poisons. Bitter taste receptors (Tas2Rs) are G-protein coupled receptors, expressed both orally and extra-orally and proposed as novel targets for several indications, including asthma. Many clinical drugs elicit bitter taste, suggesting the possibility of drugs re-purposing. On the other hand, the bitter taste of medicine presents a major compliance problem for pediatric drugs. Thus, efficient tools for predicting, measuring and masking bitterness of active pharmaceutical ingredients (APIs) are required by the pharmaceutical industry. Here we highlight the BitterDB database of bitter compounds and survey the main computational approaches to prediction of bitter taste based on compound's chemical structure. Current in silico bitterness prediction methods provide encouraging results, can be constantly improved using growing experimental data, and present a reliable and efficient addition to the APIs development toolbox. Copyright © 2017 Elsevier B.V. All rights reserved.

A Review of Disintegration Mechanisms and Measurement Techniques.

PubMed

Markl, Daniel; Zeitler, J Axel

2017-05-01

Pharmaceutical solid dosage forms (tablets or capsules) are the predominant form to administer active pharmaceutical ingredients (APIs) to the patient. Tablets are typically powder compacts consisting of several different excipients in addition to the API. Excipients are added to a formulation in order to achieve the desired fill weight of a dosage form, to improve the processability or to affect the drug release behaviour in the body. These complex porous systems undergo different mechanisms when they come in contact with physiological fluids. The performance of a drug is primarily influenced by the disintegration and dissolution behaviour of the powder compact. The disintegration process is specifically critical for immediate-release dosage forms. Its mechanisms and the factors impacting disintegration are discussed and methods used to study the disintegration in-situ are presented. This review further summarises mathematical models used to simulate disintegration phenomena and to predict drug release kinetics.

Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veinberg, Stanislav L.; Johnston, Karen E.; Jaroszewicz, Michael J.

14N ultra-wideline (UW), 1H{ 15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. Here, a case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationarymore » samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR'R"NH + and RR'NH 2 +) or other (i.e., RNH 2 and RNO 2) nitrogen environments.« less

Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

DOE PAGES

Veinberg, Stanislav L.; Johnston, Karen E.; Jaroszewicz, Michael J.; ...

2016-06-08

14N ultra-wideline (UW), 1H{ 15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. Here, a case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationarymore » samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR'R"NH + and RR'NH 2 +) or other (i.e., RNH 2 and RNO 2) nitrogen environments.« less

Trends in active pharmaceutical ingredient salt selection based on analysis of the Orange Book database.

PubMed

Paulekuhn, G Steffen; Dressman, Jennifer B; Saal, Christoph

2007-12-27

The Orange Book database published by the U.S. Drug and Food Administration (FDA) was analyzed for the frequency of occurrence of different counterions used for the formation of pharmaceutical salts. The data obtained from the present analysis of the Orange Book are compared to reviews of the Cambridge Structural Database (CSD) and of the Martindale "The Extra Pharmacopoeia". As well as showing overall distributions of counterion usage, results are broken down into 5-year increments to identify trends in counterion selection. Chloride ions continue to be the most frequently utilized anionic counterions for the formation of salts as active pharmaceutical ingredients (APIs), while sodium ions are most widely utilized for the formation of salts starting from acidic molecules. A strong trend toward a wider variety of counterions over the past decade is observed. This trend can be explained by a stronger need to improve physical chemical properties of research and development compounds.

Preparation and physicochemical characterization of matrix pellets containing APIs with different solubility via extrusion process.

PubMed

Hegyesi, Diána; Thommes, Markus; Kleinebudde, Peter; Sovány, Tamás; Kása, Péter; Kelemen, András; Pintye-Hódi, Klára; Regdon, Géza

2017-03-01

In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.

Characterization of nanoscale spatial distribution of small molecules in amorphous polymer matrices

NASA Astrophysics Data System (ADS)

Ricarte, Ralm; Hillmyer, Marc; Lodge, Timothy

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) can significantly enhance the efficacy of active pharmaceutical ingredients (APIs). Yet, the interactions between species in HPMCAS-API blends are not understood. Elucidating these interactions is difficult because the spatial distributions of HPMCAS and API in the blends are ambiguous; the polymer and drug may be molecularly mixed or the species may form phase separated domains. As these phase separated domains may be less than 100 nm in size, traditional characterization techniques may not accurately evaluate the spatial distribution. To address this challenge, we explore the use of electron energy-loss spectroscopy (EELS) for detecting the model API phenytoin in an HPMCAS-phenytoin blend. Using EELS, we directly measured with high accuracy and precision the phenytoin concentrations in several blends. We present evidence that suggests phase separation occurs in blends that have a phenytoin loading of approximately 50 wt percent. Finally, we demonstrate that this technique achieves a sub-100 nm spatial resolution and can detect several other APIs.

Quantitative Component Analysis of Solid Mixtures by Analyzing Time Domain 1H and 19F T1 Saturation Recovery Curves (qSRC).

PubMed

Stueber, Dirk; Jehle, Stefan

2017-07-01

Prevalent polymorphism and complicated phase behavior of active pharmaceutical ingredients (APIs) often result in remarkable differences in the respective biochemical and physical API properties. Consequently, API form characterization and quantification play a central role in the pharmaceutical industry from early drug development to manufacturing. Here we present a novel and proficient quantification protocol for solid mixtures (qSRC) based on the measurement and mathematical fitting of T 1 nuclear magnetic resonance (NMR) saturation recovery curves collected on a bench top time-domain NMR instrument. The saturation recovery curves of the relevant pure components are used as fingerprints. Employing a bench top NMR instrument possesses clear benefits. These instruments exhibit a small footprint, do not present any special requirements on lab space, and required sample handling is simple and fast. The qSRC analysis can easily be conducted in a conventional laboratory setting as well as in an industrial production environment, making it a versatile tool with the potential for widespread application. The accuracy and efficiency of the qSRC method is illustrated using 1 H and 19 F T 1 data of selected pharmaceutical model compounds, as well as utilizing 1 H T 1 data of an actual binary API anhydrous polymorph system of a Merck & Co., Inc. compound formerly developed as a hepatitis C virus drug. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Infrared imaging spectroscopy and chemometric tools for in situ analysis of an imiquimod pharmaceutical preparation presented as cream

NASA Astrophysics Data System (ADS)

Carneiro, Renato Lajarim; Poppi, Ronei Jesus

2014-01-01

In the present work the homogeneity of a pharmaceutical formulation presented as a cream was studied using infrared imaging spectroscopy and chemometric methodologies such as principal component analysis (PCA) and multivariate curve resolution with alternating least squares (MCR-ALS). A cream formulation, presented as an emulsion, was prepared using imiquimod as the active pharmaceutical ingredient (API) and the excipients: water, vaseline, an emulsifier and a carboxylic acid in order to dissolve the API. After exposure at 45 °C during 3 months to perform accelerated stability test, the presence of some crystals was observed, indicating homogeneity problems in the formulation. PCA exploratory analysis showed that the crystal composition was different from the composition of the emulsion, since the score maps presented crystal structures in the emulsion. MCR-ALS estimated the spectra of the crystals and the emulsion. The crystals presented amine and C-H bands, suggesting that the precipitate was a salt formed by carboxylic acid and imiquimod. These results indicate the potential of infrared imaging spectroscopy in conjunction with chemometric methodologies as an analytical tool to ensure the quality of cream formulations in the pharmaceutical industry.

Three pharmaceuticals cocrystals of adefovir: Syntheses, structures and dissolution study

NASA Astrophysics Data System (ADS)

Zhang, Xiaoming; Sun, Fuxing; Zhang, Tingting; Jia, Jiangtao; Su, Hongmin; Wang, Chenhui; Zhu, Guangshan

2015-11-01

We report here three novel cocrystals, which are composed of adefovir as the API (Active Pharmaceutical Ingredient) with p-aminobenzoic acid (1, 2C8H12N5O4P·C7H6NO2·3H2O), 3,5-dihydroxybenzoic acid (2, C8H12N5O4P·C7H6O4·H2O) and 2,6-pyridinedicarboxlic acid (3, C8H12N5O4P·C7H5NO4) as CCFs (cocrystal formers) respectively by crystal engineering strategy. Their structures were characterized by single crystal X-ray diffraction, powder X-ray diffraction (PXRD) analysis, thermogravimetric analyses (TGA), elemental analysis (EA) and infrared spectral analysis (IR). The analysis of single crystal X-ray diffraction demonstrate that cocrystal 1 and 2 form a strong hydrogen-bonded assembly through the phosphoric acids of API with water in the lattice and carboxylic acids of CCF respectively. Cocrystal 3 is formed in which the phosphoric acid groups of API are also held by the carboxylic acid groups of CCF. The PXRD results indicate their high purity of as-synthesized samples. The TGA, EA, IR and dissolution study of API and the cocrystals were also measured and discussed.

Polyoxylglycerides and glycerides: effects of manufacturing parameters on API stability, excipient functionality and processing.

PubMed

Jannin, Vincent; Rodier, Jean-David; Musakhanian, Jasmine

2014-05-15

Lipid-based formulations are a viable option to address modern drug delivery challenges such as increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol (glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more commonly used in pharmaceutical drug products but there is still a lack of understanding of how the manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within the drug product. In that regard, this review summarizes the key parameters to look at when formulating with lipid-based excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality. The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the extraction and refinement processes. Then, the key parameters during the manufacturing process influencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are discussed in relation with their intended functionality and ability to interact with APIs and others excipients within the formulation. Copyright © 2014. Published by Elsevier B.V.

Cleaning verification: Exploring the effect of the cleanliness of stainless steel surface on sample recovery.

PubMed

Haidar Ahmad, Imad A; Tam, James; Li, Xue; Duffield, William; Tarara, Thomas; Blasko, Andrei

2017-02-05

The parameters affecting the recovery of pharmaceutical residues from the surface of stainless steel coupons for quantitative cleaning verification method development have been studied, including active pharmaceutical ingredient (API) level, spiking procedure, API/excipient ratio, analyst-to-analyst variability, inter-day variability, and cleaning procedure of the coupons. The lack of a well-defined procedure that consistently cleaned coupon surface was identified as the major contributor to low and variable recoveries. Assessment of acid, base, and oxidant washes, as well as the order of treatment, showed that a base-water-acid-water-oxidizer-water wash procedure resulted in consistent, accurate spiked recovery (>90%) and reproducible results (S rel ≤4%). By applying this cleaning procedure to the previously used coupons that failed the cleaning acceptance criteria, multiple analysts were able to obtain consistent recoveries from day-to-day for different APIs, and API/excipient ratios at various spike levels. We successfully applied our approach for cleaning verification of small molecules (MW<1000Da) as well as large biomolecules (MW up to 50,000Da). Method robustness was greatly influenced by the sample preparation procedure, especially for analyses using total organic carbon (TOC) determination. Copyright © 2016 Elsevier B.V. All rights reserved.

Thermodynamic phase behavior of API/polymer solid dispersions.

PubMed

Prudic, Anke; Ji, Yuanhui; Sadowski, Gabriele

2014-07-07

To improve the bioavailability of poorly soluble active pharmaceutical ingredients (APIs), these materials are often integrated into a polymer matrix that acts as a carrier. The resulting mixture is called a solid dispersion. In this work, the phase behaviors of solid dispersions were investigated as a function of the API as well as of the type and molecular weight of the carrier polymer. Specifically, the solubility of artemisinin and indomethacin was measured in different poly(ethylene glycol)s (PEG 400, PEG 6000, and PEG 35000). The measured solubility data and the solubility of sulfonamides in poly(vinylpyrrolidone) (PVP) K10 and PEG 35000 were modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The results show that PC-SAFT predictions are in a good accordance with the experimental data, and PC-SAFT can be used to predict the whole phase diagram of an API/polymer solid dispersion as a function of the kind of API and polymer and of the polymer's molecular weight. This remarkably simplifies the screening process for suitable API/polymer combinations.

Recent trends in the impurity profile of pharmaceuticals

PubMed Central

Pilaniya, Kavita; Chandrawanshi, Harish K.; Pilaniya, Urmila; Manchandani, Pooja; Jain, Pratishtha; Singh, Nitin

2010-01-01

Various regulatory authorities such as the International Conference on Harmonization (ICH), the United States Food and Drug administration (FDA), and the Canadian Drug and Health Agency (CDHA) are emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical Ingredients (APIs). The various sources of impurity in pharmaceutical products are — reagents, heavy metals, ligands, catalysts, other materials like filter aids, charcoal, and the like, degraded end products obtained during \\ after manufacturing of bulk drugs from hydrolysis, photolytic cleavage, oxidative degradation, decarboxylation, enantiomeric impurity, and so on. The different pharmacopoeias such as the British Pharmacopoeia, United State Pharmacopoeia, and Indian Pharmacopoeia are slowly incorporating limits to allowable levels of impurities present in APIs or formulations. Various methods are used to isolate and characterize impurities in pharmaceuticals, such as, capillary electrophoresis, electron paramagnetic resonance, gas–liquid chromatography, gravimetric analysis, high performance liquid chromatography, solid-phase extraction methods, liquid–liquid extraction method, Ultraviolet Spectrometry, infrared spectroscopy, supercritical fluid extraction column chromatography, mass spectrometry, Nuclear magnetic resonance (NMR) spectroscopy, and RAMAN spectroscopy. Among all hyphenated techniques, the most exploited techniques for impurity profiling of drugs are Liquid Chromatography (LC)-Mass Spectroscopy (MS), LC-NMR, LC-NMR-MS, GC-MS, and LC-MS. This reveals the need and scope of impurity profiling of drugs in pharmaceutical research. PMID:22247862

Development and in-line validation of a Process Analytical Technology to facilitate the scale up of coating processes.

PubMed

Wirges, M; Funke, A; Serno, P; Knop, K; Kleinebudde, P

2013-05-05

Incorporation of an active pharmaceutical ingredient (API) into the coating layer of film-coated tablets is a method mainly used to formulate fixed-dose combinations. Uniform and precise spray-coating of an API represents a substantial challenge, which could be overcome by applying Raman spectroscopy as process analytical tool. In pharmaceutical industry, Raman spectroscopy is still mainly used as a bench top laboratory analytical method and usually not implemented in the production process. Concerning the application in the production process, a lot of scientific approaches stop at the level of feasibility studies and do not manage the step to production scale and process applications. The present work puts the scale up of an active coating process into focus, which is a step of highest importance during the pharmaceutical development. Active coating experiments were performed at lab and production scale. Using partial least squares (PLS), a multivariate model was constructed by correlating in-line measured Raman spectral data with the coated amount of API. By transferring this model, being implemented for a lab scale process, to a production scale process, the robustness of this analytical method and thus its applicability as a Process Analytical Technology (PAT) tool for the correct endpoint determination in pharmaceutical manufacturing could be shown. Finally, this method was validated according to the European Medicine Agency (EMA) guideline with respect to the special requirements of the applied in-line model development strategy. Copyright © 2013 Elsevier B.V. All rights reserved.

Raman spectroscopy and capillary zone electrophoresis for the analysis of degradation processes in commercial effervescent tablets containing acetylsalicylic acid and ascorbic acid.

PubMed

Neuberger, Sabine; Jooß, Kevin; Flottmann, Dirk; Scriba, Gerhard; Neusüß, Christian

2017-02-05

In order to ensure the stability of pharmaceutical products appropriate manufacturing and storage conditions are required. In general, the degradation of active pharmaceutical ingredients (APIs) and subsequent formation of degradation products affect the pharmaceutical quality. Thus, a fast and effective detection and characterization of these substances is mandatory. Here, the applicability of Raman spectroscopy and CZE for the characterization of the degradation of effervescent tablets containing acetylsalicylic acid (ASA) and ascorbic acid (AA) was evaluated. Therefore, a degradation study was performed analyzing tablets from two different manufacturers at varying conditions (relative humidity (RH) 33%, 52% and 75% at 30°C). Raman spectroscopy combined with principal component analysis could be successfully applied for the fast and easy discrimination of non-degraded and degraded effervescent tablets after a storage period of approximately 24h (RH 52%). Nevertheless, a clear identification or quantification of APIs and degradation products within the analyzed tablets was not possible, i.a. due to missing reference materials. CZE-UV enabled the quantification of the APIs (ASA, AA) and related degradation products (salicylic acid (SA); semi-quantitative also mono- and diacetylated AA) within the complex tablet mixtures. The higher the RH, the faster the degradation of ASA and AA as well as the formation of the degradation products. Mono- and diacetylated AA are major primary degradation products of AA for the applied effervescent tablets. A significant degradation of the APIs was detected earlier by CZE (6-12h, RH 52%) than by Raman spectroscopy. Summarized, Raman spectroscopy is well-suited as quick test to detect degradation of these tablets and CZE can be utilized for further detailed characterization and quantification of specific APIs and related degradation products. Copyright © 2016 Elsevier B.V. All rights reserved.

MEDICATION DISPOSAL AS A SOURCE FOR DRUGS AS ...

EPA Pesticide Factsheets

The major routes by which pharmaceuticals enter the environment are excretion, bathing, anddisposal of leftover, unwanted medications. Pharmaceuticals designed for humans and animalsoften remain unused. Leftover, accumulated drugs represent potentially environmentallyunsound disposal and suboptimal delivery of health care. They also can pose acute exposurerisks for humans and wildlife. Active pharmaceutical ingredients (APIs) directly enter theenvironment primarily via sewage. Among the three routes of entry, the relative contributions ofeach are poorly understood. In contrast to excretion, which as a source comprises continual lowlevelcontributions from multitudes of people, drug disposal comprises acute but transient andepisodic contributions from fewer people. The only route that is subject most easily to pollutionprevention or source control measures is disposal.A major unknown with respect to drugs as pollutants is what fractions of drug residues occurringin the ambient environment result from discarding leftover drugs. No studies exist that provideobjective data from well-defined populations to support any type of conclusion. Given theimportance of environmental stewardship to sustainability, a means for assessing the relativecontributions of APIs resulting from disposal would be useful in justifying the resources thatmight be devoted to controlling this source - - for example, by way of consumer

Raman Barcode for Counterfeit Drug Product Detection.

PubMed

Lawson, Latevi S; Rodriguez, Jason D

2016-05-03

Potential infiltration of counterfeit drug products-containing the wrong or no active pharmaceutical ingredient (API)-into the bona fide drug supply poses a significant threat to consumers worldwide. Raman spectroscopy offers a rapid, nondestructive avenue to screen a high throughput of samples. Traditional qualitative Raman identification is typically done with spectral correlation methods that compare the spectrum of a reference sample to an unknown. This is often effective for pure materials but is quite challenging when dealing with drug products that contain different formulations of active and inactive ingredients. Typically, reliable identification of drug products using common spectral correlation algorithms can only be made if the specific product under study is present in the library of reference spectra, thereby limiting the scope of products that can be screened. In this paper, we introduce the concept of the Raman barcode for identification of drug products by comparing the known peaks in the API reference spectrum to the peaks present in the finished drug product under study. This method requires the transformation of the Raman spectra of both API and finished drug products into a barcode representation by assigning zero intensity to every spectral frequency except the frequencies that correspond to Raman peaks. By comparing the percentage of nonzero overlap between the expected API barcode and finished drug product barcode, the identity of API present can be confirmed. In this study, 18 approved finished drug products and nine simulated counterfeits were successfully identified with 100% accuracy utilizing this method.

Understanding API-polymer proximities in amorphous stabilized composite drug products using fluorine-carbon 2D HETCOR solid-state NMR.

PubMed

Abraham, Anuji; Crull, George

2014-10-06

A simple and robust method for obtaining fluorine-carbon proximities was established using a (19)F-(13)C heteronuclear correlation (HETCOR) two-dimensional (2D) solid-state nuclear magnetic resonance (ssNMR) experiment under magic-angle spinning (MAS). The method was applied to study a crystalline active pharmaceutical ingredient (API), avagacestat, containing two types of fluorine atoms and its API-polymer composite drug product. These results provide insight into the molecular structure, aid with assigning the carbon resonances, and probe API-polymer proximities in amorphous spray dried dispersions (SDD). This method has an advantage over the commonly used (1)H-(13)C HETCOR because of the large chemical shift dispersion in the fluorine dimension. In the present study, fluorine-carbon distances up to 8 Å were probed, giving insight into the API structure, crystal packing, and assignments. Most importantly, the study demonstrates a method for probing an intimate molecular level contact between an amorphous API and a polymer in an SDD, giving insights into molecular association and understanding of the role of the polymer in API stability (such as recrystallization, degradation, etc.) in such novel composite drug products.

Physicochemical characterisation and investigation of the bonding mechanisms of API-titanate nanotube composites as new drug carrier systems.

PubMed

Sipos, Barbara; Pintye-Hódi, Klára; Kónya, Zoltán; Kelemen, András; Regdon, Géza; Sovány, Tamás

2017-02-25

Titanate nanotube (TNT) has recently been explored as a new carrier material for active pharmaceutical ingredients (API). The aim of the present work was to reveal the physicochemical properties of API-TNT composites, focusing on the interactions between the TNTs and the incorporated APIs. Drugs belonging to different Biopharmaceutical Classification System (BCS) classes were loaded into TNTs: diltiazem hydrochloride (BCS I.), diclofenac sodium (BCS II.), atenolol (BCS III.) and hydrochlorothiazide (BCS IV.). Experimental results demonstrated that it is feasible for spiral cross-sectioned titanate nanotubes to carry drugs and maintain their bioactivity. The structural properties of the composites were characterized by a range of analytical techniques, including FT-IR, DSC, TG-MS, etc. The interactions between APIs and TNTs were identified as electrostatic attractions, mainly dominated by hydrogen bonds. Based on the results, it can be stated that the strength of the association depends on the hydrogen donor strength of the API. The drug release of incorporated APIs was evaluated from compressed tablets and compared to that of pure APIs. Differences noticed in the dissolution profiles due to incorporation showed a correlation with the strength of interactions between the APIs and the TNTs observed in the above analytical studies. Copyright © 2016 Elsevier B.V. All rights reserved.

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds.

PubMed

Bana, Péter; Örkényi, Róbert; Lövei, Klára; Lakó, Ágnes; Túrós, György István; Éles, János; Faigl, Ferenc; Greiner, István

2017-12-01

Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules. Copyright © 2016 Elsevier Ltd. All rights reserved.

Using a mass balance to determine the potency loss during the production of a pharmaceutical blend.

PubMed

Mackaplow, Michael B

2010-09-01

The manufacture of a blend containing the active pharmaceutical ingredient (API) and inert excipients is a precursor for the production of most pharmaceutical capsules and tablets. However, if there is a net water gain or preferential loss of API during production, the potency of the final drug product may be less than the target value. We use a mass balance to predict the mean potency loss during the production of a blend via wet granulation and fluidized bed drying. The result is an explicit analytical equation for the change in blend potency a function of net water gain, solids losses (both regular and high-potency), and the fraction of excipients added extragranularly. This model predicts that each 1% gain in moisture content (as determined by a loss on drying test) will decrease the API concentration of the final blend at least 1% LC. The effect of pre-blend solid losses increases with their degree of superpotency. This work supports Quality by Design by providing a rational method to set the process design space to minimize blend potency losses. When an overage is necessary, the model can help justify it by providing a quantitative, first-principles understanding of the sources of potency loss. The analysis is applicable to other manufacturing processes where the primary sources of potency loss are net water gain and/or mass losses.

The influence of uncertainty and location-specific conditions on the environmental prioritisation of human pharmaceuticals in Europe.

PubMed

Oldenkamp, Rik; Huijbregts, Mark A J; Ragas, Ad M J

2016-05-01

The selection of priority APIs (Active Pharmaceutical Ingredients) can benefit from a spatially explicit approach, since an API might exceed the threshold of environmental concern in one location, while staying below that same threshold in another. However, such a spatially explicit approach is relatively data intensive and subject to parameter uncertainty due to limited data. This raises the question to what extent a spatially explicit approach for the environmental prioritisation of APIs remains worthwhile when accounting for uncertainty in parameter settings. We show here that the inclusion of spatially explicit information enables a more efficient environmental prioritisation of APIs in Europe, compared with a non-spatial EU-wide approach, also under uncertain conditions. In a case study with nine antibiotics, uncertainty distributions of the PAF (Potentially Affected Fraction) of aquatic species were calculated in 100∗100km(2) environmental grid cells throughout Europe, and used for the selection of priority APIs. Two APIs have median PAF values that exceed a threshold PAF of 1% in at least one environmental grid cell in Europe, i.e., oxytetracycline and erythromycin. At a tenfold lower threshold PAF (i.e., 0.1%), two additional APIs would be selected, i.e., cefuroxime and ciprofloxacin. However, in 94% of the environmental grid cells in Europe, no APIs exceed either of the thresholds. This illustrates the advantage of following a location-specific approach in the prioritisation of APIs. This added value remains when accounting for uncertainty in parameter settings, i.e., if the 95th percentile of the PAF instead of its median value is compared with the threshold. In 96% of the environmental grid cells, the location-specific approach still enables a reduction of the selection of priority APIs of at least 50%, compared with a EU-wide prioritisation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

PubMed Central

Hutchinson, Thomas H.; Madden, Judith C.; Naidoo, Vinny; Walker, Colin H.

2014-01-01

Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment. PMID:25405970

Particle Engineering of Excipients for Direct Compression: Understanding the Role of Material Properties.

PubMed

Mangal, Sharad; Meiser, Felix; Morton, David; Larson, Ian

2015-01-01

Tablets represent the preferred and most commonly dispensed pharmaceutical dosage form for administering active pharmaceutical ingredients (APIs). Minimizing the cost of goods and improving manufacturing output efficiency has motivated companies to use direct compression as a preferred method of tablet manufacturing. Excipients dictate the success of direct compression, notably by optimizing powder formulation compactability and flow, thus there has been a surge in creating excipients specifically designed to meet these needs for direct compression. Greater scientific understanding of tablet manufacturing coupled with effective application of the principles of material science and particle engineering has resulted in a number of improved direct compression excipients. Despite this, significant practical disadvantages of direct compression remain relative to granulation, and this is partly due to the limitations of direct compression excipients. For instance, in formulating high-dose APIs, a much higher level of excipient is required relative to wet or dry granulation and so tablets are much bigger. Creating excipients to enable direct compression of high-dose APIs requires the knowledge of the relationship between fundamental material properties and excipient functionalities. In this paper, we review the current understanding of the relationship between fundamental material properties and excipient functionality for direct compression.

Hot-stage microscopy for determination of API fragmentation: comparison with other methods.

PubMed

Šimek, Michal; Grünwaldová, Veronika; Kratochvíl, Bohumil

2016-08-01

Although the fragmentation of the active pharmaceutical ingredient (API) is a phenomenon that is mentioned in many literature sources, no well-suited analytical tools for its investigation are currently known. We used the hot-stage microscopy method, already presented in our previous work, and studied the real fragmentation of the tadalafil particles in model tablets which were prepared under different compaction pressures. The morphology, spectral imaging and evaluation of plastic and elastic energies were also analyzed to support the hot-stage method. The prepared blend of tadalafil and excipients was compacted under a several forces from 5 to 35 kN to reveal the trend of fragmentation. The exact fragmentation of tadalafil with increased compaction pressure was revealed by the hot-stage microscopic method and it was in good agreement with plastic and elastic energies. Conversely, spectral imaging, which is being used for this analysis, was considered to be inaccurate methodology as mainly agglomerates, not individual particles, were measured. The availability of the hot-stage microscopic method equips pharmaceutical scientists with an in vitro assessment technique that will more reliably determine the fragmentation of the API in finished tablets and the behavior of the particles when compacted.

Limited Influence of Excipients in Extemporaneous Compounded Suspensions

PubMed Central

Dijkers, Eli; Nanhekhan, Valerie; Thorissen, Astrid; Marro, Diego; Uriel, Marta

2017-01-01

Objective: The objective of this study was to identify whether compounding oral suspensions with SyrSpend SF based on tablets or capsules is a suitable alternative for using raw pharmaceutical materials. Methods: Suspensions based on 5 different tablets and capsules were studied in SyrSpend SF. The summary of product characteristics of these different tablets and capsules were obtained from the manufacturer. Our hypothesis was that, if the maximum beyond-use date of the study was reached, the excipient did not seem to have an influence on the stability of the active pharmaceutical ingredient (API) within the studied time frame. Results: All excipients used in flecainide acetate, labetalol HCl, and tiagabine HCl tablets as well as in celecoxib and oseltamivir capsules did not seem to influence the beyond-use date of the overall suspension based on SyrSpend SF. Conclusion: Although using raw materials as API sources is preferred, oral suspensions with SyrSpend SF prepared from crushed tablets or opened capsules could be a possible alternative. Based on this study, a wide range of different excipients does not seem to impact the beyond-use date of different APIs compounded in SyrSpend SF. PMID:29276267

Limited Influence of Excipients in Extemporaneous Compounded Suspensions.

PubMed

Dijkers, Eli; Nanhekhan, Valerie; Thorissen, Astrid; Marro, Diego; Uriel, Marta

2017-06-01

Objective: The objective of this study was to identify whether compounding oral suspensions with SyrSpend SF based on tablets or capsules is a suitable alternative for using raw pharmaceutical materials. Methods: Suspensions based on 5 different tablets and capsules were studied in SyrSpend SF. The summary of product characteristics of these different tablets and capsules were obtained from the manufacturer. Our hypothesis was that, if the maximum beyond-use date of the study was reached, the excipient did not seem to have an influence on the stability of the active pharmaceutical ingredient (API) within the studied time frame. Results: All excipients used in flecainide acetate, labetalol HCl, and tiagabine HCl tablets as well as in celecoxib and oseltamivir capsules did not seem to influence the beyond-use date of the overall suspension based on SyrSpend SF. Conclusion: Although using raw materials as API sources is preferred, oral suspensions with SyrSpend SF prepared from crushed tablets or opened capsules could be a possible alternative. Based on this study, a wide range of different excipients does not seem to impact the beyond-use date of different APIs compounded in SyrSpend SF.

Impurity profiling of liothyronine sodium by means of reversed phase HPLC, high resolution mass spectrometry, on-line H/D exchange and UV/Vis absorption.

PubMed

Ruggenthaler, M; Grass, J; Schuh, W; Huber, C G; Reischl, R J

2017-09-05

For the first time, a comprehensive investigation of the impurity profile of the synthetic thyroid API (active pharmaceutical ingredient) liothyronine sodium (LT 3 Na) was performed by using reversed phase HPLC and advanced structural elucidation techniques including high resolution tandem mass spectrometry (HRMS/MS) and on-line hydrogen-deuterium (H/D) exchange. Overall, 39 compounds were characterized and 25 of these related substances were previously unknown to literature. The impurity classification system recently developed for the closely related API levothyroxine sodium (LT 4 Na) could be applied to the newly characterized liothyronine sodium impurities resulting in a wholistic thyroid API impurity classification system. Furthermore, the mass-spectrometric CID-fragmentation of specific related substances was discussed and rationalized by detailed fragmentation pathways. Moreover, the UV/Vis absorption characteristics of the API and selected impurities were investigated to corroborate chemical structure assignments derived from MS data. Copyright © 2017 Elsevier B.V. All rights reserved.

"Dark" Singlet Oxygen and Electron Paramagnetic Resonance Spin Trapping as Convenient Tools to Assess Photolytic Drug Degradation.

PubMed

Persich, Peter; Hostyn, Steven; Joie, Céline; Winderickx, Guy; Pikkemaat, Jeroen; Romijn, Edwin P; Maes, Bert U W

2017-05-01

Forced degradation studies are an important tool for a systematic assessment of decomposition pathways and identification of reactive sites in active pharmaceutical ingredients (APIs). Two methodologies have been combined in order to provide a deeper understanding of singlet oxygen-related degradation pathways of APIs under light irradiation. First, we report that a "dark" singlet oxygen test enables the investigation of drug reactivity toward singlet oxygen independently of photolytic irradiation processes. Second, the photosensitizing properties of the API producing the singlet oxygen was proven and quantified by spin trapping and electron paramagnetic resonance analysis. A combination of these techniques is an interesting addition to the forced degradation portfolio as it can be used for (1) revealing unexpected degradation pathways of APIs due to singlet oxygen, (2) clarifying photolytic drug-drug interactions in fixed-dose combinations, and (3) synthesizing larger quantities of hardly accessible oxidative drug degradants. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Use of Spray-Dried Dispersions in Early Pharmaceutical Development: Theoretical and Practical Challenges.

PubMed

Li, Jinjiang; Patel, Dhaval; Wang, George

2017-03-01

Spray-dried dispersions (SDDs) have become an important formulation technology for the pharmaceutical product development of poorly water-soluble (PWS) compounds. Although this technology is now widely used in the industry, especially in the early-phase development, the lack of mechanistic understanding still causes difficulty in selecting excipients and predicting stability of SDD-based drug products. In this review, the authors aim to discuss several principles of polymer science pertaining to the development of SDDs, in terms of selecting polymers and solvents, optimizing drug loading, as well as assessing physical stability on storage and supersaturation maintenance after dissolution, from both thermodynamic and kinetic considerations. In order to choose compatible solvents with both polymers and active pharmaceutical ingredients (APIs), a symmetric Flory-Huggins interaction (Δχ ∼0) approach was introduced. Regarding spray drying of polymer-API solutions, low critical solution temperature (LCST) was discussed for setting the inlet temperature for drying. In addition, after being exposed to moisture, SDDs are practically converted to ternary systems with asymmetric Flory-Huggins interactions, which are thermodynamically not favored. In this case, the kinetics of phase separation plays a significant role during the storage and dissolution of SDD-based drug products. The impact of polymers on the supersaturation maintenance of APIs in dissolution media was also discussed. Moreover, the nature of SDDs, with reference to solid solution and the notion of solid solubility, was examined in the context of pharmaceutical application. Finally, the importance of robust analytical techniques to characterize the SDD-based drug products was emphasized, considering their complexity.

Radiation Impact on Pharmaceutical Stability: Retrospective Data Review

NASA Technical Reports Server (NTRS)

Daniels, V. R.; Bayuse, T. M.; McGuire, K. M.; Antonsen, E. L.; Putcha, L.

2017-01-01

Historical studies performed by the JSC Pharmacotherapeutics Discipline suggest that exposure to spaceflight conditions may compromise the safety and efficacy of some medications. Follow-on studies have revealed that affected medications demonstrate reductions in active pharmaceutical ingredient (API) concentrations and altered release characteristics. It was hypothesized that the changes in API potency and release were from the medication's exposure to the harsh environmental conditions of spaceflight. Subsequent review of the spaceflight environmental control records from the time of these studies indicated that temperature and humidity levels aboard all spacecraft remained within United States Pharmacopeia (USP) recommended ranges to maintain optimal pharmaceutical stability. Therefore, space radiation was presumed to be the source of observed drug degradation. The Pharmacotherapeutics Discipline conducted a ground analog radiation experiment in 2006 at the NASA Space Radiation Laboratory (NSRL) at Brookhaven to validate this theory and to characterize the effects of high-energy radioactive particles on pharmaceutical stability. These data were never published. Recently, the Exploration Medical Capability (ExMC) Element finalized a research plan (RP) aimed at providing a safe and effective medication formulary for exploration spaceflight. As ExMC begins to design new flight and ground analog radiation studies, further analysis of the 2006 NSRL study data is essential for the characterization of the impact of radiation on medication potency and efficacy in the exploration spaceflight environment.

Semi-quantitative prediction of a multiple API solid dosage form with a combination of vibrational spectroscopy methods.

PubMed

Hertrampf, A; Sousa, R M; Menezes, J C; Herdling, T

2016-05-30

Quality control (QC) in the pharmaceutical industry is a key activity in ensuring medicines have the required quality, safety and efficacy for their intended use. QC departments at pharmaceutical companies are responsible for all release testing of final products but also all incoming raw materials. Near-infrared spectroscopy (NIRS) and Raman spectroscopy are important techniques for fast and accurate identification and qualification of pharmaceutical samples. Tablets containing two different active pharmaceutical ingredients (API) [bisoprolol, hydrochlorothiazide] in different commercially available dosages were analysed using Raman- and NIR Spectroscopy. The goal was to define multivariate models based on each vibrational spectroscopy to discriminate between different dosages (identity) and predict their dosage (semi-quantitative). Furthermore the combination of spectroscopic techniques was investigated. Therefore, two different multiblock techniques based on PLS have been applied: multiblock PLS (MB-PLS) and sequential-orthogonalised PLS (SO-PLS). NIRS showed better results compared to Raman spectroscopy for both identification and quantitation. The multiblock techniques investigated showed that each spectroscopy contains information not present or captured with the other spectroscopic technique, thus demonstrating that there is a potential benefit in their combined use for both identification and quantitation purposes. Copyright © 2016 Elsevier B.V. All rights reserved.

Single column comprehensive analysis of pharmaceutical preparations using dual-injection mixed-mode (ion-exchange and reversed-phase) and hydrophilic interaction liquid chromatography.

PubMed

Kazarian, Artaches A; Taylor, Mark R; Haddad, Paul R; Nesterenko, Pavel N; Paull, Brett

2013-12-01

The comprehensive separation and detection of hydrophobic and hydrophilic active pharmaceutical ingredients (APIs), their counter-ions (organic, inorganic) and excipients, using a single mixed-mode chromatographic column, and a dual injection approach is presented. Using a mixed-mode Thermo Fisher Acclaim Trinity P1 column, APIs, their counter-ions and possible degradants were first separated using a combination of anion-exchange, cation-exchange and hydrophobic interactions, using a mobile phase consisting of a dual organic modifier/salt concentration gradient. A complementary method was also developed using the same column for the separation of hydrophilic bulk excipients, using hydrophilic interaction liquid chromatography (HILIC) under high organic solvent mobile phase conditions. These two methods were then combined within a single gradient run using dual sample injection, with the first injection at the start of the applied gradient (mixed-mode retention of solutes), followed by a second sample injection at the end of the gradient (HILIC retention of solutes). Detection using both ultraviolet absorbance and refractive index enabled the sensitive detection of APIs and UV-absorbing counter-ions, together with quantitative determination of bulk excipients. The developed approach was applied successfully to the analysis of a dry powder inhalers (Flixotide(®), Spiriva(®)), enabling comprehensive quantification of all APIs and excipients in the sample. Copyright © 2013 Elsevier B.V. All rights reserved.

Analytical protocol for the sensitive determination of mannitol, sorbitol and glucose containing powders in pharmaceutical workplaces by ion chromatography using a pulsed amperometric detector.

PubMed

Butler, Owen; Forder, James; Saunders, John

2015-03-15

Workers in the pharmaceutical industry can potentially be exposed to airborne dusts and powders that can contain potent active pharmaceutical ingredients (API). Occupational hygienists and health and safety professionals need to assess and ultimately minimise such inhalation and dermal exposure risks. Containment of dusts at source is the first line of defence but the performance of such technologies needs to be verified, for which purpose the good practice guide: assessing the particulate containment performance of pharmaceutical equipment, produced by the International Society for Pharmaceutical Engineering (ISPE), is a widely used reference document. This guide recommends the use of surrogate powders that can be used to challenge the performance of such containment systems. Materials such as lactose and mannitol are recommended as their physical properties (adhesion, compactability, dustiness, flow characteristics and particle sizes) mimic those of API-containing materials typically handled. Furthermore they are safe materials to use, are available in high purity and can be procured at a reasonable cost. The aim of this work was to develop and validate a sensitive ion-chromatography based analytical procedure for the determination of surrogate powders collected on filter samples so as to meet analytical requirements set out in this ISPE guide. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

¹³C solid-state NMR analysis of the most common pharmaceutical excipients used in solid drug formulations, Part I: Chemical shifts assignment.

PubMed

Pisklak, Dariusz Maciej; Zielińska-Pisklak, Monika Agnieszka; Szeleszczuk, Łukasz; Wawer, Iwona

2016-04-15

Solid-state NMR is an excellent and useful method for analyzing solid-state forms of drugs. In the (13)C CP/MAS NMR spectra of the solid dosage forms many of the signals originate from the excipients and should be distinguished from those of active pharmaceutical ingredient (API). In this work the most common pharmaceutical excipients used in the solid drug formulations: anhydrous α-lactose, α-lactose monohydrate, mannitol, sucrose, sorbitol, sodium starch glycolate type A and B, starch of different origin, microcrystalline cellulose, hypromellose, ethylcellulose, methylcellulose, hydroxyethylcellulose, sodium alginate, magnesium stearate, sodium laurilsulfate and Kollidon(®) were analyzed. Their (13)C CP/MAS NMR spectra were recorded and the signals were assigned, employing the results (R(2): 0.948-0.998) of GIPAW calculations and theoretical chemical shifts. The (13)C ssNMR spectra for some of the studied excipients have not been published before while for the other signals in the spectra they were not properly assigned or the assignments were not correct. The results summarize and complement the data on the (13)C ssNMR analysis of the most common pharmaceutical excipients and are essential for further NMR studies of API-excipient interactions in the pharmaceutical formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Microstructure of Pharmaceutical Semicrystalline Dispersions: The Significance of Polymer Conformation.

PubMed

Van Duong, Tu; Goderis, Bart; Van Humbeeck, Jan; Van den Mooter, Guy

2018-02-05

The microstructure of pharmaceutical semicrystalline solid dispersions has attracted extensive attention due to its complexity that might result in the diversity in physical stability, dissolution behavior, and pharmaceutical performance of the systems. Numerous factors have been reported that dictate the microstructure of semicrystalline dispersions. Nevertheless, the importance of the complicated conformation of the polymer has never been elucidated. In this study, we investigate the microstructure of dispersions of polyethylene glycol and active pharmaceutical ingredients by small-angle X-ray scattering and high performance differential scanning calorimetry. Polyethylene glycol with molecular weight of 2000 g/mol (PEG2000) and 6000 g/mol (PEG6000) exhibited remarkable discrepancy in the lamellar periodicity in dispersions with APIs which was attributed to the differences in their folding behavior. The long period of PEG2000 always decreased upon aging-induced exclusion of APIs from the interlamellar region of extended chain crystals whereas the periodicity of PEG6000 may decrease or increase during storage as a consequence of the competition between the drug segregation and the lamellar thickening from nonintegral-folded into integral-folded chain crystals. These processes were in turn significantly influenced by the crystallization tendency of the pharmaceutical compounds, drug-polymer interactions, as well as the dispersion composition and crystallization temperature. This study highlights the significance of the polymer conformation on the microstructure of semicrystalline systems that is critical for the preparation of solid dispersions with consistent and reproducible quality.

Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient.

PubMed

Grigori, Katerina; Loukas, Yannis L; Malenović, Anđelija; Samara, Vicky; Kalaskani, Anastasia; Dimovasili, Efi; Kalovidouri, Magda; Dotsikas, Yannis

2017-10-25

A sensitive Liquid Chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30mg/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. ‎ After the selection of the important factors affecting analytes' elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factor s between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5v/v. All impurities and internal standard omeprazole were eluted before 7.5min and at 8.0min the eluents were directed to waste. The protocol was transferred to LC-MS/MS and validated according to ICH guidelines. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimising the manufacture, formulation, and dose of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement.

PubMed

Crawford, Keith W; Ripin, David H Brown; Levin, Andrew D; Campbell, Jennifer R; Flexner, Charles

2012-07-01

It is expected that funding limitations for worldwide HIV treatment and prevention in resource-limited settings will continue, and, because the need for treatment scale-up is urgent, the emphasis on value for money has become an increasing priority. The Conference on Antiretroviral Drug Optimization--a collaborative project between the Clinton Health Access Initiative, the Johns Hopkins University School of Medicine, and the Bill & Melinda Gates Foundation--brought together process chemists, clinical pharmacologists, pharmaceutical scientists, physicians, pharmacists, and regulatory specialists to explore strategies for the reduction of antiretroviral drug costs. The antiretroviral drugs discussed were prioritised for consideration on the basis of their market impact, and the objectives of the conference were framed as discussion questions generated to guide scientific assessment of potential strategies. These strategies included modifications to the synthesis of the active pharmaceutical ingredient (API) and use of cheaper sources of raw materials in synthesis of these ingredients. Innovations in product formulation could improve bioavailability thus needing less API. For several antiretroviral drugs, studies show efficacy is maintained at doses below the approved dose (eg, efavirenz, lopinavir plus ritonavir, atazanavir, and darunavir). Optimising pharmacoenhancement and extending shelf life are additional strategies. The conference highlighted a range of interventions; optimum cost savings could be achieved through combining approaches. Copyright © 2012 Elsevier Ltd. All rights reserved.

Developing a model for agile supply: an empirical study from Iranian pharmaceutical supply chain.

PubMed

Rajabzadeh Ghatari, Ali; Mehralian, Gholamhossein; Zarenezhad, Forouzandeh; Rasekh, Hamid Reza

2013-01-01

Agility is the fundamental characteristic of a supply chain needed for survival in turbulent markets, where environmental forces create additional uncertainty resulting in higher risk in the supply chain management. In addition, agility helps providing the right product, at the right time to the consumer. The main goal of this research is therefore to promote supplier selection in pharmaceutical industry according to the formative basic factors. Moreover, this paper can configure its supply network to achieve the agile supply chain. The present article analyzes the supply part of supply chain based on SCOR model, used to assess agile supply chains by highlighting their specific characteristics and applicability in providing the active pharmaceutical ingredient (API). This methodology provides an analytical modeling; the model enables potential suppliers to be assessed against the multiple criteria using both quantitative and qualitative measures. In addition, for making priority of critical factors, TOPSIS algorithm has been used as a common technique of MADM model. Finally, several factors such as delivery speed, planning and reorder segmentation, trust development and material quantity adjustment are identified and prioritized as critical factors for being agile in supply of API.

Control of three different continuous pharmaceutical manufacturing processes: Use of soft sensors.

PubMed

Rehrl, Jakob; Karttunen, Anssi-Pekka; Nicolaï, Niels; Hörmann, Theresa; Horn, Martin; Korhonen, Ossi; Nopens, Ingmar; De Beer, Thomas; Khinast, Johannes G

2018-05-30

One major advantage of continuous pharmaceutical manufacturing over traditional batch manufacturing is the possibility of enhanced in-process control, reducing out-of-specification and waste material by appropriate discharge strategies. The decision on material discharge can be based on the measurement of active pharmaceutical ingredient (API) concentration at specific locations in the production line via process analytic technology (PAT), e.g. near-infrared (NIR) spectrometers. The implementation of the PAT instruments is associated with monetary investment and the long term operation requires techniques avoiding sensor drifts. Therefore, our paper proposes a soft sensor approach for predicting the API concentration from the feeder data. In addition, this information can be used to detect sensor drift, or serve as a replacement/supplement of specific PAT equipment. The paper presents the experimental determination of the residence time distribution of selected unit operations in three different continuous processing lines (hot melt extrusion, direct compaction, wet granulation). The mathematical models describing the soft sensor are developed and parameterized. Finally, the suggested soft sensor approach is validated on the three mentioned, different continuous processing lines, demonstrating its versatility. Copyright © 2018 Elsevier B.V. All rights reserved.

Developing a Model for Agile Supply: an Empirical Study from Iranian Pharmaceutical Supply Chain

PubMed Central

Rajabzadeh Ghatari, Ali; Mehralian, Gholamhossein; Zarenezhad, Forouzandeh; Rasekh, Hamid Reza

2013-01-01

Agility is the fundamental characteristic of a supply chain needed for survival in turbulent markets, where environmental forces create additional uncertainty resulting in higher risk in the supply chain management. In addition, agility helps providing the right product, at the right time to the consumer. The main goal of this research is therefore to promote supplier selection in pharmaceutical industry according to the formative basic factors. Moreover, this paper can configure its supply network to achieve the agile supply chain. The present article analyzes the supply part of supply chain based on SCOR model, used to assess agile supply chains by highlighting their specific characteristics and applicability in providing the active pharmaceutical ingredient (API). This methodology provides an analytical modeling; the model enables potential suppliers to be assessed against the multiple criteria using both quantitative and qualitative measures. In addition, for making priority of critical factors, TOPSIS algorithm has been used as a common technique of MADM model. Finally, several factors such as delivery speed, planning and reorder segmentation, trust development and material quantity adjustment are identified and prioritized as critical factors for being agile in supply of API. PMID:24250689

Solution Coating of Pharmaceutical Nanothin Films and Multilayer Nanocomposites with Controlled Morphology and Polymorphism.

PubMed

Horstman, Elizabeth M; Kafle, Prapti; Zhang, Fengjiao; Zhang, Yifu; Kenis, Paul J A; Diao, Ying

2018-03-28

Nanosizing is rapidly emerging as an alternative approach to enhance solubility and thus the bioavailability of poorly aqueous soluble active pharmaceutical ingredients (APIs). Although numerous techniques have been developed to perform nanosizing of API crystals, precise control and modulation of their size in an energy and material efficient manner remains challenging. In this study, we present meniscus-guided solution coating as a new technique to produce pharmaceutical thin films of nanoscale thickness with controlled morphology. We demonstrate control of aspirin film thickness over more than 2 orders of magnitude, from 30 nm to 1.5 μm. By varying simple process parameters such as the coating speed and the solution concentration, the aspirin film morphology can also be modulated by accessing different coating regimes, namely the evaporation regime and the Landau-Levich regime. Using ellipticine-a poorly water-soluble anticancer drug-as another model compound, we discovered a new polymorph kinetically trapped during solution coating. Furthermore, the polymorphic outcome can be controlled by varying coating conditions. We further performed layer-by-layer coating of multilayer nanocomposites, with alternating thin films of ellipticine and a biocompatible polymer, which demonstrate the potential of additive manufacturing of multidrug-personalized dosage forms using this approach.

Dry coating of micronized API powders for improved dissolution of directly compacted tablets with high drug loading.

PubMed

Han, Xi; Ghoroi, Chinmay; Davé, Rajesh

2013-02-14

Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t(80) for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmaceutical Wastewater Effluent—Source of Contaminants of Emerging Concern: Phytotoxicity of Metronidazole to Soybean (Glycine max)

PubMed Central

Yakubu, Okhumode H.

2017-01-01

Industrial discharge of active pharmaceutical ingredients (APIs) into the environment in some middle- and low-income countries is not sufficiently regulated. The phytotoxicity of metronidazole (FLAGYL)—one of the most commonly used over the counter (OTC) antibiotics, to soybean (Glycine max) is investigated. Relative growth rate (RGR) expressed in gram per gram per day (gg−1d−1) was applied to plants destructively harvested at maturity (42 d), to determine the toxicological impact. Differences between mean RGR of the three groups were performed at 0.05 significance level. Multiple comparisons suggest that there was a statistical significant difference among mean RGR for all treatment groups. Metronidazole is toxic to soybean plants (Glycine max) based on dose-response criterion. There is a need to enforce treatment of pharmaceutical wastewater effluent by Pharmaceutical Manufacturing Companies (PMCs) before discharge into the environment. PMID:29051442

Matrix precipitation: a general strategy to eliminate matrix interference for pharmaceutical toxic impurities analysis.

PubMed

Yang, Xiaojing; Xiong, Xuewu; Cao, Ji; Luan, Baolei; Liu, Yongjun; Liu, Guozhu; Zhang, Lei

2015-01-30

Matrix interference, which can lead to false positive/negative results, contamination of injector or separation column, incompatibility between sample solution and the selected analytical instrument, and response inhibition or even quenching, is commonly suffered for the analysis of trace level toxic impurities in drug substance. In this study, a simple matrix precipitation strategy is proposed to eliminate or minimize the above stated matrix interference problems. Generally, a sample of active pharmaceutical ingredients (APIs) is dissolved in an appropriate solvent to achieve the desired high concentration and then an anti-solvent is added to precipitate the matrix substance. As a result, the target analyte is extracted into the mixed solution with very less residual of APIs. This strategy has the characteristics of simple manipulation, high recovery and excellent anti-interference capability. It was found that the precipitation ratio (R, representing the ability to remove matrix substance) and the proportion of solvent (the one used to dissolve APIs) in final solution (P, affecting R and also affecting the method sensitivity) are two important factors of the precipitation process. The correlation between R and P was investigated by performing precipitation with various APIs in different solvent/anti-solvent systems. After a detailed mathematical reasoning process, P=20% was proved to be an effective and robust condition to perform the precipitation strategy. The precipitation method with P=20% can be used as a general strategy for toxic impurity analysis in APIs. Finally, several typical examples are described in this article, where the challenging matrix interference issues have been resolved successfully. Copyright © 2014 Elsevier B.V. All rights reserved.

New drug candidates for liposomal delivery identified by computer modeling of liposomes' remote loading and leakage.

PubMed

Cern, Ahuva; Marcus, David; Tropsha, Alexander; Barenholz, Yechezkel; Goldblum, Amiram

2017-04-28

Remote drug loading into nano-liposomes is in most cases the best method for achieving high concentrations of active pharmaceutical ingredients (API) per nano-liposome that enable therapeutically viable API-loaded nano-liposomes, referred to as nano-drugs. This approach also enables controlled drug release. Recently, we constructed computational models to identify APIs that can achieve the desired high concentrations in nano-liposomes by remote loading. While those previous models included a broad spectrum of experimental conditions and dealt only with loading, here we reduced the scope to the molecular characteristics alone. We model and predict API suitability for nano-liposomal delivery by fixing the main experimental conditions: liposome lipid composition and size to be similar to those of Doxil® liposomes. On that basis, we add a prediction of drug leakage from the nano-liposomes during storage. The latter is critical for having pharmaceutically viable nano-drugs. The "load and leak" models were used to screen two large molecular databases in search of candidate APIs for delivery by nano-liposomes. The distribution of positive instances in both loading and leakage models was similar in the two databases screened. The screening process identified 667 molecules that were positives by both loading and leakage models (i.e., both high-loading and stable). Among them, 318 molecules received a high score in both properties and of these, 67 are FDA-approved drugs. This group of molecules, having diverse pharmacological activities, may be the basis for future liposomal drug development. Copyright © 2017 Elsevier B.V. All rights reserved.

Thermal stability of synthetic thyroid hormone l-thyroxine and l-thyroxine sodium salt hydrate both pure and in pharmaceutical formulations.

PubMed

Ledeţi, Ionuţ; Ledeţi, Adriana; Vlase, Gabriela; Vlase, Titus; Matusz, Petru; Bercean, Vasile; Şuta, Lenuţa-Maria; Piciu, Doina

2016-06-05

In this paper, the thermal stability of pure l-thyroxine (THY) and l-thyroxine sodium salt hydrate (THYSS) vs. two pharmaceutical solid formulations commercialized on both Romanian and European market (with a content of 100μg, respectively 200μg THYSS per tablet) were investigated. In order to determine whether the presence of excipients affects the thermal stability of the active pharmaceutical ingredient (API), the preliminary study of thermal stability in air atmosphere was completed with an in-depth solid-state kinetic study. By kinetic analysis, the non-isothermal degradation of the selected active pharmaceutical ingredients vs. the solid formulation with strength of 200μg THYSS per tablet was investigated. Isoconversional methods (Kissinger-Akahira-Sunose, Flynn-Wall-Ozawa and Friedman) were employed for the estimation of activation energies values, at five different heating rates, β=5, 7, 10, 12 and 15°Cmin(-1). Also, a fourth method was applied in the processing of data, namely NPK, allowing an objective separation in the physical and chemical processes that contribute to the thermal degradation of the selected compounds. A discussion of thermal stability from the kinetic point of view is also presented. Copyright © 2016 Elsevier B.V. All rights reserved.

Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions.

PubMed

Hall, Zoe; Allan, Elizabeth Louise; van Schalkwyk, Donelly Andrew; van Wyk, Albert; Kaur, Harparkash

2016-05-04

Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. "Forced degradation" in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. "Natural aging" of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0-7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. © The American Society of Tropical Medicine and Hygiene.

Synthesis, characterization and dissolution of three pharmaceutical cocrystals based on deferiprone

NASA Astrophysics Data System (ADS)

Zhang, Xiaoming; Tian, Yuyang; Jia, Jiangtao; Zhang, Tingting; Zhu, Guangshan

2016-03-01

In this paper we present three new cocrystals based on deferiprone which is the first oral medicine as iron chelator. Solitary deferiprone possesses some known problems due to its good solubility and frequent dosing side effects. For these three novel co crystals, deferiprone is the active pharmaceutical ingredient (API), p-hydroxybenzoic acid (1, C7H9NO2·C7H6O3), 2, 5-dihydroxybenzoic acid (2, C7H9NO2·C7H6O4) and maleic acid (3, C7H9NO2·C4H4O4) are used as cocrystal formers (CCFs), respectively. Their structures were characterized by single crystal X-ray diffraction, powder X-ray diffraction (PXRD) analysis, thermogravimetric analyses (TGA), differential thermal analysis (DTA), elemental analysis (EA) and infrared spectral analysis (IR). Single crystal X-ray diffraction demonstrates that all three cocrystals (1-3) possess strong hydrogen-bondings assembled through hydroxyl of API and carboxylic acids of CCFs. The PXRD results indicate their high purity of as-synthesized samples. TGA, DTA, EA, IR and dissolution study of API and cocrystals were also measured and discussed, respectively. The results suggest that the cocrystals exhibit low dissolution rates comparing with solitary deferiprone, which is very advantageous for the oral medicine with frequent dosing side effects.

Simultaneous confocal fluorescence microscopy and optical coherence tomography for drug distribution and tissue integrity assessment

NASA Astrophysics Data System (ADS)

Rinehart, Matthew T.; LaCroix, Jeffrey; Henderson, Marcus; Katz, David; Wax, Adam

2011-03-01

The effectiveness of microbicidal gels, topical products developed to prevent infection by sexually transmitted diseases including HIV/AIDS, is governed by extent of gel coverage, pharmacokinetics of active pharmaceutical ingredients (APIs), and integrity of vaginal epithelium. While biopsies provide localized information about drug delivery and tissue structure, in vivo measurements are preferable in providing objective data on API and gel coating distribution as well as tissue integrity. We are developing a system combining confocal fluorescence microscopy with optical coherence tomography (OCT) to simultaneously measure local concentrations and diffusion coefficients of APIs during transport from microbicidal gels into tissue, while assessing tissue integrity. The confocal module acquires 2-D images of fluorescent APIs multiple times per second allowing analysis of lateral diffusion kinetics. The custom Fourier domain OCT module has a maximum a-scan rate of 54 kHz and provides depth-resolved tissue integrity information coregistered with the confocal fluorescence measurements. The combined system is validated by imaging phantoms with a surrogate fluorophore. Time-resolved API concentration measured at fixed depths is analyzed for diffusion kinetics. This multimodal system will eventually be implemented in vivo for objective evaluation of microbicide product performance.

Early process development of API applied to poorly water-soluble TBID.

PubMed

Meise, Marius; Niggemann, Matthias; Dunens, Alexandra; Schoenitz, Martin; Kuschnerow, Jan C; Kunick, Conrad; Scholl, Stephan

2018-05-01

Finding and optimising of synthesis processes for active pharmaceutical ingredients (API) is time consuming. In the finding phase, established methods for synthesis, purification and formulation are used to achieve a high purity API for biological studies. For promising API candidates, this is followed by pre-clinical and clinical studies requiring sufficient quantities of the active component. Ideally, these should be produced with a process representative for a later production process and suitable for scaling to production capacity. This work presents an overview of different approaches for process synthesis based on an existing lab protocol. This is demonstrated for the production of the model drug 4,5,6,7-tetrabromo-2-(1H-imidazol-2-yl) isoindolin-1,3-dione (TBID). Early batch synthesis and purification procedures typically suffer from low and fluctuating yields and purities due to poor process control. In a first step the literature synthesis and purification procedure was modified and optimized using solubility measurements, targeting easier and safer processing for consecutive studies. Copyright © 2018 Elsevier B.V. All rights reserved.

Identifying and assessing highly hazardous drugs within quality risk management programs.

PubMed

Sussman, Robert G; Schatz, Anthony R; Kimmel, Tracy A; Ader, Allan; Naumann, Bruce D; Weideman, Patricia A

2016-08-01

Historically, pharmaceutical industry regulatory guidelines have assigned certain active pharmaceutical ingredients (APIs) to various categories of concern, such as "cytotoxic", "hormones", and "steroids". These categories have been used to identify APIs requiring segregation or dedication in order to prevent cross-contamination and protect the quality and safety of drug products. Since these terms were never defined by regulatory authorities, and many novel pharmacological mechanisms challenge these categories, there is a recognized need to modify the historical use of these terms. The application of a risk-based approach using a health-based limit, such as an acceptable daily exposure (ADE), is more appropriate for the development of a Quality Risk Management Program (QRMP) than the use of categories of concern. The toxicological and pharmacological characteristics of these categories are discussed to help identify and prioritize compounds requiring special attention. Controlling airborne concentrations and the contamination of product contact surfaces in accordance with values derived from quantitative risk assessments can prevent adverse effects in workers and patients, regardless of specific categorical designations to which these APIs have been assigned. The authors acknowledge the movement away from placing compounds into categories and, while not yet universal, the importance of basing QRMPs on compound-specific ADEs and risk assessments. Based on the results of a risk assessment, segregation and dedication may also be required for some compounds to prevent cross contamination during manufacture of APIs. Copyright © 2016 Elsevier Inc. All rights reserved.

Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine.

PubMed

Verbeken, Mathieu; Suleman, Sultan; Baert, Bram; Vangheluwe, Elien; Van Dorpe, Sylvia; Burvenich, Christian; Duchateau, Luc; Jansen, Frans H; De Spiegeleer, Bart

2011-02-28

Lumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®. Several new impurities are identified, of which the desbenzylketo derivative (DBK) is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself. From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs). The in-silico toxicological investigation (Toxtree® and Derek®) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.

Comparative Solid-State Stability of Perindopril Active Substance vs. Pharmaceutical Formulation

PubMed Central

Buda, Valentina; Andor, Minodora; Ledeti, Adriana; Ledeti, Ionut; Vlase, Gabriela; Vlase, Titus; Cristescu, Carmen; Voicu, Mirela; Suciu, Liana; Tomescu, Mirela Cleopatra

2017-01-01

This paper presents the results obtained after studying the thermal stability and decomposition kinetics of perindopril erbumine as a pure active pharmaceutical ingredient as well as a solid pharmaceutical formulation containing the same active pharmaceutical ingredient (API). Since no data were found in the literature regarding the spectroscopic description, thermal behavior, or decomposition kinetics of perindopril, our goal was the evaluation of the compatibility of this antihypertensive agent with the excipients in the tablet under ambient conditions and to study the effect of thermal treatment on the stability of perindopril erbumine. ATR-FTIR (Attenuated Total Reflectance Fourier Transform Infrared) spectroscopy, thermal analysis (thermogravimetric mass curve (TG—thermogravimetry), derivative thermogravimetric mass curve (DTG), and heat flow (HF)) and model-free kinetics were chosen as investigational tools. Since thermal behavior is a simplistic approach in evaluating the thermal stability of pharmaceuticals, in-depth kinetic studies were carried out by classical kinetic methods (Kissinger and ASTM E698) and later with the isoconversional methods of Friedman, Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa. It was shown that the main thermal degradation step of perindopril erbumine is characterized by activation energy between 59 and 69 kJ/mol (depending on the method used), while for the tablet, the values were around 170 kJ/mol. The used excipients (anhydrous colloidal silica, microcrystalline cellulose, lactose, and magnesium stearate) should be used in newly-developed generic solid pharmaceutical formulations, since they contribute to an increased thermal stability of perindopril erbumine. PMID:28098840

In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs.

PubMed

Tahara, Kohei; Nishikawa, Masahiro; Matsui, Ko; Hisazumi, Koji; Onodera, Risako; Tozuka, Yuichi; Takeuchi, Hirofumi

2016-09-01

The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC). Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo. The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size. PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.

Analysis of Forensic Casework Utilizing Infrared Spectroscopic Imaging.

PubMed

Lanzarotta, Adam

2016-02-24

A search of the current scientific literature yields a limited number of studies that describe the use of Fourier transform infrared (FT-IR) spectroscopic imaging for the analysis of forensic casework, which is likely due to the fact that these instruments are fairly new commodities to the field of analytical chemistry and are therefore not yet commonplace in forensic laboratories. This report describes recent forensic case studies that have used the technique for determining the composition of a wide variety of multi-component sample types, including animal tissue sections for toxic inclusions, drugs/dietary supplements, an antibiotic with an active pharmaceutical ingredient (API) present as several different salt forms, an adulterated bulk API, unknown trace powders for illicit drugs and an ophthalmic solution suspected of being adulterated with bleach.

Analysis of Forensic Casework Utilizing Infrared Spectroscopic Imaging †

PubMed Central

Lanzarotta, Adam

2016-01-01

A search of the current scientific literature yields a limited number of studies that describe the use of Fourier transform infrared (FT-IR) spectroscopic imaging for the analysis of forensic casework, which is likely due to the fact that these instruments are fairly new commodities to the field of analytical chemistry and are therefore not yet commonplace in forensic laboratories. This report describes recent forensic case studies that have used the technique for determining the composition of a wide variety of multi-component sample types, including animal tissue sections for toxic inclusions, drugs/dietary supplements, an antibiotic with an active pharmaceutical ingredient (API) present as several different salt forms, an adulterated bulk API, unknown trace powders for illicit drugs and an ophthalmic solution suspected of being adulterated with bleach. PMID:26927101

Optimization of a two-dimensional liquid chromatography-supercritical fluid chromatography-mass spectrometry (2D-LC-SFS-MS) system to assess "in-vivo" inter-conversion of chiral drug molecules.

PubMed

Goel, Meenakshi; Larson, Eli; Venkatramani, C J; Al-Sayah, Mohammad A

2018-05-01

Enantioselective analysis is an essential requirement during the pharmaceutical development of chiral drug molecules. In pre-clinical and clinical studies, the Food and Drug Administration (FDA) mandates the assessment of "in vivo" inter-conversion of chiral drugs to determine their physiological effects. In-vivo analysis of the active pharmaceutical ingredient (API) and its potential metabolites could be quite challenging due to their low abundance (ng/mL levels) and matrix interferences. Therefore, highly selective and sensitive analytical techniques are required to separate the API and its metabolites from the matrix components and one another. Additionally, for chiral APIs, further analytical separation is required to resolve the API and its potential metabolites from their corresponding enantiomers. In this work, we demonstrate the optimization of our previously designed two-dimensional liquid chromatography-supercritical fluid chromatography-mass spectrometry (2D-LC-SFC -MS) system to achieve 10 ng/mL detection limit [1]. The first LC dimension, used as a desalting step, could efficiently separate the API from its potential metabolites and matrix components. The API and its metabolites were then trapped/focused on small trapping columns and transferred onto the second SFC dimension for chiral separation. Detection can be achieved by ultra-violet (UV) or MS detection. Different system parameters such as column dimensions, transfer volumes, trapping column stationary phase, system tubing internal diameter (i.d.), and detection techniques, were optimized to enhance the sensitivity of the 2D-LC-SFC-MS system. The limit of detection was determined to be 10 ng/mL. An application is described where a mouse hepatocyte treated sample was analyzed using the optimized 2D-LC-SFC-MS system with successful assessment of the ratio of API to its metabolite (1D-LC), as well as the corresponding enantiomeric excess values (% e.e.) of each (2D-SFC). Copyright © 2018 Elsevier B.V. All rights reserved.

Completeness assessment of type II active pharmaceutical ingredient drug master files under generic drug user fee amendment: review metrics and common incomplete items.

PubMed

Zhang, Huyi; Li, Haitao; Song, Wei; Shen, Diandian; Skanchy, David; Shen, Kun; Lionberger, Robert A; Rosencrance, Susan M; Yu, Lawrence X

2014-09-01

Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA's "Available for Reference List". The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs.

Co-extrusion as a processing technique to manufacture a dual sustained release fixed-dose combination product.

PubMed

Vynckier, An-Katrien; Voorspoels, Jody; Remon, Jean Paul; Vervaet, Chris

2016-05-01

This study aimed to design a fixed-dose combination dosage form which provides a sustained release profile for both the freely water-soluble metformin HCl and the poorly soluble gliclazide, two antidiabetic compounds used to treat diabetes mellitus. Hot-melt co-extrusion was used as an innovative manufacturing technique for a pharmaceutical fixed-dose combination product. In this way, a matrix formulation that sustained metformin release could be developed, despite the high drug load in the formulation and the freely soluble nature of the drug. It was clear that co-extrusion was perfectly suited to produce a fixed-dose combination product with adequate properties for each of the incorporated APIs. A coat layer, containing at least 30% CAPA(®) 6506 as a hydrophobic polymer, was necessary to adequately sustain the release of the highly dosed freely soluble drug from the 70% metformin HCl-loaded CAPA(®) 6506 core of the co-extrudate. To obtain a complete gliclazide release over 24-h solubilization in Kollidon(®) VA, added as a second polymer to the CAPA(®) 6506 in the coat, was needed. Both active pharmaceutical ingredients (APIs), which have different physicochemical characteristics, were formulated in a single dosage form, using co-extrusion. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

Simple transmission Raman measurements using a single multivariate model for analysis of pharmaceutical samples contained in capsules of different colors.

PubMed

Lee, Yeojin; Kim, Jaejin; Lee, Sanguk; Woo, Young-Ah; Chung, Hoeil

2012-01-30

Direct transmission Raman measurements for analysis of pharmaceuticals in capsules are advantageous since they can be used to determine active pharmaceutical ingredient (API) concentrations in a non-destructive manner and with much less fluorescence background interference from the capsules themselves compared to conventional back-scattering measurements. If a single calibration model such as developed from spectra simply collected in glass vials could be used to determine API concentrations of samples contained in capsules of different colors rather than constructing individual models for each capsule color, the utility of transmission measurements would be further enhanced. To evaluate the feasibility, transmission Raman spectra of binary mixtures of ambroxol and lactose were collected in a glass vial and a partial least squares (PLS) model for the determination of ambroxol concentration was developed. Then, the model was directly applied to determine ambroxol concentrations of samples contained in capsules of 4 different colors (blue, green, white and yellow). Although the prediction performance was slightly degraded when the samples were placed in blue or green capsules, due to the presence of weak fluorescence, accurate determination of ambroxol was generally achieved in all cases. The prediction accuracy was also investigated when the thickness of the capsule was varied. Copyright © 2011 Elsevier B.V. All rights reserved.

Gluten and Aluminum Content in Synthroid® (Levothyroxine Sodium Tablets).

PubMed

Espaillat, Ramon; Jarvis, Michael F; Torkelson, Cory; Sinclair, Brent

2017-07-01

Inquiries from healthcare providers and patients about the gluten and aluminum content of Synthroid ® (levothyroxine sodium tablets) have increased. The objective of this study was to measure and evaluate the gluten content of the raw materials used in the manufacturing of Synthroid. Additionally, this study determined the aluminum content in different strengths of Synthroid tablets by estimating the amount of aluminum in the raw materials used in the manufacturing of Synthroid. Gluten levels of three lots of the active pharmaceutical ingredient (API) and one lot of each excipient from different vendors were examined. The ingredients in all current Synthroid formulations (strengths) were evaluated for their quantity of aluminum. Gluten concentrations were below the lowest limit of detection (<3.0 ppm) for all tested lots of the API and excipients of Synthroid tablets. Aluminum content varied across tablet strengths (range 19-137 µg/tablet). Gluten levels of the API and excipients were found to be below the lowest level of detection and are considered gluten-free based on the US Food and Drug Administration (FDA) definition for food products. Across the various tablet strengths of Synthroid, the maximum aluminum levels were well below the FDA-determined minimal risk level for chronic oral aluminum exposure (1 mg/kg/day). These data demonstrate that Synthroid tablets are not a source for dietary gluten and are a minimal source of aluminum. AbbVie Inc.

Pharmacopollution and Household Waste Medicine (HWM): how reverse logistics is environmentally important to Brazil.

PubMed

Pereira, André Luiz; de Vasconcelos Barros, Raphael Tobias; Pereira, Sandra Rosa

2017-11-01

Pharmacopollution is a public health and environmental outcome of some active pharmaceutical ingredients (API) and endocrine-disrupting compounds (EDC) dispersed through water and/or soil. Its most important sources are the pharmaceutical industry, healthcare facilities (e.g., hospitals), livestock, aquaculture, and households (patients' excretion and littering). The last source is the focus of this article. Research questions are "What is the Household Waste Medicine (HWM) phenomenon?", "How HWM and pharmacopollution are related?", and "Why is a reverse logistic system necessary for HWM in Brazil?" This article followed the seven steps proposed by Rother (2007) for a systematic review based on the Cochrane Handbook and the National Health Service (NHS) Center for Reviews Dissemination (CDR) Report. The HWM phenomenon brings many environmental, public health, and, social challenges. The insufficient data is a real challenge to assessing potential human health risks and API concentrations. Therefore, the hazard of long-term exposure to low concentrations of pharmacopollutants and the combined effects of API mixtures is still uncertain. HWM are strongly related to pharmacopollution, as this review shows. The Brazilian HWM case is remarkable because it is the fourth pharmaceutical market (US$ 65,971 billion), with a wide number of private pharmacies and drugstores (3.3: 10,000 pharmacy/inhabitants), self-medication habits, and no national take-back program. The HWM generation is estimated in 56.6 g/per capita, or 10,800 t/year. The absence of a reverse logistics for HWM can lead to serious environmental and public health challenges. The sector agreement for HWM is currently under public consultation.

[Spectral Analysis about the Pharmaceutical Cocrystal Formation of Piracetam and 3-Hydroxybenzoic Acid].

PubMed

Zhang, Hui-li; Xia, Yi; Hong, Zhi; Du, Yong

2015-07-01

Pharmaceutical cocrystal can improve physical and chemical properties of active pharmaceutical ingredient (API), meanwhile this feature has shown great potential in improving the pharmaceutical's properties and characteristics. In this study, cocrystal formation between piracetam and 3-hydroxybenzoic acid (3HBA) using grinding method has been characterized by Fourier transform infrared (FTIR), Raman and terahertz (THz) spectroscopical techniques. The vibrational modes of different motions are obtained by the assignment of the peaks in the spectra of the starting materials and the cocrystal components. FTIR, Raman and THz spectroscopical results show that the vibrational modes of the cocrystal are different from those of the starting materials. In addition, the dynamic process of the above cocrystal formation is investigated in-depth with Raman and THz spec- tra. Piracetam-3HBA cocrystal is formed pretty fast in first several minutes, and then the formation rate becomes slow. After 35 minutes, such formation process has been completed. The results offer the theoretical benchmark and unique means for real-time monitoring pharmaceutical cocrystal formation and also the corresponding quantitative analysis in the pharmaceutical field.

Drug Solubility in Fatty Acids as a Formulation Design Approach for Lipid-Based Formulations: A Technical Note.

PubMed

Lee, Yung-Chi; Dalton, Chad; Regler, Brian; Harris, David

2018-06-06

Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02 μg/mL and predicted partition coefficient >7. The solubility of API ranged from 120 mg/mL to over 1 g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.

Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs.

PubMed

Vo, Chau Le-Ngoc; Park, Chulhun; Lee, Beom-Jin

2013-11-01

Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design.

PubMed

Berry, David J; Steed, Jonathan W

2017-08-01

As small molecule drugs become harder to develop and less cost effective for patient use, efficient strategies for their property improvement become increasingly important to global health initiatives. Improvements in the physical properties of Active Pharmaceutical Ingredients (APIs), without changes in the covalent chemistry, have long been possible through the application of binary component solids. This was first achieved through the use of pharmaceutical salts, within the last 10-15years with cocrystals and more recently coamorphous systems have also been consciously applied to this problem. In order to rationally discover the best multicomponent phase for drug development, intermolecular interactions need to be considered at all stages of the process. This review highlights the current thinking in this area and the state of the art in: pharmaceutical multicomponent phase design, the intermolecular interactions in these phases, the implications of these interactions on the material properties and the pharmacokinetics in a patient. Copyright © 2017 Elsevier B.V. All rights reserved.

Experimental cocrystal screening and solution based scale-up cocrystallization methods.

PubMed

Malamatari, Maria; Ross, Steven A; Douroumis, Dennis; Velaga, Sitaram P

2017-08-01

Cocrystals are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. If one of the components is an active pharmaceutical ingredient (API), the term pharmaceutical cocrystal is often used. There is a growing interest among drug development scientists in exploring cocrystals, as means to address physicochemical, biopharmaceutical and mechanical properties and expand solid form diversity of the API. Conventionally, coformers are selected based on crystal engineering principles, and the equimolar mixtures of API and coformers are subjected to solution-based crystallization that are commonly employed in polymorph and salt screening. However, the availability of new knowledge on cocrystal phase behaviour in solid state and solutions has spurred the development and implementation of more rational experimental cocrystal screening as well as scale-up methods. This review aims to provide overview of commonly employed solid form screening techniques in drug development with an emphasis on cocrystal screening methodologies. The latest developments in understanding and the use of cocrystal phase diagrams in both screening and solution based scale-up methods are also presented. Final section is devoted to reviewing the state of the art research covering solution based scale-up cocrystallization process for different cocrystals besides more recent continuous crystallization methods. Copyright © 2017 Elsevier B.V. All rights reserved.

Essential Aspects in Assessing the Safety Impact of Interactions between a Drug Product and Its Associated Manufacturing System.

PubMed

Jenke, Dennis

2012-01-01

An emerging trend in the biotechnology industry is the utilization of plastic components in manufacturing systems for the production of an active pharmaceutical ingredient (API) or a finished drug product (FDP). If the API, the FDP, or any solution used to generate them (for example, process streams such as media, buffers, and the like) come in contact with a plastic at any time during the manufacturing process, there is the potential that substances leached from the plastic may accumulate in the API or FDP, affecting safety and/or efficacy. In this article the author develops a terminology that addresses process streams associated with the manufacturing process. Additionally, the article outlines the safety assessment process for manufacturing systems, specifically addressing the topics of risk management and the role of compendial testing. Finally, the proper use of vendor-supplied extractables information is considered. Manufacturing suites used to produce biopharmaceuticals can include components that are made out of plastics. Thus it is possible that substances could leach out of the plastics and into manufacturing solutions, and it is further possible that such leachables could accumulate in the pharmaceutical product. In this article, the author develops a terminology that addresses process streams associated with the manufacturing process. Additionally, the author proposes a process by which the impact on product safety of such leached substances can be assessed.

Drop Printing of Pharmaceuticals: Effect of Molecular Weight on PEG Coated-Naproxen/PEG3350 Solid Dispersions

PubMed Central

Hsu, Hsin-Yun; Toth, Scott; Simpson, Garth J.; Harris, Michael T.

2016-01-01

Solid dispersions have been used to enhance the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the solid state phase, compositional uniformity, and scale-up problems are issues that need to be addressed. To allow for highly controllable products, the Drop Printing (DP) technique can provide precise dosages and predictable compositional uniformity of APIs in two/three dimensional structures. In this study, DP was used to prepare naproxen (NAP)/polyethylene glycol 3350 (PEG3350) solid dispersions with PEG coatings of different molecular weights (MW). A comparison of moisture-accelerated crystallization inhibition by different PEG coatings was assessed. Scanning electron microscopy (SEM), second harmonic generation (SHG) microscopy, and differential scanning calorimetry (DSC) analysis were performed to characterize the morphology and quantify the apparent crystallinity of NAP within the solid dispersions. Thermogravimetric analysis (TGA) was employed to measure the water content within each sample. The results suggest that the moisture-accelerated crystallization inhibition capability of the PEG coatings increased with increasing MW of the PEG coating. Besides, to demonstrate the flexibility of DP technology on manufacturing formulation, multilayer tablets with different PEG serving as barrier layers were also constructed, and their dissolution behavior was examined. By applying DP and appropriate materials, it is possible to design various carrier devices used to control the release dynamics of the API. PMID:27041744

Drop Printing of Pharmaceuticals: Effect of Molecular Weight on PEG Coated-Naproxen/PEG3350 Solid Dispersions.

PubMed

Hsu, Hsin-Yun; Toth, Scott; Simpson, Garth J; Harris, Michael T

2015-12-01

Solid dispersions have been used to enhance the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the solid state phase, compositional uniformity, and scale-up problems are issues that need to be addressed. To allow for highly controllable products, the Drop Printing (DP) technique can provide precise dosages and predictable compositional uniformity of APIs in two/three dimensional structures. In this study, DP was used to prepare naproxen (NAP)/polyethylene glycol 3350 (PEG3350) solid dispersions with PEG coatings of different molecular weights (MW). A comparison of moisture-accelerated crystallization inhibition by different PEG coatings was assessed. Scanning electron microscopy (SEM), second harmonic generation (SHG) microscopy, and differential scanning calorimetry (DSC) analysis were performed to characterize the morphology and quantify the apparent crystallinity of NAP within the solid dispersions. Thermogravimetric analysis (TGA) was employed to measure the water content within each sample. The results suggest that the moisture-accelerated crystallization inhibition capability of the PEG coatings increased with increasing MW of the PEG coating. Besides, to demonstrate the flexibility of DP technology on manufacturing formulation, multilayer tablets with different PEG serving as barrier layers were also constructed, and their dissolution behavior was examined. By applying DP and appropriate materials, it is possible to design various carrier devices used to control the release dynamics of the API.

Moisture-induced phase separation and recrystallization in amorphous solid dispersions.

PubMed

Luebbert, Christian; Sadowski, Gabriele

2017-10-30

Active Pharmaceutical Ingredients (APIs) are often dissolved in polymeric matrices to control the gastrointestinal dissolution and to stabilize the amorphous state of the API. During the pharmaceutical development of new formulations, stability studies via storage at certain temperature and relative humidity (RH) have to be carried out to verify the long-term thermodynamic stability of these formulations against unwanted recrystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This study focuses on predicting the MIAPS of API/polymer formulations at elevated RH. In a first step, the phase behavior of water-free formulations of ibuprofen (IBU) and felodipine (FEL) combined with the polymers poly(vinyl pyrrolidone) (PVP), poly(vinyl acetate) (PVAC) and poly (vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) was determined experimentally by differential scanning calorimetry (DSC). The phase behavior of these water-free formulations was modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Based on this, the API solubility and MIAPS in the above-mentioned formulations at humid conditions was predicted in perfect agreement with the results of two-year lasting stability studies at 25°C/0% RH and 40°C/75% RH. MIAPS was predicted and also experimentally found for the FEL/PVP, FEL/PVPVA64 and IBU/PVP formulations, whereas MIAPS was neither predicted nor measured for the IBU/PVPVA64 system and PVAC-containing formulations. It was thus shown that the results of time-consuming long-term stability tests can be correctly predicted via thermodynamic modeling with PC-SAFT. Copyright © 2017 Elsevier B.V. All rights reserved.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

PubMed

Bédard, Anne-Catherine; Longstreet, Ashley R; Britton, Joshua; Wang, Yuran; Moriguchi, Hideki; Hicklin, Robert W; Green, William H; Jamison, Timothy F

2017-12-01

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9. Copyright © 2017 Elsevier Ltd. All rights reserved.

A practical derivatization LC/MS approach for determination of trace level alkyl sulfonates and dialkyl sulfates genotoxic impurities in drug substances.

PubMed

An, Jianguo; Sun, Mingjiang; Bai, Lin; Chen, Ted; Liu, David Q; Kord, Alireza

2008-11-04

Derivatization LC/MS methodology has been developed for the determination of a group of commonly encountered alkyl esters of sulfonates or sulfates in drug substances at low ppm levels. This general method uses trimethylamine as the derivatizing reagent for ethyl/propyl/isopropyl esters and triethylamine for methyl esters. The resulting quaternary ammonium derivatization products are highly polar (ionic) and can be retained by a hydrophilic interaction liquid chromatography (HILIC) column and readily separated from the main interfering active pharmaceutical ingredient (API) peak that is usually present at very high concentration. The method gives excellent sensitivity for all the alkyl esters at typical target analyte level of 1-2 ppm when the API samples were prepared at 5mg/mL. The recoveries at 1-2 ppm were generally above 85% for all the alkyl esters in the various APIs tested. The injection precisions of the lowest concentration standards were excellent with R.S.D.=0.4-4%. A linear range for concentrations from 0.2 to 20 ppm has been established with R(2)>or=0.99. This general method has been tested in a number of API matrices and used successfully for determination of alkyl sulfonates or dialkyl sulfates in support of API batch releases at GlaxoSmithKline.

The evaluation of physical properties of injection molded systems based on poly(ethylene oxide) (PEO).

PubMed

Pajander, Jari; Rensonnet, Alexia; Hietala, Sami; Rantanen, Jukka; Baldursdottir, Stefania

2017-02-25

The effect of product design parameters on the formation and properties of an injection molded solid dosage form consisting of poly(ethylene oxide)s (PEO) and two different active pharmaceutical ingredients (APIs) was studied. The product design parameters explored were melting temperature and the duration of melting, API loading degree and the molecular weight (M w ) of PEO. The solid form composition of the model APIs, theophylline and carbamazepine, was of specific interest, and its possible impact on the in vitro drug release behavior. M w of PEO had the greatest impact on the release rate of both APIs. High M w resulted in slower API release rate. Process temperature had two-fold effect with PEO 300,000g/mol. Firstly, higher process temperature transformed the crystalline part of the polymer into metastable folded form (more folded crystalline regions) and less into the more stable extended form (more extended crystalline regions), which lead to enhanced theophylline release rate. Secondly, the higher process temperature seemed to induce carbamazepine polymorphic transformation from p-monoclinic form III (carbamazepine (M)) into trigonal form II (carbamazepine (T)). The results indicated that the actual content of carbamazepine (T) affected drug release behavior more than the magnitude of transformation. Copyright © 2016 Elsevier B.V. All rights reserved.

Mass Balance Analysis of Contaminated Heparin Product

PubMed Central

Liu, Zhenling; Xiao, Zhongping; Masuko, Sayaka; Zhao, Wenjing; Sterner, Eric; Bansal, Vinod; Fareed, Jawed; Dordick, Jonathan; Zhang, Fuming; Linhardt, Robert J.

2011-01-01

A quantitative analysis of a recalled contaminated lot of heparin (HP) sodium injection United States Pharmacopeial (USP) was undertaken in response to the controversy regarding the exact nature of the contaminant involved in the HP crisis. A mass balance analysis of the formulated drug product was performed. After freeze-drying, a 1 ml vial for injection afforded 54.8 ± 0.3 mg of dry solids. The excipients, sodium chloride and residual benzyl alcohol, accounted for 11.4 ± 0.5 mg and 0.9 ± 0.5 mg, respectively. Active pharmaceutical ingredient (API) represented 41.5 ± 1.0 mg, corresponding to 75.7 wt% of dry mass. Exhaustive treatment of API with specific enzymes, heparin lyases and/or chondroitin lyases was used to close mass balance. HP represented 30.5 ± 0.5 mg, corresponding to 73.5 wt% of the API. Dermatan sulfate (DS) impurity represented 1.7 ± 0.3 mg, corresponding to 4.1 wt% of the API. Contaminant, 9.3 ± 0.1 mg corresponding to 22.4 wt% of API, was found in the contaminated formulated drug product. The recovery of contaminant was close to quantitative (95.6-100 wt%). A single contaminant was unambiguously identified as oversulfated chondroitin sulfate (OSCS). PMID:20850409

Collaborative Health and Enforcement Operations on the Quality of Antimalarials and Antibiotics in Southeast Asia

PubMed Central

Yong, Yuk Lin; Plançon, Aline; Lau, Yen Hui; Hostetler, Dana M.; Fernández, Facundo M.; Green, Michael D.; Sounvoravong, Sourisak; Nara, Suon; Boravann, Mam; Dumrong, Thitikornkovit; Bangsawan, Nurjaya; Low, Min Yong; Lim, Chin-Chin; Ai, Ruth Lee Choo; Newton, Paul N.

2015-01-01

Counterfeit (or falsified) and substandard medicines pose a major public health risk. We describe the findings of Operation Storm I and II conducted in 2008–2009 to combat counterfeit medicines through partnership between national customs, Drug Regulatory Agencies (DRAs), and police in Cambodia, Indonesia, Laos, Myanmar, Singapore, Thailand, and Vietnam. Samples were obtained from seizures and market surveillance by national DRAs. Laboratory analysis using spectroscopic and chromatographic techniques and examination of packaging were performed. Ninety-three suspect antibiotics and 95 antimalarial samples were collected. Of the 93 antibiotics, 29 (31%) had % active pharmaceutical ingredient content (%API) < 85% or > 115% (including one counterfeit). Of the 95 antimalarials, 30 (32%) had %API < 85 > 115% API (including one counterfeit). A significant minority of samples, antimalarials (13%) and antibiotics (15%), were collected in plastic bags with minimal or no labeling. Of 20 ampicillin samples, 13 (65%) contained < 85% API (with one counterfeit containing additional amoxicillin). Of 34 oral artesunate samples, 7 (21%) contained %API out of the 85–115% range. Coordinated and synergistic partnership adopted by the participating countries, International Criminal Police Organization (INTERPOL), World Health Organization (WHO), and laboratories facilitated a platform for discussions and intelligence sharing, helping to improve each participating country's capacity to combat poor-quality medicines. PMID:25897069

High throughput screening of active pharmaceutical ingredients by UPLC.

PubMed

Al-Sayah, Mohammad A; Rizos, Panagiota; Antonucci, Vincent; Wu, Naijun

2008-07-01

Ultra performance LC (UPLC) was evaluated as an efficient screening approach to facilitate method development for drug candidates. Three stationary phases were screened: C-18, phenyl, and Shield RP 18 with column dimensions of 150 mm x 2.1 mm, 1.7 microm, which should theoretically generate 35,000 plates or 175% of the typical column plate count of a conventional 250 mm x 4.6 mm, 5 microm particle column. Thirteen different active pharmaceutical ingredients (APIs) were screened using this column set with a standardized mobile-phase gradient. The UPLC method selectivity results were compared to those obtained for these compounds via methods developed through laborious trial and error screening experiments using numerous conventional HPLC mobile and stationary phases. Peak capacity was compared for columns packed with 5 microm particles and columns packed with 1.7 microm particles. The impurities screened by UPLC were confirmed by LC/MS. The results demonstrate that simple, high efficiency UPLC gradients are a feasible and productive alternative to more conventional multiparametric chromatographic screening approaches for many compounds in the early stages of drug development.

The production and exportation of artemisinin-derived drugs in China: current status and existing challenges.

PubMed

Huang, Yangmu; Li, Hui; Peng, Danlu; Wang, Yu; Ren, Qiaomeng; Guo, Yan

2016-07-15

As the discoverer and a major manufacturer of artemisinin, China has made valuable contributions to malaria control and the global market of artemisinin-derived drugs. This study aims to explore the production and export status of artemisinin-derived drugs in China during 2011 and 2014 to provide a clear understanding of China's participation in this field and also to provide guidance for its future role on global malaria control. Production and exportation data were obtained from the Ministry of Industry and Information Technology (MIIT) database of the People's Republic China and monthly reports of the General Administration of Customs of China, respectively. The production volume, export volume, export value, and export area of artemisinin and its derivatives (artemether, artesunate, dihydroartemisinin), including both active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs), were descripted and analysed by Microsoft Excel. Between 2011 and 2013, the total production volume of artemisinin-derived APIs and FPPs reached 543.41 metric tons (MT) and 14.79 MT, respectively. The total export value and volume of artemisinin-derived APIs during 2012 and 2014 was US$ 211.39 million and 338.53 MT; the total export value and volume of FPPs was US$ 227.17 million and 4401.44 MT. Compared with the sharply decreasing trend of API exports each year, the export value of FPPs kept at a more stable level, with 14.66 % increase in 2013 and 5.31 % decrease in 2014. As for exportation areas, India was the largest purchaser of APIs, accounting for nearly a half of the total amount, while FPPs mainly exported to African countries. Exports of artemisinin derivatives for China have been transforming from API-dominated to FPP-dominated. However, the exportation of artemisinin-derived drugs in China still face the challenges of small market share in the global FPP market and indirect sale of FPPs through a third country due to the deficiency in obtaining relevant certification into global market.

A Process Analytical Technology (PAT) approach to control a new API manufacturing process: development, validation and implementation.

PubMed

Schaefer, Cédric; Clicq, David; Lecomte, Clémence; Merschaert, Alain; Norrant, Edith; Fotiadu, Frédéric

2014-03-01

Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18-1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses. © 2013 Published by Elsevier B.V.

Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Li; Hanrahan, Michael P.; Chakravarty, Paroma

Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is amore » powerful probe of structure in cocrystals and salts of APIs, however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiments by one to two orders of magnitude for salts and cocrystals of a complex API. The large sensitivity gains from DNP facilitates rapid acquisition of natural isotopic abundance 13C and 15N solid-state NMR spectra. Critically, DNP enables double resonance 1H-15N solid-state NMR experiments such as 2D 1H-15N HETCOR, 1H-15N CP-build up, 15N{1H} J-resolved/attached proton tests, 1H-15N DIPSHIFT and 1H-15N PRESTO. The latter two experiments allow 1H-15N dipolar coupling constants and H-N bond lengths to be accurately measured, providing an unambiguous assignment of nitrogen protonation state and definitive classification of the multi-component solids as cocrystals or salts. In conclusion, these types of measurements should also be extremely useful in the context of polymorph discrimination, NMR crystallography structure determination and for probing hydrogen bonding in a variety of organic materials.« less

Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

DOE PAGES

Zhao, Li; Hanrahan, Michael P.; Chakravarty, Paroma; ...

2018-02-15

Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is amore » powerful probe of structure in cocrystals and salts of APIs, however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiments by one to two orders of magnitude for salts and cocrystals of a complex API. The large sensitivity gains from DNP facilitates rapid acquisition of natural isotopic abundance 13C and 15N solid-state NMR spectra. Critically, DNP enables double resonance 1H-15N solid-state NMR experiments such as 2D 1H-15N HETCOR, 1H-15N CP-build up, 15N{1H} J-resolved/attached proton tests, 1H-15N DIPSHIFT and 1H-15N PRESTO. The latter two experiments allow 1H-15N dipolar coupling constants and H-N bond lengths to be accurately measured, providing an unambiguous assignment of nitrogen protonation state and definitive classification of the multi-component solids as cocrystals or salts. In conclusion, these types of measurements should also be extremely useful in the context of polymorph discrimination, NMR crystallography structure determination and for probing hydrogen bonding in a variety of organic materials.« less

At-line determination of pharmaceuticals small molecule's blending end point using chemometric modeling combined with Fourier transform near infrared spectroscopy

NASA Astrophysics Data System (ADS)

Tewari, Jagdish; Strong, Richard; Boulas, Pierre

2017-02-01

This article summarizes the development and validation of a Fourier transform near infrared spectroscopy (FT-NIR) method for the rapid at-line prediction of active pharmaceutical ingredient (API) in a powder blend to optimize small molecule formulations. The method was used to determine the blend uniformity end-point for a pharmaceutical solid dosage formulation containing a range of API concentrations. A set of calibration spectra from samples with concentrations ranging from 1% to 15% of API (w/w) were collected at-line from 4000 to 12,500 cm- 1. The ability of the FT-NIR method to predict API concentration in the blend samples was validated against a reference high performance liquid chromatography (HPLC) method. The prediction efficiency of four different types of multivariate data modeling methods such as partial least-squares 1 (PLS1), partial least-squares 2 (PLS2), principal component regression (PCR) and artificial neural network (ANN), were compared using relevant multivariate figures of merit. The prediction ability of the regression models were cross validated against results generated with the reference HPLC method. PLS1 and ANN showed excellent and superior prediction abilities when compared to PLS2 and PCR. Based upon these results and because of its decreased complexity compared to ANN, PLS1 was selected as the best chemometric method to predict blend uniformity at-line. The FT-NIR measurement and the associated chemometric analysis were implemented in the production environment for rapid at-line determination of the end-point of the small molecule blending operation. FIGURE 1: Correlation coefficient vs Rank plot FIGURE 2: FT-NIR spectra of different steps of Blend and final blend FIGURE 3: Predictions ability of PCR FIGURE 4: Blend uniformity predication ability of PLS2 FIGURE 5: Prediction efficiency of blend uniformity using ANN FIGURE 6: Comparison of prediction efficiency of chemometric models TABLE 1: Order of Addition for Blending Steps

Coformer screening using thermal analysis based on binary phase diagrams.

PubMed

Yamashita, Hiroyuki; Hirakura, Yutaka; Yuda, Masamichi; Terada, Katsuhide

2014-08-01

The advent of cocrystals has demonstrated a growing need for efficient and comprehensive coformer screening in search of better development forms, including salt forms. Here, we investigated a coformer screening system for salts and cocrystals based on binary phase diagrams using thermal analysis and examined the effectiveness of the method. Indomethacin and tenoxicam were used as models of active pharmaceutical ingredients (APIs). Physical mixtures of an API and 42 kinds of coformers were analyzed using Differential Scanning Calorimetry (DSC) and X-ray DSC. We also conducted coformer screening using a conventional slurry method and compared these results with those from the thermal analysis method and previous studies. Compared with the slurry method, the thermal analysis method was a high-performance screening system, particularly for APIs with low solubility and/or propensity to form solvates. However, this method faced hurdles for screening coformers combined with an API in the presence of kinetic hindrance for salt or cocrystal formation during heating or if there is degradation near the metastable eutectic temperature. The thermal analysis and slurry methods are considered complementary to each other for coformer screening. Feasibility of the thermal analysis method in drug discovery practice is ensured given its small scale and high throughput.

Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine.

PubMed

Kaminska, E; Tarnacka, M; Wlodarczyk, P; Jurkiewicz, K; Kolodziejczyk, K; Dulski, M; Haznar-Garbacz, D; Hawelek, L; Kaminski, K; Wlodarczyk, A; Paluch, M

2015-08-03

Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.

Inkjet printing for pharmaceutics - A review of research and manufacturing.

PubMed

Daly, Ronan; Harrington, Tomás S; Martin, Graham D; Hutchings, Ian M

2015-10-30

Global regulatory, manufacturing and consumer trends are driving a need for change in current pharmaceutical sector business models, with a specific focus on the inherently expensive research costs, high-risk capital-intensive scale-up and the traditional centralised batch manufacturing paradigm. New technologies, such as inkjet printing, are being explored to radically transform pharmaceutical production processing and the end-to-end supply chain. This review provides a brief summary of inkjet printing technologies and their current applications in manufacturing before examining the business context driving the exploration of inkjet printing in the pharmaceutical sector. We then examine the trends reported in the literature for pharmaceutical printing, followed by the scientific considerations and challenges facing the adoption of this technology. We demonstrate that research activities are highly diverse, targeting a broad range of pharmaceutical types and printing systems. To mitigate this complexity we show that by categorising findings in terms of targeted business models and Active Pharmaceutical Ingredient (API) chemistry we have a more coherent approach to comparing research findings and can drive efficient translation of a chosen drug to inkjet manufacturing. Copyright © 2015 Elsevier B.V. All rights reserved.

The Industrial Age of Biocatalytic Transamination.

PubMed

Fuchs, Michael; Farnberger, Judith E; Kroutil, Wolfgang

2015-11-01

During the last decade the use of ω-transaminases has been identified as a very powerful method for the preparation of optically pure amines from the corresponding ketones. Their immense potential for the preparation of chiral amines, together with their ease of use in combination with existing biocatalytic methods, have made these biocatalysts a competitor to any chemical methodology for (asymmetric) amination. An increasing number of examples, especially from industry, shows that this biocatalytic technology outmaneuvers existing chemical processes by its simple and flexible nature. In the last few years numerous publications and patents on synthetic routes, mainly to pharmaceuticals, involving ω-transaminases have been published. The review gives an overview of the application of ω-transaminases in organic synthesis with a focus on active pharmaceutical ingredients (APIs) and the developments during the last few years.

Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.

PubMed

Mickle, Travis C; Guenther, Sven M; Barrett, Andrew C; Roupe, Kathryn Ann; Zhou, Jing; Dickerson, Daniel; Webster, Lynn R

2017-10-28

Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Single-center, randomized, double-blind, crossover study. Clinical research site. Healthy adult, nondependent, recreational opioid users. Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse. © 2017 American Academy of Pain Medicine.

Metabolic engineering: the ultimate paradigm for continuous pharmaceutical manufacturing.

PubMed

Yadav, Vikramaditya G; Stephanopoulos, Gregory

2014-07-01

Research and development (R&D) expenditures by pharmaceutical companies doubled over the past decade, yet candidate attrition rates and development times rose markedly during this period. Understandably, companies have begun downsizing their pipelines and diverting investments away from R&D in favor of manufacturing. It is estimated that transitioning to continuous manufacturing could enable companies to compete for a share in emerging markets. Accordingly, the model for continuous manufacturing that has emerged commences with the conversion of late-stage intermediates into the active pharmaceutical ingredient (API) in a series of continuous flow reactors, followed by continuous solid processing to form finished tablets. The use of flow reactions for API synthesis will certainly generate purer products at higher yields in shorter times compared to equivalent batch reactions. However, transitioning from batch to flow configuration simply alleviates transport limitations within the reaction milieu. As the catalogue of reactions used in flow syntheses is a subset of batch-based chemistries, molecules such as natural products will continue to evade drug prospectors. Also, it is uncertain whether flow synthesis can deliver improvements in the atom and energy economies of API production at the scales that would achieve the levels of revenue growth targeted by companies. Instead, it is argued that implementing metabolic engineering for the production of oxidized scaffolds as gateway molecules for flow-based addition of electrophiles is a more effective and scalable strategy for accessing natural product chemical space. This new paradigm for manufacturing, with metabolic engineering as its engine, would also permit rapid optimization of production variables and allow facile scale-up from gram to ton scale to meet material requirements for clinical trials, thus recasting manufacturing as a tool for discovery. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion.

PubMed

Wesholowski, Jens; Prill, Sebastian; Berghaus, Andreas; Thommes, Markus

2018-01-11

Hot-melt extrusion on co-rotating twin screw extruders is a focused technology for the production of pharmaceuticals in the context of Quality by Design. Since it is a continuous process, the potential for minimizing product quality fluctuation is enhanced. A typical application of hot-melt extrusion is the production of solid dispersions, where an active pharmaceutical ingredient (API) is distributed within a polymer matrix carrier. For this dosage form, the product quality is related amongst others to the drug content. This can be monitored on- or inline as critical quality attribute by a process analytical technology (PAT) in order to meet the specific requirements of Quality by Design. In this study, an inline UV/Vis spectrometer from ColVisTec was implemented in an early development twin screw extruder and the performance tested in accordance to the ICH Q2 guideline. Therefore, two API (carbamazepine and theophylline) and one polymer matrix (copovidone) were considered with the main focus on the quantification of the drug load. The obtained results revealed the suitability of the implemented PAT tool to quantify the drug load in a typical range for pharmaceutical applications. The effort for data evaluation was minimal due to univariate data analysis, and in combination with a measurement frequency of 1 Hz, the system is sufficient for real-time data acquisition.

Inkjet printing of drug substances and use of porous substrates-towards individualized dosing.

PubMed

Sandler, Niklas; Määttänen, Anni; Ihalainen, Petri; Kronberg, Leif; Meierjohann, Axel; Viitala, Tapani; Peltonen, Jouko

2011-08-01

Medicines are most often oral solid dosage forms made into tablets or capsules, and there is little room for individualized doses. The drug substance and additives are processed through multiple production phases, including complex powder handling steps. In drug manufacturing, the control of the solid-state properties of active pharmaceutical ingredient (API) is essential and it offers opportunities for enhancement of drug delivery systems. In this context, inkjet printing technologies have emerged over the last decades in pharmaceutical and biological applications and offer solutions for controlling material and product characteristics with high precision. Here we report the concept of conventional inkjet printing technology to produce printable pharmaceutical dosage forms on porous substrates. Data are shown to demonstrate inkjet printing of APIs into paper substrates, and how the model drug substances (paracetamol, theophylline, and caffeine) are penetrating the porous substrates used. The method enables controlling not only the deposition but also the crystallization of the drug substances. We anticipate that the inkjet printing approach has immense potential in making sophisticated drug delivery systems by use of porous substrates in the future. For example, it may offer new perspectives for solving problems around poorly soluble drugs and dosing low-dose medicines accurately. Furthermore, with the advent of genetic mapping of humans, controlled inkjet dosing can bring solutions to fabricate on-demand individualized medicines for patients. Copyright © 2011 Wiley-Liss, Inc.

Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the Internet.

PubMed

Veronin, Michael A; Nutan, Mohammad T; Dodla, Uday Krishna Reddy

2014-10-01

The accessibility of prescription drugs produced outside of the United States, most notably sildenafil citrate (innovator product, Viagra®), has been made much easier by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The US Food and Drug Administration (FDA) has issued warnings to potential buyers that the safety of drugs purchased from the Internet cannot be guaranteed, and may present a health risk to consumers from substandard products. The objective of this study was to determine whether generic sildenafil citrate tablets from international markets obtained via the Internet are equivalent to the US innovator product regarding major aspects of pharmaceutical quality: potency, accuracy of labeling, and presence and level of impurities. This will help identify aspects of drug quality that may impact public health risks. A total of 15 sildenafil citrate tablets were obtained for pharmaceutical analysis: 14 generic samples from international Internet pharmacy websites and the US innovator product. According to US Pharmacopeial guidelines, tablet samples were tested using high-performance liquid chromatography for potency of active pharmaceutical ingredient (API) and levels of impurities (impurities A, B, C, and D). Impurity levels were compared with International Conference on Harmonisation (ICH) limits. Among the 15 samples, 4 samples possessed higher impurity B levels than the ICH qualification threshold, 8 samples possessed higher impurity C levels than the ICH qualification threshold, and 4 samples possessed more than 1% impurity quantity of maximum daily dose (MDD). For API, 6 of the samples failed to fall within the 5% assay limit. Quality assurance tests are often used to detect formulation defects of drug products during the manufacturing and/or storage process. Results suggest that manufacturing standards for sildenafil citrate generic drug products compared with the US innovator product are not equivalent with regards to potency and levels of impurities. These findings have implications for safety and effectiveness that should be addressed by clinicians to safeguard consumers who choose to purchase sildenafil citrate and foreign-manufactured drugs, in general, via the Internet.

Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the Internet

PubMed Central

Nutan, Mohammad T.; Dodla, Uday Krishna Reddy

2014-01-01

Background: The accessibility of prescription drugs produced outside of the United States, most notably sildenafil citrate (innovator product, Viagra®), has been made much easier by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The US Food and Drug Administration (FDA) has issued warnings to potential buyers that the safety of drugs purchased from the Internet cannot be guaranteed, and may present a health risk to consumers from substandard products. Objective: The objective of this study was to determine whether generic sildenafil citrate tablets from international markets obtained via the Internet are equivalent to the US innovator product regarding major aspects of pharmaceutical quality: potency, accuracy of labeling, and presence and level of impurities. This will help identify aspects of drug quality that may impact public health risks. Methods: A total of 15 sildenafil citrate tablets were obtained for pharmaceutical analysis: 14 generic samples from international Internet pharmacy websites and the US innovator product. According to US Pharmacopeial guidelines, tablet samples were tested using high-performance liquid chromatography for potency of active pharmaceutical ingredient (API) and levels of impurities (impurities A, B, C, and D). Impurity levels were compared with International Conference on Harmonisation (ICH) limits. Results: Among the 15 samples, 4 samples possessed higher impurity B levels than the ICH qualification threshold, 8 samples possessed higher impurity C levels than the ICH qualification threshold, and 4 samples possessed more than 1% impurity quantity of maximum daily dose (MDD). For API, 6 of the samples failed to fall within the 5% assay limit. Conclusions: Quality assurance tests are often used to detect formulation defects of drug products during the manufacturing and/or storage process. Results suggest that manufacturing standards for sildenafil citrate generic drug products compared with the US innovator product are not equivalent with regards to potency and levels of impurities. These findings have implications for safety and effectiveness that should be addressed by clinicians to safeguard consumers who choose to purchase sildenafil citrate and foreign-manufactured drugs, in general, via the Internet. PMID:25360239

Long-term Results of an Analytical Assessment of Student Compounded Preparations

PubMed Central

Roark, Angie M.; Anksorus, Heidi N.

2014-01-01

Objective. To investigate the long-term (ie, 6-year) impact of a required remake vs an optional remake on student performance in a compounding laboratory course in which students’ compounded preparations were analyzed. Methods. The analysis data for several preparations made by students were compared for differences in the analyzed content of the active pharmaceutical ingredient (API) and the number of students who successfully compounded the preparation on the first attempt. Results. There was a consistent statistical difference in the API amount or concentration in 4 of the preparations (diphenhydramine, ketoprofen, metoprolol, and progesterone) in each optional remake year compared to the required remake year. As the analysis requirement was continued, the outcome for each preparation approached and/or attained the expected API result. Two preparations required more than 1 year to demonstrate a statistical difference. Conclusion. The analytical assessment resulted in a consistent, long-term improvement in student performance during the 5-year period after the optional remake policy was instituted. Our assumption is that investment in such an assessment would result in a similar benefits at other colleges and schools of pharmacy. PMID:26056402

Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression.

PubMed

Chattoraj, Sayantan; Sun, Changquan Calvin

2018-04-01

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Environmental contaminants of health-care origin: Exposure and potential effects in wildlife

USGS Publications Warehouse

Bean, Thomas; Rattner, Barnett A.

2018-01-01

A diverse range of fauna could be exposed to active pharmaceutical ingredients (APIs) via diet, dermal absorption or bioconcentration. Low level exposures of free-ranging wildlife to APIs has only been demonstrated for a few pathways (e.g., ingestion of fish in estuaries by piscivorous birds), and many remain hypothetical (e.g., ingestion of invertebrates in sludge amended fields by terrestrial vertebrates). Our understanding of API dose-response relationships in wildlife have only been assessed for endocrine disrupting compounds and a few veterinary therapeutics. Drug specific responses at various levels of biological organization are poorly characterized for nearly all wildlife species, and thus our understanding of risk is limited. There is interest in using a read-across approach to fill knowledge gaps for risk. This approach, using data collected in laboratory mammals and humans, would enable predictions for likelihood of adverse effects in wildlife. Given the great diversities in physiologies among species, a combination of in vivo, in vitro and in silico approaches will be required to fill the knowledge gaps for exposure, hazard and risk.

Long-term Results of an Analytical Assessment of Student Compounded Preparations.

PubMed

Roark, Angie M; Anksorus, Heidi N; Shrewsbury, Robert P

2014-11-15

To investigate the long-term (ie, 6-year) impact of a required remake vs an optional remake on student performance in a compounding laboratory course in which students' compounded preparations were analyzed. The analysis data for several preparations made by students were compared for differences in the analyzed content of the active pharmaceutical ingredient (API) and the number of students who successfully compounded the preparation on the first attempt. There was a consistent statistical difference in the API amount or concentration in 4 of the preparations (diphenhydramine, ketoprofen, metoprolol, and progesterone) in each optional remake year compared to the required remake year. As the analysis requirement was continued, the outcome for each preparation approached and/or attained the expected API result. Two preparations required more than 1 year to demonstrate a statistical difference. The analytical assessment resulted in a consistent, long-term improvement in student performance during the 5-year period after the optional remake policy was instituted. Our assumption is that investment in such an assessment would result in a similar benefits at other colleges and schools of pharmacy.

Biowaiver monographs for immediate release solid oral dosage forms: efavirenz.

PubMed

Cristofoletti, Rodrigo; Nair, Anita; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Dressman, Jennifer B

2013-02-01

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products. Copyright © 2012 Wiley Periodicals, Inc.

Transdermal Bioavailability in Rats of Lidocaine in the Forms of Ionic Liquids, Salts, and Deep Eutectic.

PubMed

Berton, Paula; Di Bona, Kristin R; Yancey, Denise; Rizvi, Syed A A; Gray, Marquita; Gurau, Gabriela; Shamshina, Julia L; Rasco, Jane F; Rogers, Robin D

2017-05-11

Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was dissolved in a vehicle cream and topically applied to Sprague-Dawley rats. The concentrations of the active pharmaceutical ingredients (APIs) in blood plasma were monitored over time as an indication of systemic absorption. The concentration of lidocaine in plasma varied between applied API-based creams, with faster and higher systemic absorption of the hydrogen bonded deep eutectic Lid·Ibu than the absorption of the salts [Lid]Cl or [Lid][Doc]. Interestingly, a differential transdermal absorption was observed between lidocaine and ibuprofen when Lid·Ibu was applied, possibly indicating different interactions with the tissue components.

Transdermal Bioavailability in Rats of Lidocaine in the Forms of Ionic Liquids, Salts, and Deep Eutectic

PubMed Central

2017-01-01

Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was dissolved in a vehicle cream and topically applied to Sprague–Dawley rats. The concentrations of the active pharmaceutical ingredients (APIs) in blood plasma were monitored over time as an indication of systemic absorption. The concentration of lidocaine in plasma varied between applied API-based creams, with faster and higher systemic absorption of the hydrogen bonded deep eutectic Lid·Ibu than the absorption of the salts [Lid]Cl or [Lid][Doc]. Interestingly, a differential transdermal absorption was observed between lidocaine and ibuprofen when Lid·Ibu was applied, possibly indicating different interactions with the tissue components. PMID:28523100

Direct visualization of in vitro drug mobilization from Lescol XL tablets using two-dimensional (19)F and (1)H magnetic resonance imaging.

PubMed

Chen, Chen; Gladden, Lynn F; Mantle, Michael D

2014-02-03

This article reports the application of in vitro multinuclear ((19)F and (1)H) two-dimensional magnetic resonance imaging (MRI) to study both dissolution media ingress and drug egress from a commercial Lescol XL extended release tablet in a United States Pharmacopeia Type IV (USP-IV) dissolution cell under pharmacopoeial conditions. Noninvasive spatial maps of tablet swelling and dissolution, as well as the mobilization and distribution of the drug are quantified and visualized. Two-dimensional active pharmaceutical ingredient (API) mobilization and distribution maps were obtained via (19)F MRI. (19)F API maps were coregistered with (1)H T2-relaxation time maps enabling the simultaneous visualization of drug distribution and gel layer dynamics within the swollen tablet. The behavior of the MRI data is also discussed in terms of its relationship to the UV drug release behavior.

Oil-in-oil-emulsions with enhanced substantivity for the treatment of chronic skin diseases.

PubMed

Lunter, Dominique Jasmin; Rottke, Michael; Daniels, Rolf

2014-05-01

The therapy of chronic skin diseases often requires several applications of creams or ointments per day. This is inconvenient to the patients and frequently leads to poor acceptance and compliance. We therefore developed oil-in-oil-emulsions that deliver the active pharmaceutical ingredient (API) to the skin over a prolonged period of time. In this study, we compare the permeation of the API from a conventional formulation to its permeation from an oil-in-oil-emulsion under infinite and finite dosing. Furthermore, we evaluate the substantivity of the formulations. Our results show that the permeation from oil-in-oil-emulsions is constant over a prolonged time and that the emulsions show significantly higher substantivity than conventional formulations. Because of that, the treatment intervals can be extended substantially and compliance can be increased. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop

PubMed Central

Duan, J; Kesisoglou, F; Novakovic, J; Amidon, GL; Jamei, M; Lukacova, V; Eissing, T; Tsakalozou, E; Zhao, L; Lionberger, R

2017-01-01

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled “Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation.”1 The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole‐body framework.2 PMID:28571121

Reliable and fast quantitative analysis of active ingredient in pharmaceutical suspension using Raman spectroscopy.

PubMed

Park, Seok Chan; Kim, Minjung; Noh, Jaegeun; Chung, Hoeil; Woo, Youngah; Lee, Jonghwa; Kemper, Mark S

2007-06-12

The concentration of acetaminophen in a turbid pharmaceutical suspension has been measured successfully using Raman spectroscopy. The spectrometer was equipped with a large spot probe which enabled the coverage of a representative area during sampling. This wide area illumination (WAI) scheme (coverage area 28.3 mm2) for Raman data collection proved to be more reliable for the compositional determination of these pharmaceutical suspensions, especially when the samples were turbid. The reproducibility of measurement using the WAI scheme was compared to that of using a conventional small-spot scheme which employed a much smaller illumination area (about 100 microm spot size). A layer of isobutyric anhydride was placed in front of the sample vials to correct the variation in the Raman intensity due to the fluctuation of laser power. Corrections were accomplished using the isolated carbonyl band of isobutyric anhydride. The acetaminophen concentrations of prediction samples were accurately estimated using a partial least squares (PLS) calibration model. The prediction accuracy was maintained even with changes in laser power. It was noted that the prediction performance was somewhat degraded for turbid suspensions with high acetaminophen contents. When comparing the results of reproducibility obtained with the WAI scheme and those obtained using the conventional scheme, it was concluded that the quantitative determination of the active pharmaceutical ingredient (API) in turbid suspensions is much improved when employing a larger laser coverage area. This is presumably due to the improvement in representative sampling.

The influence of direct compression powder blend transfer method from the container to the tablet press on product critical quality attributes: a case study.

PubMed

Teżyk, Michał; Jakubowska, Emilia; Milczewska, Kasylda; Milanowski, Bartłomiej; Voelkel, Adam; Lulek, Janina

2017-06-01

The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets' critical quality attributes (CQA). The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues. In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU. Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading. The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API's content and uniformity when compared to industrial gravitational transfer.

Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug.

PubMed

Lakshman, Jay P; Cao, Yu; Kowalski, James; Serajuddin, Abu T M

2008-01-01

Formulation of active pharmaceutical ingredients (API) in high-energy amorphous forms is a common strategy to enhance solubility, dissolution rate and, consequently, oral bioavailability of poorly water-soluble drugs. Amorphous APIs are, however, susceptible to recrystallization and, therefore, there is a need to physically stabilize them as solid dispersions in polymeric carriers. Hot melt extrusion has in recent years gained wide acceptance as a method of choice for the preparation of solid dispersions. There is a potential that the API, the polymer or both may degrade if excessively high temperature is needed in the melt extrusion process, especially when the melting point of the API is high. This report details a novel method where the API was first converted to an amorphous form by solvent evaporation and then melt-extruded with a suitable polymer at a drug load of at least 20% w/w. By this means, melt extrusion could be performed much below the melting temperature of the drug substance. Since the glass transition temperature of the amorphous drug was lower than that of the polymer used, the drug substance itself served as the plasticizer for the polymer. The addition of surfactants in the matrix enhanced dispersion and subsequent dissolution of the drug in aqueous media. The amorphous melt extrusion formulations showed higher bioavailability than formulations containing the crystalline API. There was no conversion of amorphous solid to its crystalline form during accelerated stability testing of dosage forms.

Development of a NIR-based blend uniformity method for a drug product containing multiple structurally similar actives by using the quality by design principles.

PubMed

Lin, Yiqing; Li, Weiyong; Xu, Jin; Boulas, Pierre

2015-07-05

The aim of this study is to develop an at-line near infrared (NIR) method for the rapid and simultaneous determination of four structurally similar active pharmaceutical ingredients (APIs) in powder blends intended for the manufacturing of tablets. Two of the four APIs in the formula are present in relatively small amounts, one at 0.95% and the other at 0.57%. Such small amounts in addition to the similarity in structures add significant complexity to the blend uniformity analysis. The NIR method is developed using spectra from six laboratory-created calibration samples augmented by a small set of spectra from a large-scale blending sample. Applying the quality by design (QbD) principles, the calibration design included concentration variations of the four APIs and a main excipient, microcrystalline cellulose. A bench-top FT-NIR instrument was used to acquire the spectra. The obtained NIR spectra were analyzed by applying principal component analysis (PCA) before calibration model development. Score patterns from the PCA were analyzed to reveal relationship between latent variables and concentration variations of the APIs. In calibration model development, both PLS-1 and PLS-2 models were created and evaluated for their effectiveness in predicting API concentrations in the blending samples. The final NIR method shows satisfactory specificity and accuracy. Copyright © 2015 Elsevier B.V. All rights reserved.

An Algorithm to Identify Compounded Non-Sterile Products that Can Be Formulated on a Commercial Scale or Imported to Promote Safer Medication Use in Children

PubMed Central

Bhatt-Mehta, Varsha; MacArthur, Robert B.; Löbenberg, Raimar; Cies, Jeffrey J.; Cernak, Ibolja; Parrish, Richard H.

2015-01-01

The lack of commercially-available pediatric drug products and dosage forms is well-known. A group of clinicians and scientists with a common interest in pediatric drug development and medicines-use systems developed a practical framework for identifying a list of active pharmaceutical ingredients (APIs) with the greatest market potential for development to use in pediatric patients. Reliable and reproducible evidence-based drug formulations designed for use in pediatric patients are needed vitally, otherwise safe and consistent clinical practices and outcomes assessments will continue to be difficult to ascertain. Identification of a prioritized list of candidate APIs for oral formulation using the described algorithm provides a broader integrated clinical, scientific, regulatory, and market basis to allow for more reliable dosage forms and safer, effective medicines use in children of all ages. Group members derived a list of candidate API molecules by factoring in a number of pharmacotherapeutic, scientific, manufacturing, and regulatory variables into the selection algorithm that were absent in other rubrics. These additions will assist in identifying and categorizing prime API candidates suitable for oral formulation development. Moreover, the developed algorithm aids in prioritizing useful APIs with finished oral liquid dosage forms available from other countries with direct importation opportunities to North America and beyond. PMID:28975916

On Identification of Critical Material Attributes for Compression Behaviour of Pharmaceutical Diluent Powders

PubMed Central

Zhang, Jianyi; Pan, Xin; Wu, Chuanbin

2017-01-01

As one of the commonly-used solid dosage forms, pharmaceutical tablets have been widely used to deliver active drugs into the human body, satisfying patient’s therapeutic requirements. To manufacture tablets of good quality, diluent powders are generally used in formulation development to increase the bulk of formulations and to bind other inactive ingredients with the active pharmaceutical ingredients (APIs). For formulations of a low API dose, the drug products generally consist of a large fraction of diluent powders. Hence, the attributes of diluents become extremely important and can significantly influence the final product property. Therefore, it is essential to accurately characterise the mechanical properties of the diluents and to thoroughly understand how their mechanical properties affect the manufacturing performance and properties of the final products, which will build a sound scientific basis for formulation design and product development. In this study, a comprehensive evaluation of the mechanical properties of the widely-used pharmaceutical diluent powders, including microcrystalline cellulose (MCC) powders with different grades (i.e., Avicel PH 101, Avicel PH 102, and DG), mannitol SD 100, lactose monohydrate, and dibasic calcium phosphate, were performed. The powder compressibility was assessed with Heckel and Kawakita analyses. The material elastic recovery during decompression and in storage was investigated through monitoring the change in the dimensions of the compressed tablets over time. The powder hygroscopicity was also evaluated to examine the water absorption ability of powders from the surroundings. It was shown that the MCC tablets exhibited continuous volume expansion after ejection, which is believed to be induced by (1) water absorption from the surrounding, and (2) elastic recovery. However, mannitol tablets showed volume expansion immediately after ejection, followed by the material shrinkage in storage. It is anticipated that the expansion was induced by elastic recovery to a limited extent, while the shrinkage was primarily due to the solidification during storage. It was also found that, for all powders considered, the powder compressibility and the elastic recovery depended significantly on the particle breakage tendency: a decrease in the particle breakage tendency led to a slight decrease in the powder compressibility and a significant drop in immediate elastic recovery. This implies that the particle breakage tendency is a critical material attribute in controlling the compression behaviour of pharmaceutical powders. PMID:28773204

Trends in pharmaceutical taste masking technologies: a patent review.

PubMed

Ayenew, Zelalem; Puri, Vibha; Kumar, Lokesh; Bansal, Arvind K

2009-01-01

According to the year 2003 survey of pediatricians by the American Association of Pediatrics, unpleasant taste was the biggest barrier for completing treatment in pediatrics. The field of taste masking of active pharmaceutical ingredients (API) has been continuously evolving with varied technologies and new excipients. The article reviews the trends in taste masking technologies by studying the current state of the art patent database for the span of year 1997 to 2007. The worldwide database of European patent office (http://ep.espacenet.com) was employed to collect the patents and patent applications. It also discusses the possible reasons for the change of preferences in the taste masking technologies with time. The prime factors critical to the selection of an optimal taste masking technique such as the extent of drug bitterness, solubility, particle characteristics, dosage form and dose are briefly discussed.

Towards quality by design in pharmaceutical manufacturing: modelling and control of air jet mills

NASA Astrophysics Data System (ADS)

Bhonsale, Satyajeet; Telen, Dries; Stokbroekx, Bard; Van Impe, Jan

2017-06-01

Milling is an important step in pharmaceutical manufacturing as it not only determines the final formulation of the drug product, but also influences the bioavailability and dissolution rate of the active pharmaceutical ingredient (API). In this respect, the air jet mill (AJM) is most commonly used in the pharmaceutical industry as it is a non-contaminating and non-degrading self-classifying process capable of delivering narrow particle size distributions (PSD). Keeping the principles of Quality by Design in mind, the Critical Process Parameters (CPPs) of the AJM have been identified to be the pressures at the grinding nozzles, and the feed rate which affect the PSD, surface charge and the morphology of the product (i.e. the Critical Material Attributes (CMAs)). For the purpose of this research, the PSD is considered to be the only relevant CMA. A population balance based model is proposed to simulate the dynamics milling operation by utilizing the concept of breakage functions. This model agrees qualitatively with experimental observations of the air jet mill unit present at Janssen Pharmaceutica but further steps for model validation need to be carried out.

Investigation into the Manufacture and Properties of Inhalable High-Dose Dry Powders Produced by Comilling API and Lactose with Magnesium Stearate.

PubMed

Lau, Michael; Young, Paul M; Traini, Daniela

2017-08-01

The aim of the study was to understand the impact of different concentrations of the additive material, magnesium stearate (MGST), and the active pharmaceutical ingredient (API), respectively, on the physicochemical properties and aerosol performance of comilled formulations for high-dose delivery. Initially, blends of API/lactose with different concentrations of MGST (1-7.5% w/w) were prepared and comilled by the jet-mill apparatus. The optimal concentration of MGST in comilled formulations was investigated, specifically for agglomerate structure and strength, particle size, uniformity of content, surface coverage, and aerosol performance. Secondly, comilled formulations with different API (1-40% w/w) concentrations were prepared and similarly analyzed. Comilled 5% MGST (w/w) formulation resulted in a significant improvement in in vitro aerosol performance due to the reduction in agglomerate size and strength compared to the formulation comilled without MGST. Higher concentrations of MGST (7.5% w/w) led to reduction in aerosol performance likely due to excessive surface coverage of the micronized particles by MGST, which led to failure in uniformity of content and an increase in agglomerate strength and size. Generally, comilled formulations with higher concentrations of API increased the agglomerate strength and size, which subsequently caused a reduction in aerosol performance. High-dose delivery was achieved at API concentration of >20% (w/w). The study provided a platform for the investigation of aerosol performance and physicochemical properties of other API and additive materials in comilled formulations for the emerging field of high-dose delivery by dry powder inhalation.

Probing the particulate microstructure of the aerodynamic particle size distribution of dry powder inhaler combination products.

PubMed

Jetzer, M W; Morrical, B D; Schneider, M; Edge, S; Imanidis, G

2018-03-01

The in-vitro aerosol performance of two combination dry powder inhaler (DPI) products, Foster ® NEXThaler ® and Seretide ® Diskus ® were investigated with single particle aerosol mass spectrometry (SPAMS). The in-vitro pharmaceutical performance is markedly different for both inhalers. Foster ® NEXThaler ® generates a higher fine particle fraction (FPF <5 μm) and a much higher relative extra fine particle fraction (eFPF <2 μm). In terms of the composition of the aerodynamic particle size distribution (APSD), it could be verified with SPAMS that overall Foster ® NEXThaler ® emits a significantly higher number of fine and extra fine particles with a median aerodynamic diameter (MAD) of 2.1 μm while Seretide ® Diskus ® had a larger MAD of 3.1 μm. Additionally, the interactions between the two active pharmaceutical ingredients (APIs) in both products are different. While Seretide ® Diskus ® emits a significant (37%) number of co-associated API particles, only a negligible number of co-associated API particles were found in Foster ® NEXThaler ® (<1%). A major difference with Foster ® NEXThaler ® is that it contains magnesium stearate (MgSt) as a second excipient besides lactose in a so-called 'dual excipient' platform. The data generated using SPAMS suggested that nearly all of the beclomethasone dipropionate particles in Foster ® NEXThaler ® also contain MgSt and must therefore be co-associated with this additional excipient. This may help explain why beclomethasone dipropionate in Foster ® NEXThaler ® forms less particle co-associations with the second API, formoterol fumarate, shows a lower cohesive strength in respect to beclomethasone itself and why both APIs exhibit superior detachment from the carrier as evidenced by the increased eFPF and smaller MAD. Copyright © 2018 Elsevier B.V. All rights reserved.

Raman spectroscopy as a PAT for pharmaceutical blending: Advantages and disadvantages.

PubMed

Riolo, Daniela; Piazza, Alessandro; Cottini, Ciro; Serafini, Margherita; Lutero, Emilio; Cuoghi, Erika; Gasparini, Lorena; Botturi, Debora; Marino, Iari Gabriel; Aliatis, Irene; Bersani, Danilo; Lottici, Pier Paolo

2018-02-05

Raman spectroscopy has been positively evaluated as a tool for the in-line and real-time monitoring of powder blending processes and it has been proved to be effective in the determination of the endpoint of the mixing, showing its potential role as process analytical technology (PAT). The aim of this study is to show advantages and disadvantages of Raman spectroscopy with respect to the most traditional HPLC analysis. The spectroscopic results, obtained directly on raw powders, sampled from a two-axis blender in real case conditions, were compared with the chromatographic data obtained on the same samples. The formulation blend used for the experiment consists of active pharmaceutical ingredient (API, concentrations 6.0% and 0.5%), lactose and magnesium stearate (as excipients). The first step of the monitoring process was selecting the appropriate wavenumber region where the Raman signal of API is maximal and interference from the spectral features of excipients is minimal. Blend profiles were created by plotting the area ratios of the Raman peak of API (A API ) at 1598cm -1 and the Raman bands of excipients (A EXC ), in the spectral range between 1560 and 1630cm -1 , as a function of mixing time: the API content can be considered homogeneous when the time-dependent dispersion of the area ratio is minimized. In order to achieve a representative sampling with Raman spectroscopy, each sample was mapped in a motorized XY stage by a defocused laser beam of a micro-Raman apparatus. Good correlation between the two techniques has been found only for the composition at 6.0% (w/w). However, standard deviation analysis, applied to both HPLC and Raman data, showed that Raman results are more substantial than HPLC ones, since Raman spectroscopy enables generating data rich blend profiles. In addition, the relative standard deviation calculated from a single map (30 points) turned out to be representative of the degree of homogeneity for that blend time. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel medium-throughput technique for investigating drug-cyclodextrin complexation by pH-metric titration using the partition coefficient method.

PubMed

Dargó, Gergő; Boros, Krisztina; Péter, László; Malanga, Milo; Sohajda, Tamás; Szente, Lajos; Balogh, György T

2018-05-05

The present study was aimed to develop a medium-throughput screening technique for investigation of cyclodextrin (CD)-active pharmaceutical ingredient (API) complexes. Dual-phase potentiometric lipophilicity measurement, as gold standard technique, was combined with the partition coefficient method (plotting the reciprocal of partition coefficients of APIs as a function of CD concentration). A general equation was derived for determination of stability constants of 1:1 CD-API complexes (K 1:1,CD ) based on solely the changes of partition coefficients (logP o/w N -logP app N ), without measurement of the actual API concentrations. Experimentally determined logP value (-1.64) of 6-deoxy-6[(5/6)-fluoresceinylthioureido]-HPBCD (FITC-NH-HPBCD) was used to estimate the logP value (≈ -2.5 to -3) of (2-hydroxypropyl)-ß-cyclodextrin (HPBCD). The results suggested that the amount of HPBCD can be considered to be inconsequential in the octanol phase. The decrease of octanol volume due to the octanol-CD complexation was considered, thus a corrected octanol-water phase ratio was also introduced. The K 1:1,CD values obtained by this developed method showed a good accordance with the results from other orthogonal methods. Copyright © 2018 Elsevier B.V. All rights reserved.

Formulation design of oral pediatric Acetazolamide suspension: dose uniformity and physico-chemical stability study.

PubMed

Santoveña, Ana; Suárez-González, Javier; Martín-Rodríguez, Cristina; Fariña, José B

2017-03-01

The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

Following the surface response of caffeine cocrystals to controlled humidity storage by atomic force microscopy.

PubMed

Cassidy, A M C; Gardner, C E; Jones, W

2009-09-08

Active pharmaceutical ingredient (API) stability in solid state tablet formulation is frequently a function of the relative humidity (RH) environment in which the drug is stored. Caffeine is one such problematic API. Previously reported caffeine cocrystals, however, were found to offer increased resistance to caffeine hydrate formation. Here we report on the use of atomic force microscopy (AFM) to image the surface of two caffeine cocrystal systems to look for differences between the surface and bulk response of the cocrystal to storage in controlled humidity environments. Bulk responses have previously been assessed by powder X-ray diffraction. With AFM, pinning sites were identified at step edges on caffeine/oxalic acid, with these sites leading to non-uniform step movement on going from ambient to 0% RH. At RH >75%, areas of fresh crystal growth were seen on the cocrystal surface. In the case of caffeine/malonic acid the cocrystals were observed to absorb water anisotropically after storage at 75% RH for 2 days, affecting the surface topography of the cocrystal. These results show that AFM expands on the data gathered by bulk analytical techniques, such as powder X-ray diffraction, by providing localised surface information. This surface information may be important for better predicting API stability in isolation and at a solid state API-excipient interface.

An innovative method for the preparation of high API-loaded hollow spherical granules for use in controlled-release formulation.

PubMed

Asada, Takumi; Kobiki, Mitsuaki; Ochiai, Yasushi; Iwao, Yasunori; Itai, Shigeru

2017-05-15

The aim of this study was to prepare controlled-release (CR) granules with suitable particle strength, flowability, particle size distribution (PSD) and density characteristics for blending with other excipients. We also wanted these CR granules to contain large quantities of active pharmaceutical ingredient (API). A high shear mixer was used to mix an API with various polymers at various feed ratios, and the resulting granulated materials were sprayed with solvent. The wet granules were dried using a fluidized bed dryer to give CR granules. The API content of the granules was determined to be 95wt%. The granules were found to be spherical in shape with smooth surfaces by scanning electron microscopy. The inner structure of each granule was determined to be hollow by X-ray computed tomography, highlighting the unusual mechanism of this granulation process. The PSD of the granules was found to be dependent on that of the constituent polymer, and a narrow PSD was obtained by adjusting the PSD of the polymer. The dissolution profile of the granules was also dependent on the constituent polymer. Taken together, these results show that we have successfully developed a new manufacturing technology for the simple and low-cost preparation of ideal CR granules. Copyright © 2017 Elsevier B.V. All rights reserved.

Ultrasound-assisted powder-coating technique to improve content uniformity of low-dose solid dosage forms.

PubMed

Genina, Natalja; Räikkönen, Heikki; Antikainen, Osmo; Heinämäki, Jyrki; Yliruusi, Jouko

2010-09-01

An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.

Applications and limitations of lipid nanoparticles in dermal and transdermal drug delivery via the follicular route.

PubMed

Lauterbach, Andreas; Müller-Goymann, Christel C

2015-11-01

Lipid nanoparticles (LN) such as solid lipid nanoparticles (SLN) and nanolipid carriers (NLC) feature several claimed benefits for topical drug therapy including biocompatible ingredients, drug release modification, adhesion to the skin, and film formation with subsequent hydration of the superficial skin layers. However, penetration and permeation into and across deeper skin layers are restricted due to the barrier function of the stratum corneum (SC). As different kinds of nanoparticles provide the potential for penetration into hair follicles (HF) LN are applicable drug delivery systems (DDS) for this route in order to enhance the dermal and transdermal bioavailability of active pharmaceutical ingredients (API). Therefore, this review addresses the HF as application site, published formulations of LN which showed follicular penetration (FP), and characterization methods in order to identify and quantify the accumulation of API delivered by the LN in the HF. Since LN are based on lipids that appear in human sebum which is the predominant medium in HF an increased localization of the colloidal carriers as well as a promoted drug release may be assumed. Therefore, sebum-like lipid material and a size of less or equal 640 nm are appropriate specifications for FP of particulate formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

Influence of formulation and processing factors on stability of levothyroxine sodium pentahydrate.

PubMed

Collier, Jarrod W; Shah, Rakhi B; Gupta, Abhay; Sayeed, Vilayat; Habib, Muhammad J; Khan, Mansoor A

2010-06-01

Stability of formulations over shelf-life is critical for having a quality product. Choice of excipients, manufacturing process, storage conditions, and packaging can either mitigate or enhance the degradation of the active pharmaceutical ingredient (API), affecting potency and/or stability. The purpose was to investigate the influence of processing and formulation factors on stability of levothyroxine (API). The API was stored at long-term (25 degrees C/60%RH), accelerated (40 degrees C/75%RH), and low-humidity (25 degrees C/0%RH and 40 degrees C/0%RH) conditions for 28 days. Effect of moisture loss was evaluated by drying it (room temperature, N(2)) and placed at 25 degrees C/0%RH and 40 degrees C/0%RH. The API was incubated with various excipients (based on package insert of marketed tablets) in either 1:1, 1:10, or 1:100 ratios with 5% moisture at 60 degrees C. Commonly used ratios for excipients were used. The equilibrium sorption data was collected on the API and excipients. The API was stable in solid state for the study duration under all conditions for both forms (potency between 90% and 110%). Excipients effect on stability varied and crospovidone, povidone, and sodium laurel sulfate (SLS) caused significant API degradation where deiodination and deamination occurred. Moisture sorption values were different across excipients. Crospovidone and povidone were hygroscopic whereas SLS showed deliquescence at high RH. The transient formulation procedures where temperature might go up or humidity might go down would not have major impact on the API stability. Excipients influence stability and if possible, those three should either be avoided or used in minimum quantity which could provide more stable tablet formulations with minimum potency loss throughout its shelf-life.

Rheology Guided Rational Selection of Processing Temperature To Prepare Copovidone-Nifedipine Amorphous Solid Dispersions via Hot Melt Extrusion (HME).

PubMed

Yang, Fengyuan; Su, Yongchao; Zhang, Jingtao; DiNunzio, James; Leone, Anthony; Huang, Chengbin; Brown, Chad D

2016-10-03

The production of amorphous solid dispersions via hot melt extrusion (HME) relies on elevated temperature and prolonged residence time, which can result in potential degradation and decomposition of thermally sensitive components. Herein, the rheological properties of a physical mixture of polymer and an active pharmaceutical ingredient (API) were utilized to guide the selection of appropriate HME processing temperature. In the currently studied copovidone-nifedipine system, a critical temperature, which is substantially lower (∼13 °C) than the melting point of crystalline API, was captured during a temperature ramp examination and regarded as the critical point at which the API could molecularly dissolve into the polymer. Based on the identification of this critical point, various solid dispersions were prepared by HME processing below, at, and above the critical temperature (both below and above the melting temperature (T m ) of crystalline API). In addition, the resultant extrudates along with two control solid dispersions prepared by physical mixing and cryogenic milling were assessed by X-ray diffraction, differential scanning calorimetry, hot stage microscopy, rheology, and solid-state NMR. Physicochemical properties of resultant solid dispersions indicated that the identified critical temperature is sufficient for the polymer-API system to reach a molecular-level mixing, manifested by the transparent and smooth appearance of extrudates, the absence of API crystalline diffraction and melting peaks, dramatically decreased rheological properties, and significantly improved polymer-API miscibility. Once the critical temperature has been achieved, further raising the processing temperature only results in limited improvement of API dispersion, reflected by slightly reduced storage modulus and complex viscosity and limited improvement in miscibility.

Manufacturing Amorphous Solid Dispersions with a Tailored Amount of Crystallized API for Biopharmaceutical Testing.

PubMed

Theil, Frank; Milsmann, Johanna; Anantharaman, Sankaran; van Lishaut, Holger

2018-05-07

The preparation of an amorphous solid dispersion (ASD) by dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can improve the bioavailability by orders of magnitude. Crystallization of the API in the ASD, though, is an inherent threat for bioavailability. Commonly, the impact of crystalline API on the drug release of the dosage form is studied with samples containing spiked crystallinity. These spiked samples possess implicit differences compared to native crystalline samples, regarding size and spatial distribution of the crystals as well as their molecular environment. In this study, we demonstrate that it is possible to grow defined amounts of crystalline API in solid dosage forms, which enables us to study the biopharmaceutical impact of actual crystallization. For this purpose, we studied the crystal growth in fenofibrate tablets over time under an elevated moisture using transmission Raman spectroscopy (TRS). As a nondestructive method to assess API crystallinity in ASD formulations, TRS enables the monitoring of crystal growth in individual dosage forms. Once the kinetic trace of the crystal growth for a certain environmental condition is determined, this method can be used to produce samples with defined amounts of crystallized API. To investigate the biopharmaceutical impact of crystallized API, non-QC dissolution methods were used, designed to identify differences between the various amounts of crystalline materials present. The drug release in the samples manufactured in this fashion was compared to that of samples with spiked crystallinity. In this study, we present for the first time a method for targeted crystallization of amorphous tablets to simulate crystallized ASDs. This methodology is a valuable tool to generate model systems for biopharmaceutical studies on the impact of crystallinity on the bioavailability.

Best Practices in Stability Indicating Method Development and Validation for Non-clinical Dose Formulations.

PubMed

Henry, Teresa R; Penn, Lara D; Conerty, Jason R; Wright, Francesca E; Gorman, Gregory; Pack, Brian W

2016-11-01

Non-clinical dose formulations (also known as pre-clinical or GLP formulations) play a key role in early drug development. These formulations are used to introduce active pharmaceutical ingredients (APIs) into test organisms for both pharmacokinetic and toxicological studies. Since these studies are ultimately used to support dose and safety ranges in human studies, it is important to understand not only the concentration and PK/PD of the active ingredient but also to generate safety data for likely process impurities and degradation products of the active ingredient. As such, many in the industry have chosen to develop and validate methods which can accurately detect and quantify the active ingredient along with impurities and degradation products. Such methods often provide trendable results which are predictive of stability, thus leading to the name; stability indicating methods. This document provides an overview of best practices for those choosing to include development and validation of such methods as part of their non-clinical drug development program. This document is intended to support teams who are either new to stability indicating method development and validation or who are less familiar with the requirements of validation due to their position within the product development life cycle.

Stability of benzocaine formulated in commercial oral disintegrating tablet platforms.

PubMed

Köllmer, Melanie; Popescu, Carmen; Manda, Prashanth; Zhou, Leon; Gemeinhart, Richard A

2013-12-01

Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25°C and 60% relative humidity (RH), or under accelerated conditions, 40°C and 75% RH. Benzocaine degradation was monitored by liquid chromatography-mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25°C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions.

Formulation development and process analysis of drug-loaded filaments manufactured via hot-melt extrusion for 3D-printing of medicines.

PubMed

Korte, Carolin; Quodbach, Julian

2018-02-09

Three dimensional(3D)-printing via fused deposition modeling (FDM) allows the production of individualized solid dosage forms. However, for bringing this benefit to the patient, active pharmaceutical ingredient (API)-loaded filaments of pharmaceutical grade excipients are necessary as feedstock and have to be produced industrially. As large-scale production of API-loaded filaments has not been described in literature, this study presents a development of 3D-printable filaments, which can continuously be produced via hot-melt extrusion. Further, a combination of testing methods for mechanical resilience of filaments was applied to improve the prediction of their printability. Eudragit RL was chosen as a sustained release polymer and theophylline (30%) as thermally stable model drug. Stearic acid (7%) and polyethylene glycol 4000 (10%), were evaluated as suitable plasticizers for producing 3D-printable filaments. The two formulations were printed into solid dosage forms and analyzed regarding their dissolution profiles. This revealed that stearic acid maintained sustained release properties of the matrix whereas polyethylene glycol 4000 did not. Analysis of the continuous extrusion process was done using a design of experiments. It showed that powder feed rate and speed of the stretching device used after extrusion predominantly determine the diameter of the filament and thereby the mechanical resilience of a filament.

Measurement of residual solvents in a drug substance by a purge-and-trap method.

PubMed

Lakatos, Miklós

2008-08-05

The purge-and-trap (P&T) gas extraction method combined with gas chromatography was studied for its suitability for quantitative residual solvents determination in a water-soluble active pharmaceutical ingredient (API). Some analytical method performance characteristics were investigated, namely, the repeatability, the accuracy and the detection limit of determination. The results show that the P&T technique is--as expected--more sensitive than the static headspace, thus it can be used for the determination of residual solvents pertaining to the ICH Class 1 group. It was found that it could be an alternative sample preparation method besides the static headspace (HS) method.

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

PubMed Central

2015-01-01

Summary The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process. PMID:26425178

Recent Advances in Lipase-Mediated Preparation of Pharmaceuticals and Their Intermediates

PubMed Central

Carvalho, Ana Caroline Lustosa de Melo; Fonseca, Thiago de Sousa; de Mattos, Marcos Carlos; de Oliveira, Maria da Conceição Ferreira; de Lemos, Telma Leda Gomes; Molinari, Francesco; Romano, Diego; Serra, Immacolata

2015-01-01

Biocatalysis offers an alternative approach to conventional chemical processes for the production of single-isomer chiral drugs. Lipases are one of the most used enzymes in the synthesis of enantiomerically pure intermediates. The use of this type of enzyme is mainly due to the characteristics of their regio-, chemo- and enantioselectivity in the resolution process of racemates, without the use of cofactors. Moreover, this class of enzymes has generally excellent stability in the presence of organic solvents, facilitating the solubility of the organic substrate to be modified. Further improvements and new applications have been achieved in the syntheses of biologically active compounds catalyzed by lipases. This review critically reports and discusses examples from recent literature (2007 to mid-2015), concerning the synthesis of enantiomerically pure active pharmaceutical ingredients (APIs) and their intermediates in which the key step involves the action of a lipase. PMID:26690428

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry.

PubMed

Baumann, Marcus; Baxendale, Ian R

2015-01-01

The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process.

A risk-based statistical investigation of the quantification of polymorphic purity of a pharmaceutical candidate by solid-state 19F NMR.

PubMed

Barry, Samantha J; Pham, Tran N; Borman, Phil J; Edwards, Andrew J; Watson, Simon A

2012-01-27

The DMAIC (Define, Measure, Analyse, Improve and Control) framework and associated statistical tools have been applied to both identify and reduce variability observed in a quantitative (19)F solid-state NMR (SSNMR) analytical method. The method had been developed to quantify levels of an additional polymorph (Form 3) in batches of an active pharmaceutical ingredient (API), where Form 1 is the predominant polymorph. In order to validate analyses of the polymorphic form, a single batch of API was used as a standard each time the method was used. The level of Form 3 in this standard was observed to gradually increase over time, the effect not being immediately apparent due to method variability. In order to determine the cause of this unexpected increase and to reduce method variability, a risk-based statistical investigation was performed to identify potential factors which could be responsible for these effects. Factors identified by the risk assessment were investigated using a series of designed experiments to gain a greater understanding of the method. The increase of the level of Form 3 in the standard was primarily found to correlate with the number of repeat analyses, an effect not previously reported in SSNMR literature. Differences in data processing (phasing and linewidth) were found to be responsible for the variability in the method. After implementing corrective actions the variability was reduced such that the level of Form 3 was within an acceptable range of ±1% ww(-1) in fresh samples of API. Copyright © 2011. Published by Elsevier B.V.

The interaction of a model active pharmaceutical with cationic surfactant and the subsequent design of drug based ionic liquid surfactants.

PubMed

Qamar, Sara; Brown, Paul; Ferguson, Steven; Khan, Rafaqat Ali; Ismail, Bushra; Khan, Abdur Rahman; Sayed, Murtaza; Khan, Asad Muhammad

2016-11-01

Interactions of active pharmaceutical ingredients (API) with surfactants remain an important research area due to the need to improve drug delivery systems. In this study, UV-Visible spectrophotometry was used to investigate the interactions between a model low molecular weight hydrophilic drug sodium valproate (SV) and cationic surfactant cetyltrimethylammonium bromide (CTAB). Changes in the spectra of SV were observed in pre- and post-micellar concentrations of CTAB. The binding constant (Kb) values and the number of drug molecules encapsulated per micelle were calculated, which posed the possibility of mixed micelle formation and strong complexation between SV and CTAB. These results were compared to those of a novel room temperature surface active ionic liquid, which was synthesized by the removal of inorganic counterions from a 1:1 mixture of CTAB and SV. In this new compound the drug now constitutes a building block of the carrier and, as such, has considerably different surfactant properties to its building blocks. In addition, enhanced solubility in a range of solvents, including simulated gastric fluid, was observed. The study provides valuable experimental evidence concerning the performance of drug based surfactant ionic liquids and how their chemical manipulation, without altering the architecture of the API, leads to control of surfactant behavior and physicochemical properties. In turn, this should feed through to improved and controlled drug release rates and delivery mechanisms, and the prevention of precipitation or formation of polymorphs typical of crystalline form APIs. Copyright © 2016 Elsevier Inc. All rights reserved.

Kinetic Modeling of Accelerated Stability Testing Enabled by Second Harmonic Generation Microscopy.

PubMed

Song, Zhengtian; Sarkar, Sreya; Vogt, Andrew D; Danzer, Gerald D; Smith, Casey J; Gualtieri, Ellen J; Simpson, Garth J

2018-04-03

The low limits of detection afforded by second harmonic generation (SHG) microscopy coupled with image analysis algorithms enabled quantitative modeling of the temperature-dependent crystallization of active pharmaceutical ingredients (APIs) within amorphous solid dispersions (ASDs). ASDs, in which an API is maintained in an amorphous state within a polymer matrix, are finding increasing use to address solubility limitations of small-molecule APIs. Extensive stability testing is typically performed for ASD characterization, the time frame for which is often dictated by the earliest detectable onset of crystal formation. Here a study of accelerated stability testing on ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, has been conducted. Under the condition for accelerated stability testing at 50 °C/75%RH and 40 °C/75%RH, ritonavir crystallization kinetics from amorphous solid dispersions were monitored by SHG microscopy. SHG microscopy coupled by image analysis yielded limits of detection for ritonavir crystals as low as 10 ppm, which is about 2 orders of magnitude lower than other methods currently available for crystallinity detection in ASDs. The four decade dynamic range of SHG microscopy enabled quantitative modeling with an established (JMAK) kinetic model. From the SHG images, nucleation and crystal growth rates were independently determined.

Development of Process Analytical Technology (PAT) methods for controlled release pellet coating.

PubMed

Avalle, P; Pollitt, M J; Bradley, K; Cooper, B; Pearce, G; Djemai, A; Fitzpatrick, S

2014-07-01

This work focused on the control of the manufacturing process for a controlled release (CR) pellet product, within a Quality by Design (QbD) framework. The manufacturing process was Wurster coating: firstly layering active pharmaceutical ingredient (API) onto sugar pellet cores and secondly a controlled release (CR) coating. For each of these two steps, development of a Process Analytical Technology (PAT) method is discussed and also a novel application of automated microscopy as the reference method. Ultimately, PAT methods should link to product performance and the two key Critical Quality Attributes (CQAs) for this CR product are assay and release rate, linked to the API and CR coating steps respectively. In this work, the link between near infra-red (NIR) spectra and those attributes was explored by chemometrics over the course of the coating process in a pilot scale industrial environment. Correlations were built between the NIR spectra and coating weight (for API amount), CR coating thickness and dissolution performance. These correlations allow the coating process to be monitored at-line and so better control of the product performance in line with QbD requirements. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimization of Premix Powders for Tableting Use.

PubMed

Todo, Hiroaki; Sato, Kazuki; Takayama, Kozo; Sugibayashi, Kenji

2018-05-08

Direct compression is a popular choice as it provides the simplest way to prepare the tablet. It can be easily adopted when the active pharmaceutical ingredient (API) is unstable in water or to thermal drying. An optimal formulation of preliminary mixed powders (premix powders) is beneficial if prepared in advance for tableting use. The aim of this study was to find the optimal formulation of the premix powders composed of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) by using statistical techniques. Based on the "Quality by Design" concept, a (3,3)-simplex lattice design consisting of three components, LAC, CS, and MCC was employed to prepare the model premix powders. Response surface method incorporating a thin-plate spline interpolation (RSM-S) was applied for estimation of the optimum premix powders for tableting use. The effect of tablet shape identified by the surface curvature on the optimization was investigated. The optimum premix powder was effective when the premix was applied to a small quantity of API, although the function of premix was limited in the case of the formulation of large amount of API. Statistical techniques are valuable to exploit new functions of well-known materials such as LAC, CS, and MCC.

Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector—Results from a Nationally Representative Outlet Survey

PubMed Central

2015-01-01

Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85–115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential. PMID:25897065

Predicting concentrations of trace organic compounds in municipal wastewater treatment plant sludge and biosolids using the PhATE™ model.

PubMed

Cunningham, Virginia L; D'Aco, Vincent J; Pfeiffer, Danielle; Anderson, Paul D; Buzby, Mary E; Hannah, Robert E; Jahnke, James; Parke, Neil J

2012-07-01

This article presents the capability expansion of the PhATE™ (pharmaceutical assessment and transport evaluation) model to predict concentrations of trace organics in sludges and biosolids from municipal wastewater treatment plants (WWTPs). PhATE was originally developed as an empirical model to estimate potential concentrations of active pharmaceutical ingredients (APIs) in US surface and drinking waters that could result from patient use of medicines. However, many compounds, including pharmaceuticals, are not completely transformed in WWTPs and remain in biosolids that may be applied to land as a soil amendment. This practice leads to concerns about potential exposures of people who may come into contact with amended soils and also about potential effects to plants and animals living in or contacting such soils. The model estimates the mass of API in WWTP influent based on the population served, the API per capita use, and the potential loss of the compound associated with human use (e.g., metabolism). The mass of API on the treated biosolids is then estimated based on partitioning to primary and secondary solids, potential loss due to biodegradation in secondary treatment (e.g., activated sludge), and potential loss during sludge treatment (e.g., aerobic digestion, anaerobic digestion, composting). Simulations using 2 surrogate compounds show that predicted environmental concentrations (PECs) generated by PhATE are in very good agreement with measured concentrations, i.e., well within 1 order of magnitude. Model simulations were then carried out for 18 APIs representing a broad range of chemical and use characteristics. These simulations yielded 4 categories of results: 1) PECs are in good agreement with measured data for 9 compounds with high analytical detection frequencies, 2) PECs are greater than measured data for 3 compounds with high analytical detection frequencies, possibly as a result of as yet unidentified depletion mechanisms, 3) PECs are less than analytical reporting limits for 5 compounds with low analytical detection frequencies, and 4) the PEC is greater than the analytical method reporting limit for 1 compound with a low analytical detection frequency, possibly again as a result of insufficient depletion data. Overall, these results demonstrate that PhATE has the potential to be a very useful tool in the evaluation of APIs in biosolids. Possible applications include: prioritizing APIs for assessment even in the absence of analytical methods; evaluating sludge processing scenarios to explore potential mitigation approaches; using in risk assessments; and developing realistic nationwide concentrations, because PECs can be represented as a cumulative probability distribution. Finally, comparison of PECs to measured concentrations can also be used to identify the need for fate studies of compounds of interest in biosolids. Copyright © 2011 SETAC.

Ingredientes Farmacéuticos Activos Potencialmente Inapropiados en Adultos Mayores: Lista IFAsPIAM: Panel de Consenso Argentino.

PubMed

Marzi, Marta M; Pires, Miryam S; Quaglia, Nora B

2018-04-18

To perform a list agreed by Argentinean experts and adapted to the local context containing potentially inappropriate (PI) medications in old people (OP) usingthe Delphi consensus technique optimized for this subject. A preliminary list of potentially inappropriate medications (PIM) was drawn up based on foreign PIM lists and a selective search in the scientific literature. The iterative Delphi process was used to submit the active pharmaceutical ingredients (APIs) of the preliminary PIM list to the panel of Argentinean experts. The analysis of theanswers to determine the arrival to the consensus was carried out applying three criteria specially defined for this purpose. After two Delphi rounds, it was not reached agreement about 12 APIs. The List of explicit criteria for PIAPIs for use in OP (IFAsPIAM List) was finally constituted by 128 APIs corresponding to 9 groups of the ATC classification system to which they were organized. In addition to each API, information justifying the unfavorable benefit/risk profile and therapeutic alternatives or recommendations/precautions was recorded. The group with the most PI APIs was N (NervousSystem) (60; 47%) followed by groups C (Cardiovascular) and M (Musculoskeletal). This study presents the first Latin American list of PIM in OP developed using an expert consensus technique. The IFAs PIAM List would contribute to the rational use of drugs in elderly population, constituting a valuable tool in Argentinean public health. Copyright © 2018. Published by Elsevier Inc.

Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

PubMed

Ferreira, Anderson O; Polonini, Hudson C; Silva, Sharlene L; Patrício, Fernando B; Brandão, Marcos Antônio F; Raposo, Nádia R B

2016-01-25

The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes. Copyright © 2015 Elsevier B.V. All rights reserved.

Physical stability of API/polymer-blend amorphous solid dispersions.

PubMed

Lehmkemper, Kristin; Kyeremateng, Samuel O; Bartels, Mareike; Degenhardt, Matthias; Sadowski, Gabriele

2018-03-01

The preparation of amorphous solid dispersions (ASDs) is a well-established strategy for formulating active pharmaceutical ingredients by embedding them in excipients, usually amorphous polymers. Different polymers can be combined for designing ASDs with desired properties like an optimized dissolution behavior. One important criterion for the development of ASD compositions is the physical stability. In this work, the physical stability of API/polymer-blend ASDs was investigated by thermodynamic modeling and stability studies. Amorphous naproxen (NAP) and acetaminophen (APAP) were embedded in blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and either poly(vinylpyrrolidone) (PVP) or poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64). Parameters for modeling the API solubility in the blends and the glass-transition temperature curves of the water-free systems with Perturbed-Chain Statistical Associating Fluid Theory and Kwei equation, respectively, were correlated to experimental data. The phase behavior for standardized storage conditions (0%, 60% and 75% relative humidity (RH)) was predicted and compared to six months-long stability studies. According to modeling and experimental results, the physical stability was reduced with increasing HPMCAS content and increasing RH. This trend was observed for all investigated systems, with both APIs (NAP and APAP) and both polymer blends (PVP/HPMCAS and PVPVA64/HPMCAS). PC-SAFT and the Kwei equation turned out to be suitable tools for modeling and predicting the physical stability of the investigated API/polymer-blends ASDs. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of powder blend uniformity: Comparison of real-time NIR blend monitoring with stratified sampling in combination with HPLC and at-line NIR Chemical Imaging.

PubMed

Bakri, Barbara; Weimer, Marco; Hauck, Gerrit; Reich, Gabriele

2015-11-01

Scope of the study was (1) to develop a lean quantitative calibration for real-time near-infrared (NIR) blend monitoring, which meets the requirements in early development of pharmaceutical products and (2) to compare the prediction performance of this approach with the results obtained from stratified sampling using a sample thief in combination with off-line high pressure liquid chromatography (HPLC) and at-line near-infrared chemical imaging (NIRCI). Tablets were manufactured from powder blends and analyzed with NIRCI and HPLC to verify the real-time results. The model formulation contained 25% w/w naproxen as a cohesive active pharmaceutical ingredient (API), microcrystalline cellulose and croscarmellose sodium as cohesive excipients and free-flowing mannitol. Five in-line NIR calibration approaches, all using the spectra from the end of the blending process as reference for PLS modeling, were compared in terms of selectivity, precision, prediction accuracy and robustness. High selectivity could be achieved with a "reduced" approach i.e. API and time saving approach (35% reduction of API amount) based on six concentration levels of the API with three levels realized by three independent powder blends and the additional levels obtained by simply increasing the API concentration in these blends. Accuracy and robustness were further improved by combining this calibration set with a second independent data set comprising different excipient concentrations and reflecting different environmental conditions. The combined calibration model was used to monitor the blending process of independent batches. For this model formulation the target concentration of the API could be achieved within 3 min indicating a short blending time. The in-line NIR approach was verified by stratified sampling HPLC and NIRCI results. All three methods revealed comparable results regarding blend end point determination. Differences in both mean API concentration and RSD values could be attributed to differences in effective sample size and thief sampling errors. This conclusion was supported by HPLC and NIRCI analysis of tablets manufactured from powder blends after different blending times. In summary, the study clearly demonstrates the ability to develop efficient and robust quantitative calibrations for real-time NIR powder blend monitoring with a reduced set of powder blends while avoiding any bias caused by physical sampling. Copyright © 2015 Elsevier B.V. All rights reserved.

A New Platform for Profiling Degradation-Related Impurities Via Exploiting the Opportunities Offered by Ion-Selective Electrodes: Determination of Both Diatrizoate Sodium and Its Cytotoxic Degradation Product.

PubMed

Riad, Safaa M; Abd El-Rahman, Mohamed K; Fawaz, Esraa M; Shehata, Mostafa A

2018-05-01

Although the ultimate goal of administering active pharmaceutical ingredients (APIs) is to save countless lives, the presence of impurities and/or degradation products in APIs or formulations may cause harmful physiological effects. Today, impurity profiling (i.e., the identity as well as the quantity of impurity in a pharmaceutical) is receiving critical attention from regulatory authorities. Despite the predominant use of spectroscopic and chromatographic methods over electrochemical methods for impurity profiling of APIs, this work investigates the opportunities offered by electroanalytical methods, particularly, ion-selective electrodes (ISEs), for profiling degradation-related impurities (DRIs) compared with conventional spectroscopic and chromatographic methods. For a meaningful comparison, diatrizoate sodium (DTA) was chosen as the anionic X-ray contrast agent based on its susceptibility to deacetylation into its cytotoxic and mutagenic degradation product, 3,5-diamino-2,4,6 triiodobenzoic acid (DTB). This cationic diamino compound can be also detected as an impurity in the final product because it is used as a synthetic precursor for the synthesis of DTA. In this study, four novel sensitive and selective sensors for the determination of both DTA and its cytotoxic degradation products are presented. Sensors I and II were developed for the determination of the anionic drug, DTA, and sensors III and IV were developed for the determination of the cationic cytotoxic impurity. The use of these novel sensors not only provides a stability-indicating method for the selective determination of DTA in the presence of its degradation product, but also permits DRI profiling. Moreover, a great advantage of these proposed ISE systems is their higher sensitivity for the quantification of DTB relative to other spectroscopic and chromatographic methods, so it can measure trace amounts of DTB impurities in DTA bulk powder and pharmaceutical formulation without a need for preliminary separation.

The influence of high shear mixing on ternary dry powder inhaler formulations.

PubMed

Hertel, Mats; Schwarz, Eugen; Kobler, Mirjam; Hauptstein, Sabine; Steckel, Hartwig; Scherließ, Regina

2017-12-20

The blending process is a key step in the production of dry powder inhaler formulations, but only little is known about the influence of process parameters. This is especially true for high shear blending of ternary formulations. For this reason, this study aims to investigate the influence of high shear mixing process parameters (mixing time and rotation speed) on the fine particle fraction (FPF) of ternary mixtures when using budesonide as model drug, two different carrier materials and two different mixing orders. Prolonged mixing time and higher rotation speeds led to lower FPFs, possibly due to higher press-on forces acting on the active pharmaceutical ingredients (API). In addition, a clear correlation between the energy consumption of the blender (the energy input into the blend) and the reduction of the FPF could be shown. Furthermore blending the carrier and the fines before adding the API was also found to be favorable. Copyright © 2017 Elsevier B.V. All rights reserved.

The use of atomic spectroscopy in the pharmaceutical industry for the determination of trace elements in pharmaceuticals.

PubMed

Lewen, Nancy

2011-06-25

The subject of the analysis of various elements, including metals and metalloids, in the pharmaceutical industry has seen increasing importance in the last 10-15 years, as modern analytical instrumentation has afforded analysts with the opportunity to provide element-specific, accurate and meaningful information related to pharmaceutical products. Armed with toxicological data, compendial and regulatory agencies have revisited traditional approaches to the testing of pharmaceuticals for metals and metalloids, and analysts have begun to employ the techniques of atomic spectroscopy, such as flame- and graphite furnace atomic absorption spectroscopy (FAAS, Flame AA or FAA and GFAAS), inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and inductively coupled plasma-mass spectrometry (ICP-MS), to meet their analytical needs. Newer techniques, such as laser-induced breakdown spectroscopy (LIBS) and Laser Ablation ICP-MS (LAICP-MS) are also beginning to see wider applications in the analysis of elements in the pharmaceutical industry.This article will provide a perspective regarding the various applications of atomic spectroscopy in the analysis of metals and metalloids in drug products, active pharmaceutical ingredients (API's), raw materials and intermediates. The application of atomic spectroscopy in the analysis of metals and metalloids in clinical samples, nutraceutical, metabolism and pharmacokinetic samples will not be addressed in this work. Copyright © 2010 Elsevier B.V. All rights reserved.

Removal of APIs and bacteria from hospital wastewater by MBR plus O(3), O(3) + H(2)O(2), PAC or ClO(2).

PubMed

Nielsen, U; Hastrup, C; Klausen, M M; Pedersen, B M; Kristensen, G H; Jansen, J L C; Bak, S N; Tuerk, J

2013-01-01

The objective of this study has been to develop technologies that can reduce the content of active pharmaceutical ingredients (APIs) and bacteria from hospital wastewater. The results from the laboratory- and pilot-scale testings showed that efficient removal of the vast majority of APIs could be achieved by a membrane bioreactor (MBR) followed by ozone, ozone + hydrogen peroxide or powdered activated carbon (PAC). Chlorine dioxide (ClO(2)) was significantly less effective. MBR + PAC (450 mg/l) was the most efficient technology, while the most cost-efficient technology was MBR + ozone (156 mg O(3)/l applied over 20 min). With MBR an efficient removal of Escherichia coli and enterococci was measured, and no antibiotic resistant bacteria were detected in the effluent. With MBR + ozone and MBR + PAC also the measured effluent concentrations of APIs (e.g. ciprofloxacin, sulfamethoxazole and sulfamethizole) were below available predicted no-effect concentrations (PNEC) for the marine environment without dilution. Iodinated contrast media were also reduced significantly (80-99% for iohexol, iopromide and ioversol and 40-99% for amidotrizoateacid). A full-scale MBR treatment plant with ozone at a hospital with 900 beds is estimated to require an investment cost of €1.6 mill. and an operating cost of €1/m(3) of treated water.

Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine.

PubMed

Egorova, Ksenia S; Gordeev, Evgeniy G; Ananikov, Valentine P

2017-05-24

Ionic liquids are remarkable chemical compounds, which find applications in many areas of modern science. Because of their highly tunable nature and exceptional properties, ionic liquids have become essential players in the fields of synthesis and catalysis, extraction, electrochemistry, analytics, biotechnology, etc. Apart from physical and chemical features of ionic liquids, their high biological activity has been attracting significant attention from biochemists, ecologists, and medical scientists. This Review is dedicated to biological activities of ionic liquids, with a special emphasis on their potential employment in pharmaceutics and medicine. The accumulated data on the biological activity of ionic liquids, including their antimicrobial and cytotoxic properties, are discussed in view of possible applications in drug synthesis and drug delivery systems. Dedicated attention is given to a novel active pharmaceutical ingredient-ionic liquid (API-IL) concept, which suggests using traditional drugs in the form of ionic liquid species. The main aim of this Review is to attract a broad audience of chemical, biological, and medical scientists to study advantages of ionic liquid pharmaceutics. Overall, the discussed data highlight the importance of the research direction defined as "Ioliomics", studies of ions in liquids in modern chemistry, biology, and medicine.

Validation of pharmaceutical potency determinations by quantitative nuclear magnetic resonance spectrometry.

PubMed

Webster, Gregory K; Marsden, Ian; Pommerening, Cynthia A; Tyrakowski, Christina M

2010-05-01

With the changing development paradigms in the pharmaceutical industry, laboratories are challenged to release materials for clinical studies with rapid turnaround times. To minimize cost demands, many businesses are looking to develop ways of using early Good Manufacturing Practice (GMP) materials of active pharmaceutical ingredients (API) for Good Laboratory Practice (GLP) toxicology studies. To make this happen, the analytical laboratory releases the material by one of three scenarios: (1) holding the GLP release until full GMP testing is ready, (2) issuing a separate lot number for a portion of the GMP material and releasing the material for GLP use, or (3) releasing the lot of material for GLP using alternate (equivalent) method(s) not specified for GMP release testing. Many companies are finding the third scenario to be advantageous in terms of cost and efficiency through the use of quantitative nuclear magnetic resonance (q-NMR). The use of q-NMR has proved to be a single-point replacement for routine early development testing that previously combined elements of identity testing, chromatographic assay, moisture analysis, residual solvent analysis, and elemental analysis. This study highlights that q-NMR can be validated to meet current regulatory analytical method guidelines for routine pharmaceutical analysis.

Terahertz pulsed imaging as an advanced characterisation tool for film coatings--a review.

PubMed

Haaser, Miriam; Gordon, Keith C; Strachan, Clare J; Rades, Thomas

2013-12-05

Solid dosage forms are the pharmaceutical drug delivery systems of choice for oral drug delivery. These solid dosage forms are often coated to modify the physico-chemical properties of the active pharmaceutical ingredients (APIs), in particular to alter release kinetics. Since the product performance of coated dosage forms is a function of their critical coating attributes, including coating thickness, uniformity, and density, more advanced quality control techniques than weight gain are required. A recently introduced non-destructive method to quantitatively characterise coating quality is terahertz pulsed imaging (TPI). The ability of terahertz radiation to penetrate many pharmaceutical materials enables structural features of coated solid dosage forms to be probed at depth, which is not readily achievable with other established imaging techniques, e.g. near-infrared (NIR) and Raman spectroscopy. In this review TPI is introduced and various applications of the technique in pharmaceutical coating analysis are discussed. These include evaluation of coating thickness, uniformity, surface morphology, density, defects and buried structures as well as correlation between TPI measurements and drug release performance, coating process monitoring and scale up. Furthermore, challenges and limitations of the technique are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Investigation of the capacity of low glass transition temperature excipients to minimize amorphization of sulfadimidine on comilling.

PubMed

Curtin, Vincent; Amharar, Youness; Hu, Yun; Erxleben, Andrea; McArdle, Patrick; Caron, Vincent; Tajber, Lidia; Corrigan, Owen I; Healy, Anne Marie

2013-01-07

The coprocessing of active pharmaceutical ingredient (API) with an excipient which has a high glass transition temperature (T(g)) is a recognized strategy to stabilize the amorphous form of a drug. This work investigates whether coprocessing a model API, sulfadimidine (SDM) with a series of low T(g) excipients, prevents or reduces amorphization of the crystalline drug. It was hypothesized that these excipients could exert a T(g) lowering effect, resulting in composite T(g) values lower than that of the API alone and promote crystallization of the drug. Milled SDM and comilled SDM with glutaric acid (GA), adipic acid (AA), succinic acid (SA), and malic acid (MA) were characterized with respect to their thermal, X-ray diffraction, spectroscopic, and vapor sorption properties. SDM was predominantly amorphous when milled alone, with an amorphous content of 82%. No amorphous content was detected by dynamic vapor sorption (DVS) on comilling SDM with 50% w/w GA, and amorphous content of the API was reduced by almost 30%, relative to the API milled alone, on comilling with 50% w/w AA. In contrast, amorphization of SDM was promoted on comilling with 50% w/w SA and MA, as indicated by near-infrared (NIR) spectroscopy. Results indicated that the API was completely amorphized in the SDM:MA comilled composite. The saturated solubility of GA and AA in the amorphous API was estimated by thermal methods. It was observed that the T(g) of the comelt quenched composites reached a minimum and leveled out at this solubility concentration. Maximum crystallinity of API on comilling was reached at excipient concentrations comparable to the saturated concentration solubility of excipient in the API. Moreover, the closer the Hildebrand solubility parameter of the excipient to the API, the greater the inhibition of API amorphization on comilling. The results reported here indicate that an excipient with a low T(g) coupled with high solubility in the API can prevent or reduce the generation of an amorphous phase on comilling.

Size exclusion chromatography with evaporative light scattering detection as a method for speciation analysis of polydimethylsiloxanes. III. Identification and determination of dimeticone and simeticone in pharmaceutical formulations.

PubMed

Mojsiewicz-Pieńkowska, Krystyna

2012-01-25

The pharmaceutical industry is one of the more important sectors for the use of polydimethylsiloxanes (PDMS), which belong to the organosilicon polymers. In drugs for internal use, they are used as an active pharmaceutical ingredient (API) called dimeticone or simeticone. Due to their specific chemical nature, PDMS can have different degrees of polymerization, which determine the molecular weight and viscosity. The Pharmacopoeial monographs for dimeticone and simeticone, only give the permitted polymerization and viscosity range. It is, however, essential to know also the degree of polymerization or the specific molecular weight of PDMS that are present in pharmaceutical formulations. In the literature there is information about the impact of particle size, and thus molecular weight, on the toxicity, absorption and migration in living organisms. This study focused on the use of a developed method - the exclusion chromatography with evaporative light scattering detector (SEC-ELSD) - for identification and determination of dimeticone and simeticone in various pharmaceutical formulations. The method had a high degree of specificity and was suitable for speciation analysis of these polymers. So far the developed method has not been used in the control of medicinal products containing dimeticone or simeticone. Copyright © 2011 Elsevier B.V. All rights reserved.

Pharmaceutical cocrystals: a comparison of sulfamerazine with sulfamethazine

NASA Astrophysics Data System (ADS)

Lu, Jie; Li, Yi-Ping; Wang, Jing; Li, Zhen; Rohani, Sohrab; Ching, Chi-Bun

2011-11-01

Although there has been much debate about its definition among scientists, a cocrystal may be defined as a crystalline material that consists of two or more electrically neutral molecular species held together by non-covalent forces, and meanwhile all components are solids at room temperature. Obviously it is great to introduce predictable structural motifs to an active pharmaceutical ingredient (API) by design. One widely used approach to cocrystal design is based on the consideration of Δp Ka, which can represent the propensity of molecular species to form a cocrystal or a salt. In this work, p-aminobenzoic acid (PABA) was mixed with sulfamerazine (SMZ) or sulfamethazine (STH) by use of neat cogrinding and solvent-drop cogrinding. It was found that PABA and SMZ with a Δp Ka of 2.13 would form a binary eutectic, while PABA and STH with a larger Δp Ka of 2.59 can form a cocrystal in the ratio of 1:1. The phenomenon indicates that not only the Δp Ka but also the stereo-hindrance effect (geometric fit) should be considered during the design of pharmaceutical cocrystals.

Orlistat interaction with sibutramine and carnitine. A physicochemical and theoretical study

NASA Astrophysics Data System (ADS)

Nicolás-Vázquez, Inés; Hinojosa Torres, Jaime; Cruz Borbolla, Julián; Miranda Ruvalcaba, René; Aceves-Hernández, Juan Manuel

2014-03-01

Chemical degradation of orlistat, (ORT) after melting and reaction of decomposition byproducts with sibutramine, SIB was studied. Interactions between the active pharmaceutical ingredients by using thermal analysis, TA, methods and other experimental techniques such as PXRD, IR and UV-vis spectroscopies were carried out to investigate chemical reactions between components. It was found that orlistat melts with decomposition and byproducts quickly affect sibutramine molecule and then reacting also with carnitine, CRN when the three active pharmaceutical ingredients (API's) are mixed. However ORT byproducts do not react when ORT is mixed only with carnitine. It was found that compounds containing chlorine atoms react easily with orlistat when the temperature increases up to its melting point. Some reaction mechanisms of orlistat decomposition are proposed, the fragments in the mechanisms were found in the corresponding mass spectra. Results obtained indicate that special studies should be carried out in the formulation stage before the final composition of a poly-pill could be established. Similar results are commonly found for compounds very prone to react in presence of water, light and/or temperature. In order to explain the reactivity of orlistat with sibutramine and carnitine, theoretical calculations were carried out and the results are in agreement with the experimental results.

Conception, realization and qualification of a radioactive clean room lab facility dedicated to the synthesis of radiolabeled API for human ADME studies.

PubMed

Loewe, Claudia; Atzrodt, Jens; Reschke, Kai; Schofield, Joe

2016-12-01

The human absorption, distribution, metabolism and elimination study administering radiolabeled drugs to human volunteers is an important clinical study in the development program of new drug candidates. The manufacture of radiolabeled Active Pharmaceutical Ingredients is covered by national drug laws and may come within the scope of regulatory GMP requirements. Additionally, authorities may request an appropriate environmental zoning to minimize the risk of microbiological contaminations particularly during the synthesis of radiolabeled Active Pharmaceutical Ingredients intended for parenteral application. Thus, a radioactive clean room lab facility in line with both GMP and radiation safety regulations was installed and the environmental zoning validated by appropriate testing of technical parameters and microbial and particle monitoring. The considerations detailed in this paper cover only GMP aspects related to the synthesis of radioactive drug substance. The subsequent, final formulation step in the overall process for manufacturing of radioactive drug product for any kind of administration is not within the scope of this paper. Under these qualified and controlled environmental conditions, we are now in a position to provide radiolabeled drug substances for all kinds of drug administration including both po and iv. Copyright © 2016 John Wiley & Sons, Ltd.

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop.

PubMed

Zhang, X; Duan, J; Kesisoglou, F; Novakovic, J; Amidon, G L; Jamei, M; Lukacova, V; Eissing, T; Tsakalozou, E; Zhao, L; Lionberger, R

2017-08-01

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Solid-state NMR studies of form I of atorvastatin calcium.

PubMed

Wang, Wei David; Gao, Xudong; Strohmeier, Mark; Wang, Wei; Bai, Shi; Dybowski, Cecil

2012-03-22

Solid-state (13)C, (19)F, and (15)N magic angle spinning NMR studies of Form I of atorvastatin calcium are reported, including chemical shift tensors of all resolvable carbon sites and fluorine sites. The complete (13)C and (19)F chemical shift assignments are given based on an extensive analysis of (13)C-(1)H HETCOR and (13)C-(19)F HETCOR results. The solid-state NMR data indicate that the asymmetric unit of this material contains two atorvastatin molecules. A possible structure of Form I of atorvastatin calcium (ATC-I), derived from solid-state NMR data and density functional theory calculations of various structures, is proposed for this important active pharmaceutical ingredient (API).

Cocrystal solubility product analysis - Dual concentration-pH mass action model not dependent on explicit solubility equations.

PubMed

Avdeef, Alex

2017-12-15

A novel general computational approach is described to address many aspects of cocrystal (CC) solubility product (K sp ) determination of drug substances. The CC analysis program, pDISOL-X, was developed and validated with published model systems of various acid-base combinations of active pharmaceutical ingredients (APIs) and coformers: (i) carbamazepine cocrystal systems with 4-aminobenzoic acid, cinnamic acid, saccharin, and salicylic acid, (ii) for indomethacin with saccharin, (iii) for nevirapine with maleic acid, saccharin, and salicylic acid, and (iv) for gabapentin with 3-hydroxybenzoic acid. In all systems but gabapentin, the coformer is much more soluble than the API. The model systems selected are those with available published dual concentration-pH data, one set for the API and one set for the coformer, generally measured at eutectic points (thermodynamically-stable three phases: solution, cocrystal, and crystalline API or coformer). The carbamazepine-cinnamic acid CC showed a substantial elevation in the API equilibrium concentration above pH5, consistent with the formation of a complex between carbamazepine and cinnamate anion. The analysis of the gabapentin:3-hydroxybenzoic acid 1:1 CC system indicated four zones of solid suspensions: coformer (pH<3.25), coformer and cocrystal eutectic (pH3.25-4.44), cocrystal (pH4.44-5.62), and API (pH>5.62). The general approach allows for testing of many possible equilibrium models, including those comprising drug-coformer complexation. The program calculates the ionic strength at each pH. From this, the equilibrium constants are adjusted for activity effects, based on the Stokes-Robinson hydration theory. The complete speciation analysis of the CC systems may provide useful insights into pH-sensitive dissolution effects that could potentially influence bioavailability. Copyright © 2017 Elsevier B.V. All rights reserved.

Continuous manufacturing and analytical characterization of fixed-dose, multilayer orodispersible films.

PubMed

Thabet, Yasmin; Lunter, Dominique; Breitkreutz, Joerg

2018-05-30

Various drug therapies require more than one active pharmaceutical ingredient (API) for an effective treatment. There are many advantages, e.g. to improve the compliance or pharmacodynamic response in comparison to a monotherapy or to increase the therapy safety. Until now, there are only a few products available for the paediatric population due to the lack of age appropriate dosage forms or studies proving the efficacy and safety of these products. This study aims to develop orodispersible films (ODFs) in a continuous solvent casting process as child appropriate dosage form containing both enalapril maleate (EM) and hydrochlorothiazide (HCT) separated in different film layers. Furthermore, they should be characterised and the API migration analysed by confocal Raman microscopy (CRM). ODFs were successfully produced in a continuous manufacturing process in form of double- and triple-layer formulations based on hydroxypropylcellulose (HPC) or a combination of HPC and polyvinyl alcohol (PVA). CRM revealed that both APIs migrate within the film layers shortly after manufacturing. PVA inhibits the migration inside the double-layer film, but is not able to prevent the API migration as an interlayer inside a triple-layer ODF. With increasing film layers, the content of residual solvents and the disintegration time increases (mono-layer films: <10 s, triple-layer films: 37 s). In conclusion, it was feasible to produce fixed-dose combinations in therapeutic doses up to 9 mg HCT and 3.5 mg EM for the double-layer film with adequate mechanical properties, which enable coiling up onto jumbo rolls directly after production. The best separation of the two APIs was achieved by casting a double-layer ODF consisting of different film forming polymers, which can be beneficial when processing two incompatible APIs. Copyright © 2018 Elsevier B.V. All rights reserved.

Surface acidity and solid-state compatibility of excipients with an acid-sensitive API: case study of atorvastatin calcium.

PubMed

Govindarajan, Ramprakash; Landis, Margaret; Hancock, Bruno; Gatlin, Larry A; Suryanarayanan, Raj; Shalaev, Evgenyi Y

2015-04-01

The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pHeq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pHeq. No lactone formation was observed in mixtures with excipients having pHeq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pHeq < 3. The three pHeq regions (> 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pHeq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pHeq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.

Sulfamerazine: Understanding the Influence of Slip Planes in the Polymorphic Phase Transformation through X-Ray Crystallographic Studies and ab Initio Lattice Dynamics.

PubMed

Pallipurath, Anuradha R; Skelton, Jonathan M; Warren, Mark R; Kamali, Naghmeh; McArdle, Patrick; Erxleben, Andrea

2015-10-05

Understanding the polymorphism exhibited by organic active-pharmaceutical ingredients (APIs), in particular the relationships between crystal structure and the thermodynamics of polymorph stability, is vital for the production of more stable drugs and better therapeutics, and for the economics of the pharmaceutical industry in general. In this article, we report a detailed study of the structure-property relationships among the polymorphs of the model API, Sulfamerazine. Detailed experimental characterization using synchrotron radiation is complemented by computational modeling of the lattice dynamics and mechanical properties, in order to study the origin of differences in millability and to investigate the thermodynamics of the phase equilibria. Good agreement is observed between the simulated phonon spectra and mid-infrared and Raman spectra. The presence of slip planes, which are found to give rise to low-frequency lattice vibrations, explains the higher millability of Form I compared to Form II. Energy/volume curves for the three polymorphs, together with the temperature dependence of the thermodynamic free energy computed from the phonon frequencies, explains why Form II converts to Form I at high temperature, whereas Form III is a rare polymorph that is difficult to isolate. The combined experimental and theoretical approach employed here should be generally applicable to the study of other systems that exhibit polymorphism.

Fused deposition modeling provides solution for magnetic resonance imaging of solid dosage form by advancing design quickly from prototype to final product.

PubMed

Charest, Ken; Mak-Jurkauskas, Melody L; Cinicola, Daniel; Clausen, Andrew M

2013-02-01

The release profile of active pharmaceutical ingredient (API) from its solid dosage form is an important aspect of drug development as it is often used to predict potential drug release characteristics of a product in vivo. In recent years, magnetic resonance imaging has emerged as a nondestructive technique that captures the physical changes of solid dosage forms during dissolution. An example that highlights this application is in the dissolution of modified-release tablet studies. As the tablet dissolves, API disperses in a hydrogel matrix within the tablet, and swelling of the hydrogel layer eventually leads to release of API over time. To achieve optimum signal-to-noise ratios, the tablet should be placed in the most homogeneous region of the magnet and remain there throughout the dissolution experiment. Moreover, the tablet holder must maintain the tablet position without interfering with the natural dissolution process, such as by crushing the softened tablet. This can be difficult because the size, shape, and rigidity of the tablet change during dissolution. This article describes the process, material, and manufacture of a novel device that meets these challenges, with emphasis on how additive manufacturing on a 3D printer enabled an efficient and inexpensive process of design improvements.

Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector--Results from a Nationally Representative Outlet Survey.

PubMed

Act Consortium Drug Quality Project Team And The Impact Study Team

2015-06-01

Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85-115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential. © The American Society of Tropical Medicine and Hygiene.

Role of herbal bioactives as a potential bioavailability enhancer for Active Pharmaceutical Ingredients.

PubMed

Ajazuddin; Alexander, Amit; Qureshi, Azra; Kumari, Leena; Vaishnav, Pramudita; Sharma, Mukesh; Saraf, Swarnlata; Saraf, Shailendra

2014-09-01

The current review emphasizes on the herbal bioenhancers which themselves do not possess inherent pharmacological activity of their own but when co-administered with Active Pharmaceutical Ingredients (API), enhances their bioavailability and efficacy. Herbal bioenhancers play a crucial role in enhancing the bioavailability and bioefficacy of different classes of drugs, such as antihypertensives, anticancer, antiviral, antitubercular and antifungal drugs at low doses. This paper highlights various natural compounds that can be utilized as an efficient bioenhancer. Several herbal compounds including piperine, quercetin, genistein, naringin, sinomenine, curcumin, and glycyrrhizin have demonstrated capability to improve the pharmacokinetic parameters of several potent API. This article also focuses on various United States patents on herbal bioenhancers, which has proved to be beneficial in improving oral absorption of nutraceuticals like vitamins, minerals, amino acids and certain herbal compounds. The present paper also describes proposed mechanism of action, which mainly includes absorption process, drug metabolism, and action on drug target. The herbal bioenhancers are easily available, safe, free from side effects, minimizes drug toxicity, shortens the duration of treatment, lowers the drug resistance problems and minimizes the cost of treatment. Inspite of the fact that herbal bioenhancers provide an innovative concept for enhancing the bioavailability of several potent drugs, there are numerous bioenhancers of herbal origin that are yet to be explored in several vital areas. These bioenhancers must also be implied to enhance the bioavailability and bioefficacy through routes other than the oral route of drug delivery. There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. The toxicity profiles of these herbal bioenhancers must not be overlooked. Researches must be carried out to solve these issues and to deliver a safe and effective dose of drugs to attain desired pharmacological response. Copyright © 2014 Elsevier B.V. All rights reserved.

Treatment of human and livestock helminth infections in a mobile pastoralist setting at Lake Chad: Attitudes to health and analysis of active pharmaceutical ingredients of locally available anthelminthic drugs.

PubMed

Greter, Helena; Cowan, Noemi; Ngandolo, Bongo N; Kessely, Hamit; Alfaroukh, Idriss O; Utzinger, Jürg; Keiser, Jennifer; Zinsstag, Jakob

2017-11-01

Mobile pastoralists face challenges in accessing quality health care and medication for managing human and animal diseases. We determined livestock disease priorities, health seeking behaviour of people bearing helminthiases and - placing particular emphasis on trematode infections - treatment strategies and outcome satisfaction among mobile pastoralists of four ethnic groups in the Lake Chad area using focus group discussions. People suffering from schistosomiasis were interviewed about symptoms, health seeking behaviour and their satisfaction with respect to the provided treatment. Anthelminthic drugs for human and veterinary use obtained from various health care structures were analysed for active pharmaceutical ingredients (API) and quantity, using high pressure liquid chromatography-UV and liquid chromatography combined with tandem mass spectrometry. Most people suffering from schistosomiasis sought treatment at health care centres. Yet, they also consulted informal providers without medical training. Regarding animal health, self-mediated therapy was common to manage suspected livestock fascioliasis. Self-reported treatment satisfaction for human schistosomiasis and trematodiasis treatment outcome in livestock were low. Mobile pastoralists perceived the purchased drugs to be of low quality. Among 33 products locally sold as anthelminthic drugs for human or veterinary use, 27 contained albendazole or mebendazole, varying between 91% and 159% of the labelled amount. Six products were sold loosely with incomplete information and their API could not be identified. No counterfeit anthelminthic drugs were detected. None of the samples contained praziquantel or triclabendazole, the drugs of choice against schistosomiasis and fascioliasis, respectively. The perceived unsatisfactory treatment outcomes in humans and animals infected with trematodes are most likely due to empiric diagnosis and the resulting use of inadequate therapy for human schistosomiasis and the lack of efficacious drugs against livestock fascioliasis. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhancement of dissolution rate through eutectic mixture and solid solution of posaconazole and benznidazole.

PubMed

Figueirêdo, Camila Bezerra Melo; Nadvorny, Daniela; de Medeiros Vieira, Amanda Carla Quintas; Soares Sobrinho, José Lamartine; Rolim Neto, Pedro José; Lee, Ping I; de La Roca Soares, Monica Felts

2017-06-15

Benznidazole (BNZ), the only commercialized antichagasic drug, and the antifungal compound posaconazole (PCZ) have shown synergistic action in the therapy of Chagas disease, however both active pharmaceutical ingredients (APIs) exhibit low aqueous solubility potentially limiting their bioavailability and therapeutic efficacy. In this paper, we report for the first time the formation of a eutectic mixture as well as an amorphous solid solution of PCZ and BNZ (at the same characteristic ratio of 80:20wt%), which provided enhanced solubility and dissolution rate for both APIs. This eutectic system was characterized by DSC and the melting points obtained were used for the construction of a phase diagram. The preservation of the characteristic PXRD patterns and the IR spectra of the parent APIs, and the visualization of a characteristic eutectic lamellar crystalline microstructure using Confocal Raman Microscopy confirm this system as a true eutectic mixture. The PXRD result also confirms the amorphous nature of the prepared solid solution. Theoretical chemical analyses indicate the predominance of π-stacking interactions in the amorphous solid solution, whereas an electrostatic interaction between the APIs is responsible for maintaining the alternating lamellar crystalline microstructure in the eutectic mixture. Both the eutectic mixture and the amorphous solid solution happen to have a characteristic PCZ to BNZ ratio similar to that of their pharmacological doses for treating Chagas disease, thus providing a unique therapeutic combination dose with enhanced apparent solubility and dissolution rate. Copyright © 2017 Elsevier B.V. All rights reserved.

Supercritical fluid particle design for poorly water-soluble drugs (review).

PubMed

Sun, Yongda

2014-01-01

Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water-soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio-drug particles) to improve solubility and dissolution rate of poorly water-soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review.

Application of the SeDeM Diagram and a new mathematical equation in the design of direct compression tablet formulation.

PubMed

Suñé-Negre, Josep M; Pérez-Lozano, Pilar; Miñarro, Montserrat; Roig, Manel; Fuster, Roser; Hernández, Carmen; Ruhí, Ramon; García-Montoya, Encarna; Ticó, Josep R

2008-08-01

Application of the new SeDeM Method is proposed for the study of the galenic properties of excipients in terms of the applicability of direct-compression technology. Through experimental studies of the parameters of the SeDeM Method and their subsequent mathematical treatment and graphical expression (SeDeM Diagram), six different DC diluents were analysed to determine whether they were suitable for direct compression (DC). Based on the properties of these diluents, a mathematical equation was established to identify the best DC diluent and the optimum amount to be used when defining a suitable formula for direct compression, depending on the SeDeM properties of the active pharmaceutical ingredient (API) to be used. The results obtained confirm that the SeDeM Method is an appropriate system, effective tool for determining a viable formulation for tablets prepared by direct compression, and can thus be used as the basis for the relevant pharmaceutical development.

Soft, chewable gelatin-based pharmaceutical oral formulations: a technical approach.

PubMed

Dille, Morten J; Hattrem, Magnus N; Draget, Kurt I

2018-06-01

Hard tablets and capsules for oral drug delivery cause problems for people experiencing dysphagia. This work describes the formulation and properties of a gelatin based, self-preserved, and soft chewable tablet as an alternative and novel drug delivery format. Gelatin (8.8-10% in 24.7-29% water) constituted the matrix of the soft, semi-solid tablets. Three different pharmaceuticals (Ibuprofen 10%, Acetaminophen 15%, and Meloxicam 1.5%) were tested in this formulation. Microbial stability was controlled by lowering the water activity with a mixture of sorbitol and xylitol (45.6-55%). Rheological properties were tested applying small strain oscillation measurements. Taste masking of ibuprofen soft-chew tablets was achieved by keeping the ibuprofen insoluble at pH 4.5 and keeping the processing temperature below the crystalline-to-amorphous transition temperature. Soft-chew formulations showed good stability for all three pharmaceuticals (up to 24 months), and the ibuprofen containing formulation exhibited comparable dissolution to a standard oral tablet as well as good microbial stability. The rheological properties of the ibuprofen/gelatin formulation had the fingerprint of a true gelatin gel, albeit higher moduli, and melting temperature. The results suggest that easy-to-swallow and well taste-masked soft chewable tablet formulations with extended shelf life are within reach for several active pharmaceutical ingredients (APIs).

Evaluation of physicochemical properties as supporting information on quality control of raw materials and veterinary pharmaceutical formulations.

PubMed

Anacleto, Sara da Silva; Borges, Marcella Matos Cordeiro; de Oliveira, Hanna Leijoto; Vicente, Andressa Reis; de Figueiredo, Eduardo Costa; de Oliveira, Marcone Augusto Leal; Borges, Bárbara Juliana Pinheiro; de Oliveira, Marcelo Antonio; Borges, Warley de Souza; Borges, Keyller Bastos

2018-06-01

This study aimed to show that the physicochemical proprieties obtained by Fourier transform infrared spectroscopy (FTIR), thermogravimetry (TG), and scanning electronic microscopy (SEM) can be useful tools for evaluating the quality of active pharmaceutical ingredients (APIs) and pharmaceutical products. In addition, a simple, sensitive, and efficient method employing HPLC-DAD was developed for simultaneous determination of lidocaine (LID), ciprofloxacin (CFX) and enrofloxacin (EFX) in raw materials and in veterinary pharmaceutical formulations. Compounds were separated using a Gemini C 18 (250 mm × 4.6 mm, 5 µm) Phenomenex ® column, at a temperature of 25 °C, with a mobile phase containing 10 mM of phosphoric acid (pH 3.29): acetonitrile (85.7:14.3, v/v) and a flow rate of 1.5 mL/min. Physicochemical characterization by TG, FTIR, and SEM of raw materials of LID, CFX, and EFX provided information useful for the evaluation, differentiation, and qualification of raw materials. Finally, the HPLC method was proved to be useful for evaluation of raw material and finished products, besides satisfying the need for an analytical method that allows simultaneous determination of EFX, CFX, and LID, which can also be extended to other matrices and applications.

Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century.

PubMed

Tiwari, Roshan V; Patil, Hemlata; Repka, Michael A

2016-01-01

Hot-melt extrusion (HME) technology is applied successfully in the plastic, rubber and food industry. HME has also emerged as an important technology for drug delivery applications in pharmaceutical research and manufacturing because of its process automation and low-cost scale-up properties, which reduce labor costs and capital investment. There are a number of commercial FDA-approved HME-derived products, signifying the commercial feasibility of this novel technique in drug delivery applications. HME is a highly efficient, solvent-free continuous processing technique for the development of solid dispersions; thus, research efforts to develop sustained, modified and targeted drug delivery systems to improve the solubility and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) are of interest. This review focuses on both the innovations and applications of HME in the production of pharmaceutical formulations, and on the significant findings of the general principles regarding formulation and process development via HME as described in published articles. Challenges faced by pharmaceutical companies to produce efficient drug formulations may be partly overcome by HME's advantages - high drug-loading capacity, good content uniformity, cost-effectiveness, and ease of processing scale-up. Nevertheless, HME's high processing temperatures may be an obstacle if adequate knowledge about the product's formulation is lacking.

Comprehensive study of the drug delivery properties of poly(l-lactide)-poly(ethylene glycol) nanoparticles in rats and tumor-bearing mice.

PubMed

Shalgunov, Vladimir; Zaytseva-Zotova, Daria; Zintchenko, Arkadi; Levada, Tatiana; Shilov, Yuri; Andreyev, Dmitry; Dzhumashev, Dzhangar; Metelkin, Evgeny; Urusova, Alexandra; Demin, Oleg; McDonnell, Kevin; Troiano, Greg; Zale, Stephen; Safarovа, Elmira

2017-09-10

Nanoparticles made of polylactide-poly(ethylene glycol) block-copolymer (PLA-PEG) are promising vehicles for drug delivery due to their biodegradability and controllable payload release. However, published data on the drug delivery properties of PLA-PEG nanoparticles are heterogeneous in terms of nanoparticle characteristics and mostly refer to low injected doses (a few mg nanoparticles per kg body weight). We have performed a comprehensive study of the biodistribution of nanoparticle formulations based on PLA-PEG nanoparticles of ~100nm size at injected doses of 30 to 140mg/kg body weight in healthy rats and nude tumor-bearing mice. Nanoparticle formulations differed by surface PEG coverage and by release kinetics of the encapsulated model active pharmaceutical ingredient (API). Increase in PEG coverage prolonged nanoparticle circulation half-life up to ~20h in rats and ~10h in mice and decreased retention in liver, spleen and lungs. Circulation half-life of the encapsulated API grew monotonously as the release rate slowed down. Plasma and tissue pharmacokinetics was dose-linear for inactive nanoparticles, but markedly dose-dependent for the model therapeutic formulation, presumably because of the toxic effects of released API. A mathematical model of API distribution calibrated on the data for inactive nanoparticles and conventional API form correctly predicted the distribution of the model therapeutic formulation at the lowest investigated dose, but for higher doses the toxic action of the released API had to be explicitly modelled. Our results provide a coherent illustration of the ability of controllable-release PLA-PEG nanoparticles to serve as an effective drug delivery platform to alter API biodistribution. They also underscore the importance of physiological effects of released drug in determining the biodistribution of therapeutic drug formulations at doses approaching tolerability limits. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Near infra red spectroscopy as a multivariate process analytical tool for predicting pharmaceutical co-crystal concentration.

PubMed

Wood, Clive; Alwati, Abdolati; Halsey, Sheelagh; Gough, Tim; Brown, Elaine; Kelly, Adrian; Paradkar, Anant

2016-09-10

The use of near infra red spectroscopy to predict the concentration of two pharmaceutical co-crystals; 1:1 ibuprofen-nicotinamide (IBU-NIC) and 1:1 carbamazepine-nicotinamide (CBZ-NIC) has been evaluated. A partial least squares (PLS) regression model was developed for both co-crystal pairs using sets of standard samples to create calibration and validation data sets with which to build and validate the models. Parameters such as the root mean square error of calibration (RMSEC), root mean square error of prediction (RMSEP) and correlation coefficient were used to assess the accuracy and linearity of the models. Accurate PLS regression models were created for both co-crystal pairs which can be used to predict the co-crystal concentration in a powder mixture of the co-crystal and the active pharmaceutical ingredient (API). The IBU-NIC model had smaller errors than the CBZ-NIC model, possibly due to the complex CBZ-NIC spectra which could reflect the different arrangement of hydrogen bonding associated with the co-crystal compared to the IBU-NIC co-crystal. These results suggest that NIR spectroscopy can be used as a PAT tool during a variety of pharmaceutical co-crystal manufacturing methods and the presented data will facilitate future offline and in-line NIR studies involving pharmaceutical co-crystals. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Microbiological contamination in counterfeit and unapproved drugs

PubMed Central

2014-01-01

Background Counterfeit and unapproved medicines are inherently dangerous and can cause patient injury due to ineffectiveness, chemical or biological contamination, or wrong dosage. Growth of the counterfeit medical market in developed countries is mainly attributable to life-style drugs, which are used in the treatment of non-life-threatening and non-painful conditions, such as slimming pills, cosmetic-related pharmaceuticals, and drugs for sexual enhancement. One of the main tasks of health authorities is to identify the exact active pharmaceutical ingredients (APIs) in confiscated drugs, because wrong API compounds, wrong concentrations, and/or the presence of chemical contaminants are the main risks associated with counterfeit medicines. Serious danger may also arise from microbiological contamination. We therefore performed a market surveillance study focused on the microbial burden in counterfeit and unapproved medicines. Methods Counterfeit and unapproved medicines confiscated in Canada and Austria and controls from the legal market were examined for microbial contaminations according to the US and European pharmacopoeia guidelines. The microbiological load of illegal and legitimate samples was statistically compared with the Wilcoxon rank-sum test. Results Microbial cultivable contaminations in counterfeit and unapproved phosphodiesterase type 5 inhibitors were significantly higher than in products from the legal medicines market (p < 0.0001). Contamination levels exceeding the USP and EP limits were seen in 23% of the tested illegal samples in Canada. Additionally, microbiological contaminations above the pharmacopoeial limits were detected in an anabolic steroid and an herbal medicinal product in Austria (6% of illegal products tested). Conclusions Our results show that counterfeit and unapproved pharmaceuticals are not manufactured under the same hygienic conditions as legitimate products. The microbiological contamination of illegal medicinal products often exceeds USP and EP limits, representing a potential threat to consumer health. PMID:24965483

Microbiological contamination in counterfeit and unapproved drugs.

PubMed

Pullirsch, Dieter; Bellemare, Julie; Hackl, Andreas; Trottier, Yvon-Louis; Mayrhofer, Andreas; Schindl, Heidemarie; Taillon, Christine; Gartner, Christian; Hottowy, Brigitte; Beck, Gerhard; Gagnon, Jacques

2014-06-26

Counterfeit and unapproved medicines are inherently dangerous and can cause patient injury due to ineffectiveness, chemical or biological contamination, or wrong dosage. Growth of the counterfeit medical market in developed countries is mainly attributable to life-style drugs, which are used in the treatment of non-life-threatening and non-painful conditions, such as slimming pills, cosmetic-related pharmaceuticals, and drugs for sexual enhancement. One of the main tasks of health authorities is to identify the exact active pharmaceutical ingredients (APIs) in confiscated drugs, because wrong API compounds, wrong concentrations, and/or the presence of chemical contaminants are the main risks associated with counterfeit medicines. Serious danger may also arise from microbiological contamination. We therefore performed a market surveillance study focused on the microbial burden in counterfeit and unapproved medicines. Counterfeit and unapproved medicines confiscated in Canada and Austria and controls from the legal market were examined for microbial contaminations according to the US and European pharmacopoeia guidelines. The microbiological load of illegal and legitimate samples was statistically compared with the Wilcoxon rank-sum test. Microbial cultivable contaminations in counterfeit and unapproved phosphodiesterase type 5 inhibitors were significantly higher than in products from the legal medicines market (p < 0.0001). Contamination levels exceeding the USP and EP limits were seen in 23% of the tested illegal samples in Canada. Additionally, microbiological contaminations above the pharmacopoeial limits were detected in an anabolic steroid and an herbal medicinal product in Austria (6% of illegal products tested). Our results show that counterfeit and unapproved pharmaceuticals are not manufactured under the same hygienic conditions as legitimate products. The microbiological contamination of illegal medicinal products often exceeds USP and EP limits, representing a potential threat to consumer health.

Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

PubMed

Lennernäs, H; Aarons, L; Augustijns, P; Beato, S; Bolger, M; Box, K; Brewster, M; Butler, J; Dressman, J; Holm, R; Julia Frank, K; Kendall, R; Langguth, P; Sydor, J; Lindahl, A; McAllister, M; Muenster, U; Müllertz, A; Ojala, K; Pepin, X; Reppas, C; Rostami-Hodjegan, A; Verwei, M; Weitschies, W; Wilson, C; Karlsson, C; Abrahamsson, B

2014-06-16

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes. Copyright © 2013 Elsevier B.V. All rights reserved.

Increasing dissolution of trospium chloride by co-crystallization with urea

NASA Astrophysics Data System (ADS)

Skořepová, Eliška; Hušák, Michal; Čejka, Jan; Zámostný, Petr; Kratochvíl, Bohumil

2014-08-01

The search for various solid forms of an active pharmaceutical ingredient (API) is an important step in drug development. Our aim was to prepare co-crystals of trospium chloride, an anticholinergic drug used for the treatment of incontinence, and to investigate if they have advantageous properties for drug formulation. Phase identification was done by powder X-ray diffraction and single-crystal X-ray diffraction. The chemical composition was verified by solution NMR and the dissolution rate of the prepared phases was studied by IDR (intrinsic dissolution rate). For further analysis of phase stability and transitions, combined thermal analysis and temperature-resolved X-ray powder diffraction were used. Urea was selected as a co-crystallization partner. Trospium chloride urea (1:1) co-crystal was prepared by a solvent evaporation. From single-crystal data, the co-crystal structure was solved in a space group P21/c and compared to previously published structures of trospium chloride. Intrinsic dissolution rate revealed that the co-crystal dissolves 32% faster than pure API. However, its low thermal and pressure stability makes it a challenging choice for the final drug formulation.

A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin.

PubMed

Brenna, Davide; Pirola, Margherita; Raimondi, Laura; Burke, Anthony J; Benaglia, Maurizio

2017-12-01

The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Facile LC-UV methods for simultaneous monitoring of ciprofloxacin and rosuvastatin in API, formulations and human serum.

PubMed

Arayne, M Saeed; Sultana, Najma; Tabassum, Arman

2015-02-01

An efficient, selective and cost-effective liquid chromatographic assay was developed and validated for the simultaneous quantification of ciprofloxacin and rosuvastatin in Active Pharmaceutical Ingredients (API), pharmaceutical formulations and in human serum. The chromatographic system consisted of mobile phase methanol-water, 90:10 v/v at pH 3.0 adjusted with o-phosphoric acid, pumped at 1.0 mL/min through a prepacked Purospher Star C18 (5 µm, 25 × 0.46 cm) column and effluent was monitored at the isosbestic point (255 nm) as well as at the λmax of individual drugs (243 and 271 nm). The method was validated over a linear concentration range of 0.25-15 µg/mL for ciprofloxacin and 0.33-20 µg/mL for rosuvastatin (r(2)  ≥ 0.999). The ranges of reliable response (limits of detection and quantitation) for ciprofloxacin were 3-15 and 9-45 ng/mL and 17-29 and 52-88 ng/mL, respectively, for rosuvastatin in all API, pharmaceutical formulations and human serum. Analytical recovery from human serum was >98% and relative standard deviation (RSD) was <2. The accuracies were 97.13-102.55 and 97.41-101.31% and precisions in RSD were 0.04-1.90 and 0.02-1.23% for ciprofloxacin and rosuvastatin, respectively. No matrix interferences, ion suppression/enhancement and carry-over were detected. The total assay run time was less than 5 min. In another study, for optimum performance the detector was programmed for multiwavelength scanning at the absorption maxima of each component. Consequently, the linearity range was improved and limit of detection and quantitation values were down to 1-4 and 4-12 ng/mL for ciprofloxacin and 3-5 and 9-15 ng/mL for rosuvastatin, respectively. The validation parameters fitted ICH guidelines through the isosbestic and individual λmax approach. The small sample volume and simplicity of preparation make this method suitable for use in human serum samples, pharmaceutical formulations, quality control, drug-drug interaction studies, clinical laboratories, drug research centers and forensic medical centers. Copyright © 2014 John Wiley & Sons, Ltd.

Classification and Visualization of Physical and Chemical Properties of Falsified Medicines with Handheld Raman Spectroscopy and X-Ray Computed Tomography.

PubMed

Kakio, Tomoko; Yoshida, Naoko; Macha, Susan; Moriguchi, Kazunobu; Hiroshima, Takashi; Ikeda, Yukihiro; Tsuboi, Hirohito; Kimura, Kazuko

2017-09-01

Analytical methods for the detection of substandard and falsified medical products (SFs) are important for public health and patient safety. Research to understand how the physical and chemical properties of SFs can be most effectively applied to distinguish the SFs from authentic products has not yet been investigated enough. Here, we investigated the usefulness of two analytical methods, handheld Raman spectroscopy (handheld Raman) and X-ray computed tomography (X-ray CT), for detecting SFs among oral solid antihypertensive pharmaceutical products containing candesartan cilexetil as an active pharmaceutical ingredient (API). X-ray CT visualized at least two different types of falsified tablets, one containing many cracks and voids and the other containing aggregates with high electron density, such as from the presence of the heavy elements. Generic products that purported to contain equivalent amounts of API to the authentic products were discriminated from the authentic products by the handheld Raman and the different physical structure on X-ray CT. Approach to investigate both the chemical and physical properties with handheld Raman and X-ray CT, respectively, promise the accurate discrimination of the SFs, even if their visual appearance is similar with authentic products. We present a decision tree for investigating the authenticity of samples purporting to be authentic commercial tablets. Our results indicate that the combination approach of visual observation, handheld Raman and X-ray CT is a powerful strategy for nondestructive discrimination of suspect samples.

Levothyroxine sodium revisited: A wholistic structural elucidation approach of new impurities via HPLC-HRMS/MS, on-line H/D exchange, NMR spectroscopy and chemical synthesis.

PubMed

Ruggenthaler, M; Grass, J; Schuh, W; Huber, C G; Reischl, R J

2017-02-20

The structural elucidation of unknown pharmaceutical impurities plays an important role in the quality control of newly developed and well-established active pharmaceutical ingredients (APIs). The United States Pharmacopeia (USP) monograph for the API Levothyroxine Sodium, a synthetic thyroid hormone, features two high pressure liquid chromatography (HPLC) methods using UV-VIS absorption detection to determine organic impurities in the drug substance. The impurity profile of the first USP method ("Procedure 1") has already been extensively studied, however for the second method ("Procedure 2"), which exhibits a significantly different impurity profile, no wholistic structural elucidation of impurities has been performed yet. Applying minor modifications to the chromatographic parameters of USP "Procedure 2" and using various comprehensive structural elucidation methods such as high resolution tandem mass spectrometry with on-line hydrogen-deuterium (H/D) exchange or two-dimensional nuclear magnetic resonance spectroscopy (NMR) we gained new insights about the complex impurity profile of the synthetic thyroid hormone. This resulted in the characterization of 24 compounds previously unknown to literature and the introduction of two new classes of Levothyroxine Sodium impurities. Five novel compounds were unambiguously identified via isolation or synthesis of reference substances and subsequent NMR spectroscopic investigation. Additionally, Collision-Induced Dissociation (CID)-type fragmentation of identified major impurities as well as neutral loss fragmentation patterns of many characterized impurities were discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Quantitative analysis of curcumin-loaded alginate nanocarriers in hydrogels using Raman and attenuated total reflection infrared spectroscopy.

PubMed

Miloudi, Lynda; Bonnier, Franck; Bertrand, Dominique; Byrne, Hugh J; Perse, Xavier; Chourpa, Igor; Munnier, Emilie

2017-07-01

Core-shell nanocarriers are increasingly being adapted in cosmetic and dermatological fields, aiming to provide an increased penetration of the active pharmaceutical or cosmetic ingredients (API and ACI) through the skin. In the final form, the nanocarriers (NC) are usually prepared in hydrogels, conferring desired viscous properties for topical application. Combined with the high chemical complexity of the encapsulating system itself, involving numerous ingredients to form a stable core and quantifying the NC and/or the encapsulated active without labor-intensive and destructive methods remains challenging. In this respect, the specific molecular fingerprint obtained from vibrational spectroscopy analysis could unambiguously overcome current obstacles in the development of fast and cost-effective quality control tools for NC-based products. The present study demonstrates the feasibility to deliver accurate quantification of the concentrations of curcumin (ACI)-loaded alginate nanocarriers in hydrogel matrices, coupling partial least square regression (PLSR) to infrared (IR) absorption and Raman spectroscopic analyses. With respective root mean square errors of 0.1469 ± 0.0175% w/w and 0.4462 ± 0.0631% w/w, both approaches offer acceptable precision. Further investigation of the PLSR results allowed to highlight the different selectivity of each approach, indicating only IR analysis delivers direct monitoring of the NC through the quantification of the Labrafac®, the main NC ingredient. Raman analyses are rather dominated by the contribution of the ACI which opens numerous perspectives to quantify the active molecules without interferences from the complex core-shell encapsulating systems thus positioning the technique as a powerful analytical tool for industrial screening of cosmetic and pharmaceutical products. Graphical abstract Quantitative analysis of encapuslated active molecules in hydrogel-based samples by means of infrared and Raman spectroscopy.

Low level drug product API form analysis - Avalide tablet NIR quantitative method development and robustness challenges.

PubMed

Pan, Duohai; Crull, George; Yin, Shawn; Grosso, John

2014-02-01

Avalide(@), a medication used for the treatment of hypertension, is a combination of Irbesartan, and Hydrochlorothiazide. Irbesartan, one of the active pharmaceutical ingredients (API) in Avalide products, exists in two neat crystalline forms: Form A and Form B. Irbesartan Form A is the API form used in a wet granulation for the preparation of Avalide tablets. The presence of the less soluble Irbesartan Form B in Avalide tablets may result in the slower dissolution. In this paper, we have presented our work on the method development, verification and challenges of quantitatively detecting, via NIR and ssNMR, very small amounts of Irbesartan Form B in Avalide tablets. As part of the NIR method development and qualification, limit of detection, linearity and accuracy were examined. In addition, a limited study of the robustness of the method was conducted and a bias in the level of Form B was correlated to the ambient humidity. ssNMR, a primary method for the determination of polymorphic composition, was successfully used as an orthogonal technique to verify the accuracy of the NIR method and added to the confidence in the NIR method. The speed and efficiency of the NIR method make it a suitable and convenient tool for routine analysis of Avalide tablets for Form B in a QC environment. Copyright © 2013 Elsevier B.V. All rights reserved.

Novel technology to prepare oral formulations for preclinical safety studies.

PubMed

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, HSDSC and Raman microscopy.

PubMed

Kanaujia, Parijat; Lau, Grace; Ng, Wai Kiong; Widjaja, Effendi; Schreyer, Martin; Hanefeld, Andrea; Fischbach, Matthias; Saal, Christoph; Maio, Mario; Tan, Reginald B H

2011-09-01

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials(®) to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.

How do formulation and process parameters impact blend and unit dose uniformity? Further analysis of the product quality research institute blend uniformity working group industry survey.

PubMed

Hancock, Bruno C; Garcia-Munoz, Salvador

2013-03-01

Responses from the second Product Quality Research Institute (PQRI) Blend Uniformity Working Group (BUWG) survey of industry have been reanalyzed to identify potential links between formulation and processing variables and the measured uniformity of blends and unit dosage forms. As expected, the variability of the blend potency and tablet potency data increased with a decrease in the loading of the active pharmaceutical ingredient (API). There was also an inverse relationship between the nominal strength of the unit dose and the blend uniformity data. The data from the PQRI industry survey do not support the commonly held viewpoint that granulation processes are necessary to create and sustain tablet and capsule formulations with a high degree of API uniformity. There was no correlation between the blend or tablet potency variability and the type of process used to manufacture the product. Although it is commonly believed that direct compression processes should be avoided for low API loading formulations because of blend and tablet content uniformity concerns, the data for direct compression processes reported by the respondents to the PQRI survey suggest that such processes are being used routinely to manufacture solid dosage forms of acceptable quality even when the drug loading is quite low. Copyright © 2012 Wiley Periodicals, Inc.

Production of drug nanosuspensions: effect of drug physical properties on nanosizing efficiency.

PubMed

Liu, Tao; Müller, Rainer H; Möschwitzer, Jan P

2018-02-01

Drug nanosuspension is one of the established methods to improve the bioavailability of poorly soluble drugs. Drug physical properties aspect (morphology, solid state, starting size et al) is a critical parameter determining the production efficiency. Some drug modification approaches such as spray-drying were proved to improve the millability of drug powders. However, the mechanism behind those improved performances is unclear. This study is to systematically investigate the influence of those physical properties. Five different APIs (active pharmaceutical ingredients) with different millabilities, i.e. resveratrol, hesperetin, glibenclamide, rutin, and quercetin, were processed by standard high pressure homogenization (HPH), wet bead milling (WBM), and a combinative method of spray-drying and HPH. Smaller starting sizes of certain APIs could accelerate the particle size reduction velocity during both HPH and WBM processes. Spherical particles were observed for almost all spray-dried powders (except spray-dried hesperetin) after spray-drying. The crystallinity of some spray-dried samples such as rutin and glibenclamide became much lower than their corresponding unmodified powders. Almost all spray-dried drug powders after HPH processes could lead to smaller nanocrystal particle size than unmodified APIs. The modified microstructure instead of solid state after spray-drying explained the potential reason for improved nanosizing efficiency. In addition, the contribution of starting size on the production efficiency was also critical according to both HPH and WBM results.

On-line near infrared spectroscopy as a Process Analytical Technology (PAT) tool to control an industrial seeded API crystallization.

PubMed

Schaefer, C; Lecomte, C; Clicq, D; Merschaert, A; Norrant, E; Fotiadu, F

2013-09-01

The final step of an active pharmaceutical ingredient (API) manufacturing synthesis process consists of a crystallization during which the API and residual solvent contents have to be quantified precisely in order to reach a predefined seeding point. A feasibility study was conducted to demonstrate the suitability of on-line NIR spectroscopy to control this step in line with new version of the European Medicines Agency (EMA) guideline [1]. A quantitative method was developed at laboratory scale using statistical design of experiments (DOE) and multivariate data analysis such as principal component analysis (PCA) and partial least squares (PLS) regression. NIR models were built to quantify the API in the range of 9-12% (w/w) and to quantify the residual methanol in the range of 0-3% (w/w). To improve the predictive ability of the models, the development procedure encompassed: outliers elimination, optimum model rank definition, spectral range and spectral pre-treatment selection. Conventional criteria such as, number of PLS factors, R(2), root mean square errors of calibration, cross-validation and prediction (RMSEC, RMSECV, RMSEP) enabled the selection of three model candidates. These models were tested in the industrial pilot plant during three technical campaigns. Results of the most suitable models were evaluated against to the chromatographic reference methods. Maximum relative bias of 2.88% was obtained about API target content. Absolute bias of 0.01 and 0.02% (w/w) respectively were achieved at methanol content levels of 0.10 and 0.13% (w/w). The repeatability was assessed as sufficient for the on-line monitoring of the 2 analytes. The present feasibility study confirmed the possibility to use on-line NIR spectroscopy as a PAT tool to monitor in real-time both the API and the residual methanol contents, in order to control the seeding of an API crystallization at industrial scale. Furthermore, the successful scale-up of the method proved its capability to be implemented in the manufacturing plant with the launch of the new API process. Copyright © 2013 Elsevier B.V. All rights reserved.

The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon, granule and tablet properties using multivariate data analysis.

PubMed

Boersen, Nathan; Carvajal, M Teresa; Morris, Kenneth R; Peck, Garnet E; Pinal, Rodolfo

2015-01-01

While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API. Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data. Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength. Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.

Rat Palatability Study for Taste Assessment of Caffeine Citrate Formulation Prepared via Hot-Melt Extrusion Technology

PubMed Central

Tiwari, Roshan V.; Polk, Ashley N.; Patil, Hemlata; Ye, Xingyou; Pimparade, Manjeet B.; Repka, Michael A.

2017-01-01

Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs, and overcomes some of the limitations of the existing taste masking techniques. Likewise, analytical taste assessment is an important quality control parameter evaluated by several in vivo and in vitro methods, such as the human taste panel, electrophysiological methods, electronic sensor, and animal preference tests to aid in selecting a taste-masked formulation. However, the most appropriate in-vivo method to assess the taste-masking efficacy of pediatric formulations remains unknown, because it is not known to what extent the human taste panel/electronic tongue can predict the palatability in the pediatric patients. The purpose of this study was to develop taste-masked caffeine citrate extrudates via HME, and to demonstrate the wide applicability of a single bottle-test rat model to record and compare the volume consumed of the taste-masked solutions to that of the pure API. Thus, this rat model can be considered as a low-cost alternative taste-assessment method to the most commonly used expensive human taste panel/electronic tongue method for pediatric formulations. PMID:26573158

Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold.

PubMed

Wenzel, Tim; Stillhart, Cordula; Kleinebudde, Peter; Szepes, Anikó

2017-08-01

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.

Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating.

PubMed

Huang, Zhonghui; Scicolone, James V; Han, Xi; Davé, Rajesh N

2015-01-30

The improvements in the flow and packing of fine pharmaceutical powder blends due to dry coating of micronized acetaminophen (mAPAP, ∼11μm), a model poorly flowing drug, are quantified. Poor flow and packing density of fine excipients (∼20μm) allowed testing the hypothesis that dry coating of cohesive API may counteract poor flow and packing of fine pharmaceutical powder blends. Further, fine excipients could improve compaction and reduce segregation tendency. It was found that flow function coefficient (FFC) and bulk density enhancements for 10%, 30%, and 60% (w/w), API loading blends with dry coated API are significantly higher than those without coated silica. At the highest API loading, for which coarser excipients were also used as reference, the flow and packing of dry coated mAPAP blends were significantly increased regardless of the excipient particle size, exceeding those of a well compacting excipient, Avicel 102. In addition, tensile strength of tablets with fine excipients was significantly higher, indicating improved compactibility. These results show for the first time that dry coating of fine, cohesive API powder leads to significantly improved flow and packing of high API loading blends consisting of fine excipients, while achieving improved tablet compactibility, suggesting suitability for direct compaction. Copyright © 2014 Elsevier B.V. All rights reserved.

21 CFR 212.50 - What production and process controls must I have?

Code of Federal Regulations, 2011 CFR

2011-04-01

... containers, closures, and packaging materials, including a specimen or copy of each label and all other... radioactivity or other measurement of each active pharmaceutical ingredient and each inactive ingredient per... active pharmaceutical ingredient and each inactive ingredient per batch or per unit of radioactivity or...

Solid Lipid Nanoparticle-Based Calix[n]arenes and Calix-Resorcinarenes as Building Blocks: Synthesis, Formulation and Characterization

PubMed Central

Montasser, Imed; Shahgaldian, Patrick; Perret, Florent; Coleman, Anthony W.

2013-01-01

Solid lipid nanoparticles (SLNs) have attracted increasing attention during recent years. This paper presents an overview about the use of calix[n]arenes and calix-resorcinarenes in the formulation of SLNs. Because of their specific inclusion capability both in the intraparticle spaces and in the host cavities as well as their capacity for functionalization, these colloidal nanostructures represent excellent tools for the encapsulation of different active pharmaceutical ingredients (APIs) in the area of drug targeting, cosmetic additives, contrast agents, etc. Various synthetic routes to the supramolecular structures will be given. These various routes lead to the formulation of the corresponding SLNs. Characterization, properties, toxicological considerations as well as numerous corresponding experimental studies and analytical methods will be also exposed and discussed. PMID:24196356

Pharmaceutical cocrystals: walking the talk.

PubMed

Bolla, Geetha; Nangia, Ashwini

2016-06-28

Pharmaceutical cocrystals belong to a sub-class of cocrystals wherein one of the components is a drug molecule (or an active pharmaceutical ingredient, API) and the second is a benign food or drug grade additive (generally regarded as safe, GRAS). The two components are hydrogen-bonded in a fixed stoichiometric ratio in the crystal lattice. In the past decade, pharmaceutical cocrystals have demonstrated significant promise in their ability to modify the physicochemical and pharmacokinetic properties of drug substances, such as the solubility and dissolution rate, bioavailability, particle morphology and size, tableting and compaction, melting point, physical form, biochemical and hydration stability, and permeability. In this feature review, we highlight some prominent examples of drug cocrystals which exhibit variable hardness/softness and elasticity/plasticity depending on coformer selection, improvement of solubility and permeability in the same cocrystal, increase of the melting point for solid formulation, enhanced color performance, photostability and hydration stability, and a longer half-life. Cocrystals of flavanoids and polyphenols can make improved pharmaceuticals and also extend to the larger class of nutraceuticals. The application of crystal engineering to assemble ternary cocrystals expands this field to drug-drug cocrystals which may be useful in multi-drug resistance, mitigating side effects of drugs, or attenuating/enhancing drug action synergistically by rational selection. The advent of new techniques for structural characterization beyond the standard X-ray diffraction will provide a better understanding of drug phases which are at the borderline of crystalline-amorphous nature and even newer opportunities in the future.

Comparison of the antifungal efficacy of terbinafine hydrochloride and ciclopirox olamine containing formulations against the dermatophyte Trichophyton rubrum in an infected nail plate model.

PubMed

Täuber, Anja; Müller-Goymann, Christel C

2014-07-07

Onychomycosis is a fungal infection mostly induced by dermatophytes such as Trichophyton rubrum. Due to slow nail growth, the treatment takes 3-9 months depending on the nail size and infected area. Hence, high efficacy of the active ingredient without systemic side effects is of major interest. To test the efficacy of an antifungal formulation, an appropriate in vitro model reflecting the in vivo situation as close as possible is required. In this study, a variety of antifungal formulations, i.e., commercial ones (Ciclopoli and Lamisil cream), those used in compounding pharmacies (Pentravan) as well as poloxamer 407-based systems, have been evaluated in an infected nail plate model. The active pharmaceutical ingredients (APIs) were ciclopirox olamine and terbinafine hydrochloride. The poloxamer 407-based formulations consisted of poloxamer 407, double distilled water, propylene glycol, isopropyl alcohol, medium chain triglycerides and either 1% ciclopirox olamine or 1% terbinafine hydrochloride as API, respectively. Former studies have shown high permeation rates of terbinafine hydrochloride from similar poloxamer 407-based formulations with dimethyl isosorbide instead of propylene glycol. The present contribution shows superior inhibition of T. rubrum growth from poloxamer 407-based formulations in comparison to the commercial Lamisil cream. Moreover, poloxamer 407-based formulations were equally effective as the nail lacquer Ciclopoli even though the poloxamer formulations contained only 1% of the drug instead of 8% in the marketed lacquer. Poloxamer 407-based systems containing ciclopirox olamine proved to be about as effective as similar terbinafine hydrochloride systems.

The Matthew Effect and widely prescribed pharmaceuticals lacking environmental monitoring: case study of an exposure-assessment vulnerability.

PubMed

Daughton, Christian G

2014-01-01

Assessing ambient exposure to chemical stressors often begins with time-consuming and costly monitoring studies to establish environmental occurrence. Both human and ecological toxicology are currently challenged by the unknowns surrounding low-dose exposure/effects, compounded by the reality that exposure undoubtedly involves mixtures of multiple stressors whose identities and levels can vary over time. Long absent from the assessment process, however, is whether the full scope of the identities of the stressors is sufficiently known. The Matthew Effect (a psychosocial phenomenon sometimes informally called the "bandwagon effect" or "iceberg effect," among others) may adversely bias or corrupt the exposure assessment process. The Matthew Effect is evidenced by decisions that base the selection of stressors to target in environmental monitoring surveys on whether they have been identified in prior studies, rather than considering the possibility that additional, but previously unreported, stressors might also play important roles in an exposure scenario. The possibility that the Matthew Effect might influence the scope of environmental stressor research is explored for the first time in a comprehensive case study that examines the preponderance of "absence of data" (in contrast to positive data and "data of absence") for the environmental occurrence of a very large class of potential chemical stressors associated with ubiquitous consumer use - active pharmaceutical ingredients (APIs). Comprehensive examination of the published data for an array of several hundred of the most frequently used drugs for whether their APIs are environmental contaminants provides a prototype example to catalyze discussion among the many disciplines involved with assessing risk. The findings could help guide the selection of those APIs that might merit targeting for environmental monitoring (based on the absence of data for environmental occurrence) as well as the prescribing of those medications that might have minimal environmental impact (based on data of absence for environmental occurrence). © 2013. Published by Elsevier B.V. All rights reserved.

Stability studies of anticancer agent bis(4-fluorobenzyl)trisulfide and synthesis of related substances.

PubMed

Bao, Yimei; Mo, Xiaopeng; Xu, Xiaoying; He, Yuyu; Xu, Xiao; An, Haoyun

2008-11-04

Bis(4-fluorobenzyl)trisulfide, fluorapacin, has been extensively developed as a promising new anticancer drug candidate. Its degradation products were identified and verified by the newly synthesized compounds bis(4-fluorobenzyl)disulfide (A) and bis(4-fluorobenzyl)tetrasulfide (B) which were resulted from the disproportionation of fluorapacin under forced conditions. A stability-indicating HPLC method was used for the stability evaluation of active pharmaceutical ingredient (API) fluorapacin and finished pharmaceutical product (FPP) under various conditions. High recovery (99.57%) of API was found after three freeze-thaw cycle processes of fluorapacin FPP. Susceptibility of fluorapacin to oxidative degradation was studied by treating fluorapacin and FPP in 30% hydrogen peroxide aqueous solution, and the result verified the oxidative stability of fluorapacin. However, treatment of this drug candidate under strong light (4500 Lx+/-500 Lx) for 10 days showed substantial effect on the recovery of fluorapacin, especially from fluorapacin FPP. Strong acid (1.0M, HCl) did not affect the recovery of fluorapacin while strong basic condition (1.0M, NaOH) accelerated the disproportionation of fluorapacin to its related substances A and B. The stability of fluorapacin in its aqueous media at a pH range of 2.0-10.0 for up to 6h was further investigated, and 4.0-8.0 was found to be the most stable pH range. Fluorapacin and FPP were exposed to the elevated temperatures of 40 and 60 degrees C for 10 days without obvious impact on their stability. The thermal stability of fluorapacin API and FPP under constant humidity with light protection was also thoroughly investigated under accelerated (40+/-2 degrees C, RH 75+/-5%, 6 months) and long-term (25+/-2 degrees C, RH 60+/-10%, 24 months) conditions. There was no significant change except minor color change of fluorapacin FPP. Therefore, fluorapacin has excellent stability as a potential drug candidate for further clinical development investigation.

Rapid and specific drug quality testing assay for artemisinin and its derivatives using a luminescent reaction and novel microfluidic technology.

PubMed

Ho, Nga T; Desai, Darash; Zaman, Muhammad H

2015-06-01

Globally, it is estimated that about 10-30% of pharmaceuticals are of poor quality. Poor-quality drugs lead to long-term drug resistance, create morbidity, and strain the financial structure of the health system. The current technologies for substandard drug detection either are too expensive for low-resource regions or only provide qualitative results. To address the current limitations with point-of-care technologies, we have developed an affordable and robust assay to quantify the amount of active pharmaceutical ingredients (APIs) to test product quality. Our novel assay consists of two parts: detection reagent (probe) and a microfluidic testing platform. As antimalarials are of high importance in the global fight against malaria and are often substandard, they are chosen as the model to validate our assay. As a proof-of-concept, we have tested the assay with artesunate pure and substandard samples (Arsuamoon tablets) from Africa and compared with the conventional 96-well plate with spectrophotometer to demonstrate the quantitative efficacy and performance of our system. © The American Society of Tropical Medicine and Hygiene.

Influence of process parameters on content uniformity of a low dose active pharmaceutical ingredient in a tablet formulation according to GMP.

PubMed

Muselík, Jan; Franc, Aleš; Doležel, Petr; Goněc, Roman; Krondlová, Anna; Lukášová, Ivana

2014-09-01

The article describes the development and production of tablets using direct compression of powder mixtures. The aim was to describe the impact of filler particle size and the time of lubricant addition during mixing on content uniformity according to the Good Manufacturing Practice (GMP) process validation requirements. Processes are regulated by complex directives, forcing the producers to validate, using sophisticated methods, the content uniformity of intermediates as well as final products. Cutting down of production time and material, shortening of analyses, and fast and reliable statistic evaluation of results can reduce the final price without affecting product quality. The manufacturing process of directly compressed tablets containing the low dose active pharmaceutical ingredient (API) warfarin, with content uniformity passing validation criteria, is used as a model example. Statistic methods have proved that the manufacturing process is reproducible. Methods suitable for elucidation of various properties of the final blend, e.g., measurement of electrostatic charge by Faraday pail and evaluation of mutual influences of researched variables by partial least square (PLS) regression, were used. Using these methods, it was proved that the filler with higher particle size increased the content uniformity of both blends and the ensuing tablets. Addition of the lubricant, magnesium stearate, during the blending process improved the content uniformity of blends containing the filler with larger particles. This seems to be caused by reduced sampling error due to the suppression of electrostatic charge.

Predicting melt rheology for hot-melt extrusion by means of a simple Tg-measurement.

PubMed

Bochmann, Esther S; Üstüner, Elgin E; Gryczke, Andreas; Wagner, Karl G

2017-10-01

The feasibility of predicting melt rheology by using the glass transition temperature (T g ) of a desired amorphous solid dispersion (ASD) for hot-melt extrusion (HME) and other melt based processes is presented. Three groups of three different active pharmaceutical ingredients (APIs) or plasticizer/copovidone mixtures, with identical glass transition in rheological testing, were used. Their rheological behavior as a function of temperature and frequency were analyzed by means of small amplitude oscillatory shear (SAOS) on an oscillatory rheometer. The zero-shear viscosity (η 0 ) identified at 150°C was compared to T g , measured by differential scanning calorimetry (DSC) and SAOS. A strong correlation between η 0 and T g was identified, independent of the API or plasticizer used to achieve T g of the mixture. To evaluate and rate the discrepancy in η 0 of the different mixtures at same T g , hot-melt extrusion trials were conducted to measure torque and mean residence time. In this paper, carbamazepine, dipyridamole, indomethacin, ibuprofen, polyethylene glycol (PEG 1500) in vinylpyrrolidone-vinyl acetate copolymer (copovidone) as matrix polymer were used. Copyright © 2017. Published by Elsevier B.V.

Theoretical and experimental study of fenofibrate and simvastatin

NASA Astrophysics Data System (ADS)

Nicolás Vázquez, Inés; Rodríguez-Núñez, Jesús Rubén; Peña-Caballero, Vicente; Ruvalcaba, Rene Miranda; Aceves-Hernandez, Juan Manuel

2017-12-01

Fenofibrate, an oral fibrate lipid lowering agent, and simvastatin, which reduces plasma levels of low-density lipoprotein cholesterol, are active pharmaceutical ingredients (APIs), currently in the market. We characterized these APIs by thermal analysis and conducted X-ray powder diffraction techniques. Studies should be carried out in the formulation stage before the final composition of a polypill may be established. Thus, it was found in thermochemical studies that both compounds present no chemical interactions in an equimolar mixture of solid samples at room temperature. Theoretical studies were employed to determine possible interactions between fenofibrate and simvastatin. A very weak intramolecular hydrogen bond is formed between the hydroxyl group (O5H5) of the simvastatin with chlorine and carbonyl group (C11O4, C1O2) of the fenofibrate molecule. These weak energy hydrogen bonds have no effect on the chemical stability of the compounds studied. The results were obtained using Density Functional Theory methods; particularly the BPE1BPE and B3LYP functional and 6-31++G** basis set. The values of energy show good approximation when are compared with similar calculations previously reported. Infrared spectra of monomers and dimers were obtained via theoretical calculations.

Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

PubMed

Doncel, Gustavo F; Clark, Meredith R

2010-12-01

A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

Applications of NIR spectroscopy to monitoring and analyzing the solid state during industrial crystallization processes.

PubMed

Févotte, G; Calas, J; Puel, F; Hoff, C

2004-04-01

Fiber-optic near infrared (NIR) spectroscopy was used to investigate several key features of the polymorphic transitions observed during the crystallization and the filtration of SaC, an Active Pharmaceutical Ingredient (API) produced by Sanofi-Synthelabo. Using few samples, the spectroscopic data were calibrated to provide measurements of the polymorphic composition of the solid product which is likely to appear in two crystalline forms or in the amorphous state. Both qualitative and quantitative methods were successfully evaluated to characterize the API. The NIR spectroscopy measurement was then applied to investigate the kinetic behavior of the phase transition phenomena against various operating conditions. From the viewpoint of industrial process development several applications are presented. The effects of temperature and seed crystal habits on the rate of transition of filtration cakes are briefly investigated; and a study of the effect of residual water in the solvent on the transition occurring during filtration is more deeply analyzed. The experimental results demonstrate that highly valuable information can be provided by the NIR spectroscopy measurements, when one aims at understanding more deeply and optimizing the consequences of various and complex phenomena involved during the solid processing chain.

Crystal Nucleation Using Surface-Energy-Modified Glass Substrates.

PubMed

Nordquist, Kyle A; Schaab, Kevin M; Sha, Jierui; Bond, Andrew H

2017-08-02

Systematic surface energy modifications to glass substrates can induce nucleation and improve crystallization outcomes for small molecule active pharmaceutical ingredients (APIs) and proteins. A comparatively broad probe for function is presented in which various APIs, proteins, organic solvents, aqueous media, surface energy motifs, crystallization methods, form factors, and flat and convex surface energy modifications were examined. Replicate studies ( n ≥ 6) have demonstrated an average reduction in crystallization onset times of 52(4)% (alternatively 52 ± 4%) for acetylsalicylic acid from 91% isopropyl alcohol using two very different techniques: bulk cooling to 0 °C using flat surface energy modifications or microdomain cooling to 4 °C from the interior of a glass capillary having convex surface energy modifications that were immersed in the solution. For thaumatin and bovine pancreatic trypsin, a 32(2)% reduction in crystallization onset times was demonstrated in vapor diffusion experiments ( n ≥ 15). Nucleation site arrays have been engineered onto form factors frequently used in crystallization screening, including microscope slides, vials, and 96- and 384-well high-throughput screening plates. Nucleation using surface energy modifications on the vessels that contain the solutes to be crystallized adds a layer of useful variables to crystallization studies without requiring significant changes to workflows or instrumentation.

Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid.

PubMed

Dressman, Jennifer B; Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Zimmer, Markus

2012-08-01

A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance. Copyright © 2012 Wiley Periodicals, Inc.

The Effects of Pharmaceutical Excipients on Gastrointestinal Tract Metabolic Enzymes and Transporters-an Update.

PubMed

Zhang, Wenpeng; Li, Yanyan; Zou, Peng; Wu, Man; Zhang, Zhenqing; Zhang, Tao

2016-07-01

Accumulating evidence from the last decade has shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on metabolic enzymes and/or drug transporters. Hence, the absorption, distribution, metabolism, and elimination (ADME) of active pharmaceutical ingredients (APIs) may be altered due to the modulation of their metabolism and transport by excipients. The impact of excipients is a potential concern for Biopharmaceutics Classification System (BCS)-based biowaivers, particularly as the BCS-based biowaivers have been extended to class 3 drugs in certain dosage forms. The presence of different excipients or varying amounts of excipients between formulations may result in bio-inequivalence. The excipient impact may lead to significant variations in clinical outcomes as well. The aim of this paper is to review the recent findings of excipient effects on gastrointestinal (GI) absorption, focusing on their interactions with the metabolic enzymes and transporters in the GI tract. A wide range of commonly used excipients such as binders, diluents, fillers, solvents, and surfactants are discussed here. We summarized the reported effects of those excipients on GI tract phase I and phase II enzymes, uptake and efflux transporters, and relevant clinical significance. This information can enhance our understanding of excipient influence on drug absorption and is useful in designing pharmacokinetic studies and evaluating the resultant data.

Quantitative determination of salbutamol sulfate impurities using achiral supercritical fluid chromatography.

PubMed

Dispas, Amandine; Desfontaine, Vincent; Andri, Bertyl; Lebrun, Pierre; Kotoni, Dorina; Clarke, Adrian; Guillarme, Davy; Hubert, Philippe

2017-02-05

In the last years, supercritical fluid chromatography has largely been acknowledged as a singular and performing technique in the field of separation sciences. Recent studies highlighted the interest of SFC for the quality control of pharmaceuticals, especially in the case of the determination of the active pharmaceutical ingredient (API). Nevertheless, quality control requires also the determination of impurities. The objectives of the present work were to (i) demonstrate the interest of SFC as a reference technique for the determination of impurities in salbutamol sulfate API and (ii) to propose an alternative to a reference HPLC method from the European Pharmacopeia (EP) involving ion-pairing reagent. Firstly, a screening was carried out to select the most adequate and selective stationary phase. Secondly, in the context of robust optimization strategy, the method was developed using design space methodology. The separation of salbutamol sulfate and related impurities was achieved in 7min, which is seven times faster than the LC-UV method proposed by European Pharmacopeia (total run time of 50min). Finally, full validation using accuracy profile approach was successfully achieved for the determination of impurities B, D, F and G in salbutamol sulfate raw material. The validated dosing range covered 50 to 150% of the targeted concentration (corresponding to 0.3% concentration level), LODs close to 0.5μg/mL were estimated. The SFC method proposed in this study could be presented as a suitable fast alternative to EP LC method for the quantitative determination of salbutamol impurities. Copyright © 2016 Elsevier B.V. All rights reserved.

Simultaneous determination of the impurity and radial tensile strength of reduced glutathione tablets by a high selective NIR-PLS method.

PubMed

Li, Juan; Jiang, Yue; Fan, Qi; Chen, Yang; Wu, Ruanqi

2014-05-05

This paper establishes a high-throughput and high selective method to determine the impurity named oxidized glutathione (GSSG) and radial tensile strength (RTS) of reduced glutathione (GSH) tablets based on near infrared (NIR) spectroscopy and partial least squares (PLS). In order to build and evaluate the calibration models, the NIR diffuse reflectance spectra (DRS) and transmittance spectra (TS) for 330 GSH tablets were accurately measured by using the optimized parameter values. For analyzing GSSG or RTS of GSH tablets, the NIR-DRS or NIR-TS were selected, subdivided reasonably into calibration and prediction sets, and processed appropriately with chemometric techniques. After selecting spectral sub-ranges and neglecting spectrum outliers, the PLS calibration models were built and the factor numbers were optimized. Then, the PLS models were evaluated by the root mean square errors of calibration (RMSEC), cross-validation (RMSECV) and prediction (RMSEP), and by the correlation coefficients of calibration (R(c)) and prediction (R(p)). The results indicate that the proposed models have good performances. It is thus clear that the NIR-PLS can simultaneously, selectively, nondestructively and rapidly analyze the GSSG and RTS of GSH tablets, although the contents of GSSG impurity were quite low while those of GSH active pharmaceutical ingredient (API) quite high. This strategy can be an important complement to the common NIR methods used in the on-line analysis of API in pharmaceutical preparations. And this work expands the NIR applications in the high-throughput and extraordinarily selective analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

Exploring the salt–cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering

PubMed Central

Rajput, Lalit; Banik, Manas; Yarava, Jayasubba Reddy; Joseph, Sumy; Pandey, Manoj Kumar

2017-01-01

There has been significant recent interest in differentiating multicomponent solid forms, such as salts and cocrystals, and, where appropriate, in determining the position of the proton in the X—H⋯A—Y X −⋯H—A +—Y continuum in these systems, owing to the direct relationship of this property to the clinical, regulatory and legal requirements for an active pharmaceutical ingredient (API). In the present study, solid forms of simple cocrystals/salts were investigated by high-field (700 MHz) solid-state NMR (ssNMR) using samples with naturally abundant 15N nuclei. Four model compounds in a series of prototypical salt/cocrystal/continuum systems exhibiting {PyN⋯H—O—}/{PyN+—H⋯O−} hydrogen bonds (Py is pyridine) were selected and prepared. The crystal structures were determined at both low and room temperature using X-ray diffraction. The H-atom positions were determined by measuring the 15N—1H distances through 15N-1H dipolar interactions using two-dimensional inversely proton-detected cross polarization with variable contact-time (invCP-VC) 1H→15N→1H experiments at ultrafast (νR ≥ 60–70 kHz) magic angle spinning (MAS) frequency. It is observed that this method is sensitive enough to determine the proton position even in a continuum where an ambiguity of terminology for the solid form often arises. This work, while carried out on simple systems, has implications in the pharmaceutical industry where the salt/cocrystal/continuum condition of APIs is considered seriously. PMID:28875033

Exploring the salt-cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering.

PubMed

Rajput, Lalit; Banik, Manas; Yarava, Jayasubba Reddy; Joseph, Sumy; Pandey, Manoj Kumar; Nishiyama, Yusuke; Desiraju, Gautam R

2017-07-01

There has been significant recent interest in differentiating multicomponent solid forms, such as salts and cocrystals, and, where appropriate, in determining the position of the proton in the X -H⋯ A - Y X - ⋯H- A + - Y continuum in these systems, owing to the direct relationship of this property to the clinical, regulatory and legal requirements for an active pharmaceutical ingredient (API). In the present study, solid forms of simple cocrystals/salts were investigated by high-field (700 MHz) solid-state NMR (ssNMR) using samples with naturally abundant 15 N nuclei. Four model compounds in a series of prototypical salt/cocrystal/continuum systems exhibiting {PyN⋯H-O-}/{PyN + -H⋯O - } hydrogen bonds (Py is pyridine) were selected and prepared. The crystal structures were determined at both low and room temperature using X-ray diffraction. The H-atom positions were determined by measuring the 15 N- 1 H distances through 15 N- 1 H dipolar interactions using two-dimensional inversely proton-detected cross polarization with variable contact-time (invCP-VC) 1 H→ 15 N→ 1 H experiments at ultrafast (ν R ≥ 60-70 kHz) magic angle spinning (MAS) frequency. It is observed that this method is sensitive enough to determine the proton position even in a continuum where an ambiguity of terminology for the solid form often arises. This work, while carried out on simple systems, has implications in the pharmaceutical industry where the salt/cocrystal/continuum condition of APIs is considered seriously.

Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride.

PubMed

Shehata, Mostafa A; Fawaz, Esraa M; El-Rahman, Mohamed K Abd; Abdel-Moety, Ezzat M

2017-11-30

Acquisition of the dissolution profiles of more than single active ingredient in a multi-analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off-line separation-based chromatographic methods. This contribution adopts a new "Double-Track" approach with the ultimate goal of advancing the in-line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real-time measurements is the key driver for adoption of "green analytical chemistry" (GAC) principles aiming to expand the application of eco-friendly analytical methods With the aim of performing a side-by-side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm ® tablets was selected as a model for which dissolution profiles were attained by two techniques. The first "Double-Track" in-line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4-chlorophenyl) borate as a cation exchanger. The second off-line strategy utilizes a separation-based HPLC method via off-line tracking the increase of peak area by UV detection at 220nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced "Double-Track" approach regarding GAC principles are highlighted, and the merits of these benign real-time analyzers (ISEs) that can deliver equivalent analytical results as HPLC while significantly reducing solvent consumption/waste generation are described. Copyright © 2017 Elsevier B.V. All rights reserved.

Can pharmaceutical co-crystals provide an opportunity to modify the biological properties of drugs?

PubMed

Dalpiaz, Alessandro; Pavan, Barbara; Ferretti, Valeria

2017-08-01

Poorly soluble and/or permeable molecules jeopardize the discovery and development of innovative medicines. Pharmaceutical co-crystals, formed by an active pharmaceutical substance (API) and a co-crystal former, can show enhanced dissolution and permeation values compared with those of the parent crystalline pure phases. It is currently assumed that co-crystallization with pharmaceutical excipients does not affect the pharmacological activity of an API or, indeed, might even improve physical properties such as solubility and permeability. However, as we highlight here, the biological behavior of co-crystals can differ drastically with respect to that of their parent physical mixtures. Copyright © 2017 Elsevier Ltd. All rights reserved.

Raman spectroscopy for the analytical quality control of low-dose break-scored tablets.

PubMed

Gómez, Diego A; Coello, Jordi; Maspoch, Santiago

2016-05-30

Quality control of solid dosage forms involves the analysis of end products according to well-defined criteria, including the assessment of the uniformity of dosage units (UDU). However, in the case of break-scored tablets, given that tablet splitting is widespread as a means to adjust doses, the uniform distribution of the active pharmaceutical ingredient (API) in all the possible fractions of the tablet must be assessed. A general procedure to accomplish with both issues, using Raman spectroscopy, is presented. It is based on the acquisition of a collection of spectra in different regions of the tablet, that later can be selected to determine the amount of API in the potential fractions that can result after splitting. The procedure has been applied to two commercial products, Sintrom 1 and Sintrom 4, with API (acenocoumarol) mass proportion of 2% and 0.7% respectively. Partial Least Squares (PLS) calibration models were constructed for the quantification of acenocoumarol in whole tablets using HPLC as a reference analytical method. Once validated, the calibration models were used to determine the API content in the different potential fragments of the scored Sintrom 4 tablets. Fragment mass measurements were also performed to estimate the range of masses of the halves and quarters that could result after tablet splitting. The results show that Raman spectroscopy can be an alternative analytical procedure to assess the uniformity of content, both in whole tablets as in its potential fragments, and that Sintrom 4 tablets can be perfectly split in halves, but some cautions have to be taken when considering the fragmentation in quarters. A practical alternative to the use of UDU test for the assessment of tablet fragments is proposed. Copyright © 2016 Elsevier B.V. All rights reserved.

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug

PubMed Central

Alyami, Hamad; Dahmash, Eman; Bowen, James

2017-01-01

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation. PMID:28609454

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug.

PubMed

Alyami, Hamad; Dahmash, Eman; Bowen, James; Mohammed, Afzal R

2017-01-01

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

Limitations of high dose carrier based formulations.

PubMed

Yeung, Stewart; Traini, Daniela; Tweedie, Alan; Lewis, David; Church, Tanya; Young, Paul M

2018-06-10

This study was performed to investigate how increasing the active pharmaceutical ingredient (API) content within a formulation affects the dispersion of particles and the aerosol performance efficiency of a carrier based dry powder inhalable (DPI) formulation, using a custom dry powder inhaler (DPI) development rig. Five formulations with varying concentrations of API beclomethasone dipropionate (BDP) between 1% and 30% (w/w) were formulated as a multi-component carrier system containing coarse lactose and fine lactose with magnesium stearate. The morphology of the formulation and each component were investigated using scanning electron micrographs while the particle size was measured by laser diffraction. The aerosol performance, in terms of aerodynamic diameter, was assessed using the British pharmacopeia Apparatus E cascade impactor (Next generation impactor). Chemical analysis of the API was observed by high performance liquid chromatography (HPLC). Increasing the concentration of BDP in the blend resulted in increasing numbers and size of individual agglomerates and densely packed BDP multi-layers on the surface of the lactose carrier. BDP present within the multi-layer did not disperse as individual primary particles but as dense agglomerates, which led to a decrease in aerosol performance and increased percentage of BDP deposition within the Apparatus E induction port and pre-separator. As the BDP concentration in the blends increases, aerosol performance of the formulation decreases, in an inversely proportional manner. Concurrently, the percentage of API deposition in the induction port and pre-separator could also be linked to the amount of micronized particles (BDP and Micronized composite carrier) present in the formulation. The effect of such dose increase on the behaviour of aerosol dispersion was investigated to gain greater insight in the development and optimisation of higher dosed carrier-based formulations. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System.

PubMed

Vosburg, Suzanne K; Severtson, S Geoffrey; Dart, Richard C; Cicero, Theodore J; Kurtz, Steven P; Parrino, Mark W; Green, Jody L

2018-04-01

Tapentadol, a Schedule II opioid with a combination of µ-opioid activity and norepinephrine reuptake inhibition, is used for the management of moderate to severe acute and chronic pain. Its dual mechanism of action is thought to reduce opioid-related side effects that can complicate pain management. Since approval, tapentadol has been tracked across multiple outcomes suggesting abuse liability, and a pattern of relatively low, although not absent, abuse liability has been found. This retrospective cohort study further details the abuse liability of tapentadol as an active pharmaceutical ingredient (API) when immediate-release as well as extended-release formulations were on the market together (fourth quarter of 2011 to second quarter of 2016). Tapentadol (API) was compared with tramadol, hydrocodone, morphine, oxycodone, hydromorphone, and oxymorphone across Poison Center, Drug Diversion, and Treatment Center Programs Combined data streams from the Researched Abuse, Diversion and Addiction-Related Surveillance system. Findings suggest the public health burden related to tapentadol to date is low, but present. Event rates of abuse per population-level denominators were significantly lower than all other opioids examined. However, when adjusted for drug availability, event rates of abuse were lower than most Schedule II opioids studied, but were not the lowest. Disentangling these 2 sets of findings further by examining various opioid formulations, such as extended-release and the role of abuse-deterrent formulations, is warranted. This article presents the results from an examination of tapentadol API across the Researched Abuse, Diversion and Addiction-Related Surveillance System: a broad and carefully designed postmarketing mosaic. Data to date from Poison Center, Drug Diversion, and Treatment Centers combined suggest a low, but present public health burden related to tapentadol. Copyright © 2018. Published by Elsevier Inc.

Neotropics and natural ingredients for pharmaceuticals: why isn't South American biodiversity on the crest of the wave?

PubMed

Desmarchelier, Cristian

2010-06-01

Despite the advent of biotechnology and modern methods of combinatorial chemistry and rational drug design, nature still plays a surprisingly important role as a source of new pharmaceutical compounds. These are marketed either as herbal drugs or as single active ingredients. South American tropical ecosystems (or the Neotropics) encompass one-third of the botanical biodiversity of the planet. For centuries, indigenous peoples have been using plants for healing purposes, and scientists are making considerable efforts in order to validate these uses from a pharmacological/phytochemical point of view. However, and despite the unique plant diversity in the region, very few natural pharmaceutical ingredients from this part of the world have reached the markets in industrialized countries. The present review addresses the importance of single active ingredients and herbal drugs from South American flora as natural ingredients for pharmaceuticals; it highlights the most relevant cases in terms of species of interest; and discusses the key entry barriers for these products in industrialized countries. It explores the reasons why, in spite of the region's competitive advantages, South American biodiversity has been a poor source of natural ingredients for the pharmaceutical industry. (c) 2010 John Wiley & Sons, Ltd.

Dose-to-dose variations with single packages of counterfeit medicines and adulterated dietary supplements as a potential source of false negatives and inaccurate health risk assessments.

PubMed

Venhuis, B J; Zwaagstra, M E; Keizers, P H J; de Kaste, D

2014-02-01

In this report, we show three examples of how the variability in dose units in single packages of counterfeit medicines and adulterated dietary supplements may contribute to a false negative screening result and inaccurate health risk assessments. We describe a counterfeit Viagra 100mg blister pack and a box of an instant coffee both containing dose units with and without an active pharmaceutical ingredient (API). We also describe a purportedly herbal slimming product with capsules that mutually differed in API and impurities. The adulterated dietary supplements contained sibutramine, benzyl-sibutramine, N-desmethyl-sibutramine (DMS), N,N-didesmethyl-sibutramine (DDMS) and several other related impurities. Counterfeit medicines and adulterated dietary supplements are a health risk because their quality is unreliable. Health risks are even greater when such unreliability extends to fundamental differences between dose units in one package. Because dose-to-dose variability for these products is unpredictable, the confidence interval of a sample size is unknown. Consequently, the analyses of a selection of dose units may not be representative for the package. In the worst case, counterfeit or unauthorised medicines are not recognised as such or a health risk is not identified. In order to reduce erroneous results particular care should be taken when analysing a composite of dose units, when finding no API in a dietary supplement and when finding conformity in a suspect counterfeit medicine. Copyright © 2013 Elsevier B.V. All rights reserved.

Development Considerations for Nanocrystal Drug Products.

PubMed

Chen, Mei-Ling; John, Mathew; Lee, Sau L; Tyner, Katherine M

2017-05-01

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals.

PubMed

Yamamoto, Katsuhiko; Tsutsumi, Shunichirou; Ikeda, Yukihiro

2012-11-01

Cocrystals (CCs) used in the pharmaceutical industry are defined as complex crystals formed by reaction between an API and a cocrystal former (CCF); unlike salts, CCs do not show proton transfer. Recently, pharmaceutical CCs have been used to improve the drug-likeness of APIs, such as solubility and stability. Grinding is more effective for CC synthesis than crystallization from solution because in the former case, the API can predominantly interact with the CCF without being affected by solvents. However, this method is tedious because the API is ground with only one CCF at a time. We developed a cocktail cocrystal grinding (CCG) method, in which a mixture of CCFs having the same functional group was used. No false negatives/positives were observed in CCG when carbamazepine was used as the model compound. This method could be used to obtain CCs of piroxicam and spironolactone. False negatives were observed for only one compound from among three model compounds, indicating that CCG facilitates efficient CC detection and that it has higher throughput than does the conventional method. Further, CCG is fast and suitable for rational CC screening, and it helps identify the partial structure of CCFs that forms synthons with an API. Copyright © 2012 Elsevier B.V. All rights reserved.

Containment challenges in HPAPI manufacture for ADC generation.

PubMed

Dunny, Elizabeth; O'Connor, Imelda; Bones, Jonathan

2017-06-01

Antibody-drug conjugates (ADCs) are emerging as an impactful class of therapeutics for the treatment of cancer because of their ability to harness the specificity of an antibody and the cytotoxic potential of the payload to target and destroy cancer cells. However, the potent nature of the cytotoxic payload creates associated manufacturing challenges for active pharmaceutical ingredient (API) manufacturers, because huge investment in containment technology is required to ensure the protection of operators and the environment. Here, we examine the differing attitudes to high-potency categorisation and levels of containment control. We also provide an overview of the most widely used containment strategies for facility design, powder handling, purification, analysis, and cleaning. Finally, we briefly consider the health and safety regulatory challenges associated with the manufacture of cytotoxic payloads for use in antibody-drug conjugates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Topical otic drugs in a multi-purpose manufacturing facility: a guide on determination and application of permitted daily exposure (PDE).

PubMed

Wiesner, Lisa; Prause, Maarten; Lovsin Barle, Ester

2018-03-01

Due to newly introduced EU GMP (Good Manufacturing Practice) guideline for Medicinal Products for Human and Veterinary use, product specific permitted daily exposure (PDE) for toxicological evaluation in multi-purpose facilities are required within a documented process for risk assessment. European Medicines Agency (EMA) guidance on setting PDE limits so far focused on systemic administration routes such as intravenous (IV), oral or inhalation. This article provides guidance on setting PDE values for risk management purposes in multi-purpose facilities for active pharmaceutical ingredients (APIs) applied as topical otic drugs to the outer ear canal. The therewith determined PDE otic, is used for the calculation of maximum safe carry-over (MSC) in manufacturing scenarios where a topical otic product is manufactured followed by another topical otic product.

Solid-state NMR of Complex Nano- and Microcrystalline Materials

NASA Astrophysics Data System (ADS)

Hirsh, David A.

The work in this thesis demonstrates the utility and broad applicability of solid-state nuclear magnetic resonance (SSNMR) spectroscopy to the study of complex materials containing mixtures of multiple structures and/or disparate local environments. Multinuclear SSNMR is particularly well-suited to the characterization of such systems, and can provide a wealth of information that cannot be obtained with other instrumental methods. Studies involving two classes of materials are detailed herein, namely rare-earth nanoparticles and active pharmaceutical ingredients. The first three projects described involve the study of inorganic rare-earth (RE, RE = Y, Sc, La-Lu) nanoparticles (NP), which have unique optical and magnetic properties that are desirable for a diverse range of applications. Many of the properties of these materials are related to the incorporation of dopants into the host structures. The chemical reactions necessary to prepare these materials are complex and challenging to optimize; however, careful structural analysis of these materials is imperative to inform and to improve their rational design. Herein, we first use multinuclear (i.e., 19F, 23Na, 89Y, 1H, 13C, 45Sc) SSNMR to establish the molecular-level structure of a widely used undoped host material, beta-NaYF4, resolving a longstanding debate regarding the crystal structure. Similar experiments are used to probe the structures of NaYF4 nanomaterials formed with advanced core/shell structures containing multiple RE-materials and having oleates bound to their surfaces. Expanding on this foundation, the structural effects of the incorporation of paramagnetic dopant ions in NaYF4 NPs is described in a second study. Through the use of ultra-fast magic angle spinning (UFMAS) SSNMR experiments, we have obtained spectra with valuable details regarding the distributions of the dopant ions and their mean distances from other atoms in the NP cores and surfaces. The final project in this area pertains to a distinct class of zeolitic RE-doped nanomaterials, where the structural effects of different dopants are compared using numerous characterization techniques, including multinuclear SSNMR spectroscopy, powder X-ray diffraction (PXRD), transmission electron microscopy (TEM), and electron paramagnetic resonance (EPR) spectroscopy. The second half of this thesis concerns a prominent class of materials found in everyday life, active pharmaceutical ingredients (APIs). The identification of solid forms of APIs plays an important role in drug development, both in the discovery of new forms and quality assurance in manufacturing. Herein, three important areas of pharmaceutical research are addressed using multinuclear SSNMR methods, with a primary focus on the application of ultra-wideline 35Cl SSNMR. (35Cl is a spin-3/2 quadrupolar nucleus). First, methods to improve the lower detection limit of Cl in low wt-% dosage formulations through the use of dynamic nuclear polarization (DNP) enhanced ultra-wideline 35Cl SSNMR spectra are presented. Next, a new method using 35Cl SSNMR for the quantification of APIs in dosage formulations with a high level of accuracy is detailed. In this proof-of-concept study, it is also shown how quantification methods can be used to measure the amount of disproportionation (i.e., conversion of cationic APIs to neutral free-base forms with distinct structures and properties) that occurs in a model dosage formulation. Finally, a case study of a variable hydrate HCl salt API is presented. Such materials form stable structures over a continuous range of non-stoichiometric hydration levels. This work demonstrates how 35Cl SSNMR is well-suited to characterize such materials, given the ability of this technique to probe the sites of hydration and detect changes in the hydrated C- anion environments as the material is dehydrated or rehydrated. For each of these projects, 35Cl SSNMR data are supported by additional multinuclear experiments (e.g., 1H, 2H, 13C, 19F, 23Na) and other characterization methods ( e.g., XRD and thermal analysis).

Dissolution testing of isoniazid, rifampicin, pyrazinamide and ethambutol tablets using near-infrared spectroscopy (NIRS) and multivariate calibration.

PubMed

de Oliveira Neves, Ana Carolina; Soares, Gustavo Mesquita; de Morais, Stéphanie Cavalcante; da Costa, Fernanda Saadna Lopes; Porto, Dayanne Lopes; de Lima, Kássio Michell Gomes

2012-01-05

This work utilized the near-infrared spectroscopy (NIRS) and multivariate calibration to measure the percentage drug dissolution of four active pharmaceutical ingredients (APIs) (isoniazid, rifampicin, pyrazinamide and ethambutol) in finished pharmaceutical products produced in the Federal University of Rio Grande do Norte (Brazil). The conventional analytical method employed in quality control tests of the dissolution by the pharmaceutical industry is high-performance liquid chromatography (HPLC). The NIRS is a reliable method that offers important advantages for the large-scale production of tablets and for non-destructive analysis. NIR spectra of 38 samples (in triplicate) were measured using a Bomen FT-NIR 160 MB in the range 1100-2500nm. Each spectrum was the average of 50 scans obtained in the diffuse reflectance mode. The dissolution test, which was initially carried out in 900mL of 0.1N hydrochloric acid at 37±0.5°C, was used to determine the percentage a drug that dissolved from each tablet measured at the same time interval (45min) at pH 6.8. The measurement of the four API was performed by HPLC (Shimadzu, Japan) in the gradiente mode. The influence of various spectral pretreatments (Savitzky-Golay smoothing, Multiplicative Scatter Correction (MSC), and Savitzky-Golay derivatives) and multivariate analysis using the partial least squares (PLS) regression algorithm was calculated by the Unscrambler 9.8 (Camo) software. The correlation coefficient (R(2)) for the HPLC determination versus predicted values (NIRS) ranged from 0.88 to 0.98. The root-mean-square error of prediction (RMSEP) obtained from PLS models were 9.99%, 8.63%, 8.57% and 9.97% for isoniazid, rifampicin, ethambutol and pyrazinamide, respectively, indicating that the NIR method is an effective and non-destructive tool for measurement of drug dissolution from tablets. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

21 CFR 212.50 - What production and process controls must I have?

Code of Federal Regulations, 2010 CFR

2010-04-01

... containers, closures, and packaging materials, including a specimen or copy of each label and all other..., the name and radioactivity or other measurement of each active pharmaceutical ingredient and each... active pharmaceutical ingredient and each inactive ingredient per batch or per unit of radioactivity or...

Investigation of Dissolution Behavior HPMC/Eudragit®/Magnesium Aluminometasilicate Oral Matrices Based on NMR Solid-State Spectroscopy and Dynamic Characteristics of Gel Layer.

PubMed

Naiserová, M; Kubová, K; Vysloužil, J; Pavloková, S; Vetchý, D; Urbanová, M; Brus, J; Vysloužil, J; Kulich, P

2018-02-01

Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required for burst effect reduction. Promising variant could be seen in combination of HPMC and insoluble Eudragits ® as water dispersions. These can be applied only on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam from HPMC/Eudragit ® NE matrices using magnesium aluminometasilicate (Neusilin ® US2) as filler with excellent WAC. Part of this study was also to assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin ® allowed the application of Eudragit ® dispersion to API/Neusilin ® mixture in one step during high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decrease in burst effect (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit ® NE concentration. The explanation was done by ssNMR, which clearly showed a significant reduction of the API particle size (150-500 nm) in granules as effect of surfactant present in dispersion in dependence on Eudragit ® NE amount. This change in API particle size resulted in a significantly larger interface between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.

Compatibility of cholecalciferol, haloperidol, imipramine hydrochloride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimus monohydrate, terbinafine, tramadol hydrochloride and valsartan in SyrSpend SF PH4 oral suspensions.

PubMed

Polonini, H C; Silva, S L; Cunha, C N; Brandão, M A F; Ferreira, A O

2016-04-01

A challenge with compounding oral liquid formulations is the limited availability of data to support the physical, chemical and microbiological stability of the formulation. This poses a patient safety concern and a risk for medication errors. The objective of this study was to evaluate the compatibility of the following active pharmaceutical ingredients (APIs) in 10 oral suspensions, using SyrSpend SF PH4 (liquid) as the suspending vehicle: cholecalciferol 50,000 IU/mL, haloperidol 0.5 mg/mL, imipramine hydrochloride 5.0 mg/mL, levodopa/carbidopa 5.0/1.25 mg/mL, lorazepam 1.0 mg/mL, minocycline hydrochloride 10.0 mg/mL, tacrolimus monohydrate 1.0 mg/mL, terbinafine 25.0 mg/mL, tramadol hydrochloride 10.0 mg/mL and valsartan 4.0 mg/mL. The suspensions were stored both refrigerated (2 - 8 degrees C) and at controlled room temperature (20 - 25 degrees C). This is the first stability study for these APIs in SyrSpend SF PH4 (liquid). Further, the stability of haloperidol,ilmipramine hydrochloride, minocycline, and valsartan in oral suspension has not been previously reported in the literature. Compatibility was assessed by measuring percent recovery at varying time points throughout a 90 days period. Quantification of the APIs was performed by high performance liquid chromatography (HPLC-UV). Given the percentage of recovery of the APIs within the suspensions, the beyond-use date of the final preparations was found to be at least 90 days for most suspensions both refrigerated and at room temperature. Exceptions were: Minocycline hydrochloride at both storage temperatures (60 days), levodopa/carbidopa at room temperature (30 days), and lorazepam at room temperature (60 days). This suggests that compounded suspensions of APIs from different pharmacological classes in SyrSpend SF PH4 (liquid) are stable.

Advances in simultaneous DSC-FTIR microspectroscopy for rapid solid-state chemical stability studies: some dipeptide drugs as examples.

PubMed

Lin, Shan-Yang; Wang, Shun-Li

2012-04-01

The solid-state chemistry of drugs has seen growing importance in the pharmaceutical industry for the development of useful API (active pharmaceutical ingredients) of drugs and stable dosage forms. The stability of drugs in various solid dosage forms is an important issue because solid dosage forms are the most common pharmaceutical formulation in clinical use. In solid-state stability studies of drugs, an ideal accelerated method must not only be selected by different complicated methods, but must also detect the formation of degraded product. In this review article, an analytical technique combining differential scanning calorimetry and Fourier-transform infrared (DSC-FTIR) microspectroscopy simulates the accelerated stability test, and simultaneously detects the decomposed products in real time. The pharmaceutical dipeptides aspartame hemihydrate, lisinopril dihydrate, and enalapril maleate either with or without Eudragit E were used as testing examples. This one-step simultaneous DSC-FTIR technique for real-time detection of diketopiperazine (DKP) directly evidenced the dehydration process and DKP formation as an impurity common in pharmaceutical dipeptides. DKP formation in various dipeptides determined by different analytical methods had been collected and compiled. Although many analytical methods have been applied, the combined DSC-FTIR technique is an easy and fast analytical method which not only can simulate the accelerated drug stability testing but also at the same time enable to explore phase transformation as well as degradation due to thermal-related reactions. This technique offers quick and proper interpretations. Copyright © 2012 Elsevier B.V. All rights reserved.

New protocol for αAstree electronic tongue enabling full performance qualification according to ICH Q2.

PubMed

Pein, Miriam; Eckert, Carolin; Preis, Maren; Breitkreutz, Jörg

2013-09-01

Performance qualification (PQ) of taste sensing systems is mandatory for their use in pharmaceutical industry. According to ICH Q2 (R1) and a recent adaptation for taste sensing systems, non-specificity, log-linear relationships between the concentration of analytes and the sensor signal as well as a repeatability with relative standard deviation (RSD) values <4% were defined as basic requirements to pass a PQ. In the present work, the αAstree taste sensing system led to a successful PQ procedure by the use of recent sensor batches for pharmaceutical applications (sensor set #2) and a modified measurement protocol. Log-linear relationships between concentration and responses of each sensor were investigated for different bitter tasting active pharmaceutical ingredients (APIs). Using the new protocol, RSD values <2.1% were obtained in the repeatability study. Applying the visual evaluation approach, detection and quantitation limit could be determined for caffeine citrate with every sensor (LOD 0.05-0.5 mM, LOQ: 0.1-0.5 mM). In addition, the sensor set marketed for food applications (sensor set #5) was proven to show beneficial effects regarding the log-linear relationship between the concentration of quinine hydrochloride and the sensor signal. By the use of our proposed protocol, it is possible to implement the αAstree taste sensing system as a tool to assure quality control in the pharmaceutical industry. Copyright © 2013 Elsevier B.V. All rights reserved.

Rapid classification of pharmaceutical ingredients with Raman spectroscopy using compressive detection strategy with PLS-DA multivariate filters.

PubMed

Cebeci Maltaş, Derya; Kwok, Kaho; Wang, Ping; Taylor, Lynne S; Ben-Amotz, Dor

2013-06-01

Identifying pharmaceutical ingredients is a routine procedure required during industrial manufacturing. Here we show that a recently developed Raman compressive detection strategy can be employed to classify various widely used pharmaceutical materials using a hybrid supervised/unsupervised strategy in which only two ingredients are used for training and yet six other ingredients can also be distinguished. More specifically, our liquid crystal spatial light modulator (LC-SLM) based compressive detection instrument is trained using only the active ingredient, tadalafil, and the excipient, lactose, but is tested using these and various other excipients; microcrystalline cellulose, magnesium stearate, titanium (IV) oxide, talc, sodium lauryl sulfate and hydroxypropyl cellulose. Partial least squares discriminant analysis (PLS-DA) is used to generate the compressive detection filters necessary for fast chemical classification. Although the filters used in this study are trained on only lactose and tadalafil, we show that all the pharmaceutical ingredients mentioned above can be differentiated and classified using PLS-DA compressive detection filters with an accumulation time of 10ms per filter. Copyright © 2013 Elsevier B.V. All rights reserved.

Stability of Acetazolamide, Baclofen, Dipyridamole, Mebeverine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4.

PubMed

Ferreira, Anderson de Oliveira; Polonini, Hudson; da Silva, Sharlene Loures; Aglio, Natália Cristina Buzinari; Abreu, Jordana; Fernandes, Brandão Marcos Antônio

2017-01-01

The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

WHO Expert Committee on Specifications for Pharmaceutical Preparations.

PubMed

2009-01-01

The Expert Committee on Specifications for Pharmaceutical Preparations works towards clear, independent and practical standards and guidelines for the quality assurance of medicines. Standards are developed by the Committee through worldwide consultation and an international consensus-building process. The following new standards and guidelines were adopted and recommended for use: the current list of available International Chemical Reference Substances and International Infrared Reference Spectra; guidelines on stability testing of active pharmaceutical ingredients and finished pharmaceutical products; procedure for prequalification of pharmaceutical products; and the procedure for assessing the acceptability, in principle, of active pharmaceutical ingredients for use in pharmaceutical products.

An atmospheric pressure ionization source using a high voltage target compared to electrospray ionization for the LC/MS analysis of pharmaceutical compounds.

PubMed

Lubin, Arnaud; De Vries, Ronald; Cabooter, Deirdre; Augustijns, Patrick; Cuyckens, Filip

2017-08-05

The type and design of an ionization source can have a significant influence on the performances of a bioanalytical method. It is, therefore, of high interest to evaluate the performances of newly introduced sources to highlight their benefits and limitations in comparison to other well established sources. In this paper, liquid chromatography - mass spectrometry (LC/MS) performances of a new atmospheric pressure ionization (API) source, commercialized as UniSpray, is evaluated. The dynamic range of 24 pharmaceutical and biological compounds is compared between the new API source and electrospray ionization (ESI) for 3 different mobile phase conditions. Matrix effects are also compared with ESI on a refined selection of 19 pharmaceutical and biological compounds in 4 matrices commonly encountered in bioanalysis. A slightly better dynamic range towards lower concentrations was often observed with the new API source. Matrix effects were quite similar between the two sources with a small, but statistically significant, lower percentage of matrix effects observed for the new API source in plasma and bile in the positive ion mode, and bile in negative ion mode for ESI. Finally, the sensitivity of late eluting compounds could be improved on the new API source by post-column addition of water. Copyright © 2017 Elsevier B.V. All rights reserved.

21 CFR 212.1 - What are the meanings of the technical terms used in these regulations?

Code of Federal Regulations, 2011 CFR

2011-04-01

... permit the use of a component, container and closure, in-process material, packaging material, or..., and Cosmetic Act, as amended (21 U.S.C. 321 et seq.). Active pharmaceutical ingredient means a... ingredient means any intended component of the PET drug other than the active pharmaceutical ingredient. In...

Real-time assessment of critical quality attributes of a continuous granulation process.

PubMed

Fonteyne, Margot; Vercruysse, Jurgen; Díaz, Damián Córdoba; Gildemyn, Delphine; Vervaet, Chris; Remon, Jean Paul; De Beer, Thomas

2013-02-01

There exists the intention to shift pharmaceutical manufacturing of solid dosage forms from traditional batch production towards continuous production. The currently applied conventional quality control systems, based on sampling and time-consuming off-line analyses in analytical laboratories, would annul the advantages of continuous processing. It is clear that real-time quality assessment and control is indispensable for continuous production. This manuscript evaluates strengths and weaknesses of several complementary Process Analytical Technology (PAT) tools implemented in a continuous wet granulation process, which is part of a fully continuous from powder-to-tablet production line. The use of Raman and NIR-spectroscopy and a particle size distribution analyzer is evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline- lactose blend. The solid state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the active pharmaceutical ingredient (API). A higher barrel temperature and a higher powder feed rate, resulted in larger granules.

The global biopharma industry and the rise of Indian drug multinationals: implications for Australian generics policy.

PubMed

Löfgren, Hans

2007-06-01

This article provides a synopsis of the new dynamics of the global biopharma industry. The emergence of global generics companies with capabilities approximating those of 'big pharma' has accelerated the blurring of boundaries between the innovator and generics sectors. Biotechnology-based products form a large and growing segment of prescription drug markets and regulatory pathways for biogenerics are imminent. Indian biopharma multinationals with large-scale efficient manufacturing plants and growing R&D capabilities are now major suppliers of Active Pharmaceutical Ingredients (APIs) and generic drugs across both developed and developing countries. In response to generic competition, innovator companies employ a range of life cycle management techniques, including the launch of 'authorised generics'. The generics segment in Australia will see high growth rates in coming years but the prospect for local manufacturing is bleak. The availability of cheap generics in international markets has put pressure on Pharmaceutical Benefits Scheme (PBS) pricing arrangements, and a new policy direction was announced in November 2006. Lower generics prices will have a negative impact on some incumbent suppliers but industrial renewal policies for the medicines industry in Australia are better focused on higher value R&D activities and niche manufacturing of sophisticated products.

Selected pharmaceuticals entering an estuary: Concentrations, temporal trends, partitioning, and fluxes.

PubMed

Cantwell, Mark G; Katz, David R; Sullivan, Julia C; Ho, Kay; Burgess, Robert M; Cashman, Michaela

2016-11-01

In many coastal watersheds and ecosystems, rivers discharging to estuaries receive waters from domestic wastewater-treatment plants resulting in the release and distribution of pharmaceuticals to the marine environment. In the present study, 15 active pharmaceutical ingredients were measured regularly over 1 yr in the dissolved and particulate phases as they entered Narragansett Bay from the Pawtuxet River in Cranston (Rhode Island, USA). Of the active pharmaceutical ingredients measured, 14 were consistently present in the dissolved phase, with concentrations ranging from below detection to >310 ng/L, whereas 8 were present in the particulate phase (0.2-18 ng/g). Partition coefficients (K d s and K OC s) were determined, and organic carbon normalization reduced variability associated with K d s for the active pharmaceutical ingredients evaluated. Flux estimates based on river flow were calculated for both dissolved and particulate-phase active pharmaceutical ingredients, with particulate fluxes being low (1-12 g/yr) and dissolved fluxes of active pharmaceutical ingredients being 155 g/yr to 11 600 g/yr. Results indicate that the pharmaceuticals measured in the present study reside primarily in the dissolved phase and thus are likely bioavailable on entering the estuarine waters of Narragansett Bay. This long-term temporal study provides important information on seasonal and annual dynamics of pharmaceuticals in an urban estuarine watershed. Environ Toxicol Chem 2016;35:2665-2673. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.

Visualization and Non-Destructive Quantification of Inkjet-Printed Pharmaceuticals on Different Substrates Using Raman Spectroscopy and Raman Chemical Imaging.

PubMed

Edinger, Magnus; Bar-Shalom, Daniel; Rantanen, Jukka; Genina, Natalja

2017-05-01

The purpose of this study was to investigate the applicability of Raman spectroscopy for visualization and quantification of inkjet-printed pharmaceuticals. Haloperidol was used as a model active pharmaceutical ingredient (API), and a printable ink base containing lactic acid and ethanol was developed. Inkjet printing technology was used to apply haloperidol ink onto three different substrates. Custom-made inorganic compacts and dry foam, as well as marketed paracetamol tablets were used as the substrates. Therapeutic personalized doses were printed by using one to ten printing rounds on the substrates. The haloperidol content in the finished dosage forms were determined by high-performance liquid chromatography (HPLC). The distribution of the haloperidol on the dosage forms were visualized using Raman chemical imaging combined with principal components analysis (PCA). Raman spectroscopy combined with modeling by partial least squares (PLS) regression was used for establishment of a quantitative model of the haloperidol content in the printed dosage forms. A good prediction of the haloperidol content was achieved for the inorganic compacts, while a slightly poorer prediction was observed for the paracetamol tablets. It was not possible to quantify haloperidol on the dry foam due to the low and varying density of the substrate. Raman spectroscopy is a useful tool for visualization and quality control of inkjet printed personalized medicine.

Development and characterization of voriconazole loaded nanoparticles for parenteral delivery.

PubMed

Füredi, Petra; Kovács, Kristóf; Ludányi, Krisztina; Antal, István; Klebovich, Imre

2016-08-20

Human serum albumin (HSA) has attracted the most attention in the last decades as a new nanocarrier system of active pharmaceutical ingredients (API) due to its biocompatibility and high binding capacity to hydrophobic drugs. Voriconazole (VCZ), an antifungal agent with low water solubility, was selected to produce albumin based nanoparticles using nanoparticle albumin-bound technology (nab™-technology). Aim of our study was to study the development process of VCZ-loaded nanoparticles for parenteral drug delivery, such as homogenizing pressure, homogenizing cycle number and drug loading capacity. The main characters of nanoparticles such as particle size distribution and polydispersity index (PDI) were determined by dynamic light scattering. Six homogenization cycles at 1800bar were ensured the acceptable PDI value (lower than 0.3) of the VCZ content nanoparticles. Optimized formulation process produced 81.2±1nm average particle size which meets the requirements of intravenous administration. Furthermore, the encapsulated concentration of VCZ was 69.7±4.2% and the water solubility was over 2 times greater than the API itself which were determined by the developed HPLC method. The in vivo release behavior can be predicted from our applied in vitro dissolution study. Almost 50% of VCZ was liberated from the nanoparticles in the first 60min. Copyright © 2016 Elsevier B.V. All rights reserved.

Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C.

PubMed

Hill, Andrew; Simmons, Bryony; Gotham, Dzintars; Fortunak, Joseph

2016-01-01

Novel treatments for hepatitis C demonstrate high cure rates, but current high prices can be a barrier to rapid global treatment scale-up. Generic competition can rapidly lower drug prices. Using data on exports of raw materials in 2015, we calculated currently feasible generic prices of sofosbuvir and daclatasvir. Data on per-kilogram prices of sofosbuvir and daclatasvir active pharmaceutical ingredients (API) exported from India were extracted from an online database. To the cost of the amount of API needed for a 12-week treatment course, we added cost estimates for formulation (40%), packaging (US$0.35/month), and a mark-up (50%). Between 1 January and 15 October 2015, over 5 tons of sofosbuvir were exported, with prices decreasing by US$702/kg/month, and observed prices of US$2501/kg in early September. Over the same period, 84 kg of daclatasvir were exported, with prices decreasing by US$1664/kg/month to US$1897/kg. Using the price estimation algorithm, we estimated the price of a generic sofosbuvir-daclatasvir combination regimen at US$200 per patient for a 12-week treatment course. The costs of generic production of sofosbuvir and daclatasvir are rapidly decreasing. Sofosbuvir-daclatasvir combination treatment could be produced for US$200 per patient per 12-week course.

Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

PubMed

Penkina, Anna; Semjonov, Kristian; Hakola, Maija; Vuorinen, Sirpa; Repo, Timo; Yliruusi, Jouko; Aruväli, Jaan; Kogermann, Karin; Veski, Peep; Heinämäki, Jyrki

2016-01-01

Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used.

Preparation and In Vitro/In Vivo Evaluation of Vinpocetine Elementary Osmotic Pump System

PubMed Central

Ning, Meiying; Zhou, Yue; Chen, Guojun; Mei, Xingguo

2011-01-01

Preparation and in vitro and in vivo evaluation of vinpocetine (VIN) elementary osmotic pump (EOP) formulations were investigated. A method for the preparation of VIN elementary osmotic pump tablet was obtained by adding organic acid additives to increase VIN solubility. VIN was used as the active pharmaceutical ingredient, lactose and mannitol as osmotic agent. Citric acid was used as increasing API solubility and without resulting in the API degradation. It is found that the VIN release rate was increasing with the citric acid amount at a constant range. Cellulose acetate 398-3 was employed as semipermeable membrane containing polyethylene glycol 6000 and diethyl-o-phthalate as pore-forming agent and plasticizer for controlling membrane permeability. In addition, a clear difference between the pharmacokinetic patterns of VIN immediate release and VIN elementary osmotic pump formulations was revealed. The area under the plasma concentration-time curve after oral administration of elementary osmotic pump formulations was equivalent to VIN immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VIN from elementary osmotic pump formulations. These results suggest that the VIN osmotic pump controlled release tablets have marked controlled release characters and the VIN osmotic pump controlled release tablets and the normal tablets were bioequivalent. PMID:21577257

Production of antiretroviral drugs in middle- and low-income countries.

PubMed

Pinheiro, Eloan dos Santos; Brüning, Karin; Macedo, M Fernanda; Siani, Antonio C

2014-01-01

This review outlines the main issues concerning the production of antiretroviral (ARV) drugs in middle- and low-income countries and the relevant political, legal and technical requirements for supporting such production. The requirements for efficient local production, including the manufacture of generic and branded products and public demand, have been considered from economic, market and socio-political perspectives. A steady and consistent government policy is crucial to success. Additional crucial factors in establishing local production are adequate infrastructure, qualified human resources in technical and managerial areas, and production-distribution logistics systems. The creation or strengthening of a national drug regulatory agency is a basic requirement. Production of ARVs relies on the structure of the international market for active pharmaceutical ingredients (APIs), which are highly monopolized for inclusion in branded or patented drugs, or are concentrated in a few Asian generic companies. Countries seeking to begin local production must develop strategies to overcome the various barriers. For instance, sub-Saharan African countries may benefit from developing multilateral health agreements with neighbouring countries. Such agreements are recommended and should be complemented by technology transfers, especially for the manufacture of APIs. Achieving a production level that is sustainable in the long term is crucial to maintaining patients' access to ARVs.

Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins.

PubMed

Bloomquist, Cameron J; Mecham, Michael B; Paradzinsky, Mark D; Janusziewicz, Rima; Warner, Samuel B; Luft, J Christopher; Mecham, Sue J; Wang, Andrew Z; DeSimone, Joseph M

2018-05-28

Mass customization along with the ability to generate designs using medical imaging data makes 3D printing an attractive method for the fabrication of patient-tailored drug and medical devices. Herein we describe the application of Continuous Liquid Interface Production (CLIP) as a method to fabricate biocompatible and drug-loaded devices with controlled release properties, using liquid resins containing active pharmaceutical ingredients (API). In this work, we characterize how the release kinetics of a model small molecule, rhodamine B-base (RhB), are affected by device geometry, network crosslink density, and the polymer composition of polycaprolactone- and poly (ethylene glycol)-based networks. To demonstrate the applicability of using API-loaded liquid resins with CLIP, the UV stability was evaluated for a panel of clinically-relevant small molecule drugs. Finally, select formulations were tested for biocompatibility, degradation and encapsulation of docetaxel (DTXL) and dexamethasone-acetate (DexAc). Formulations were shown to be biocompatible over the course of 175 days of in vitro degradation and the clinically-relevant drugs could be encapsulated and released in a controlled fashion. This study reveals the potential of the CLIP manufacturing platform to serve as a method for the fabrication of patient-specific medical and drug-delivery devices for personalized medicine. Copyright © 2018. Published by Elsevier B.V.

Impact of sodium chloride on the expansion of a liquid-liquid miscibility gap in an API/water system. Case study of Brivaracetam.

PubMed

Couvrat, Nicolas; Mahieux, Julien; Fours, Baptiste; Cartigny, Yohann; Schenkel, Eric; Aerts, Luc; Quéré, Luc; Coquerel, Gérard

2016-12-30

Brivaracetam, or (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, is an active pharmaceutical ingredient designed for the treatment of epilepsy. During the development of the IV administration mode, a liquid-liquid miscibility gap has been observed with pure water, isotonic and hypertonic solutions (vehicle at 0.9% w/w and 5%w/w NaCl respectively). The study reveals that the NaCl concentration has a direct impact on the extent of the demixing domain; from a sub-micronic demixing in pure water towards a macroscopic miscibility gap in hypertonic aqueous solutions. The thorough exploration of these heterogeneous equilibria led to define experimental parameters for safe IV injections without risk of liquid - liquid miscibility gap at 37°C. Copyright © 2016 Elsevier B.V. All rights reserved.

Adulteration and Counterfeiting of Online Nutraceutical Formulations in the United States: Time for Intervention?

PubMed

Nounou, Mohamed Ismail; Ko, Yamin; Helal, Nada A; Boltz, Jeremy F

2017-10-11

Global prevalence of nutraceuticals is noticeably high. The American market is flooded with nutraceuticals claiming to be of natural origin and sold with a therapeutic claim by major online retail stores such as Amazon and eBay. The objective of this commentary is to highlight the possible problems of online-sold nutraceuticals in the United States with respect to claim, adulterants, and safety. Furthermore, there is a lack of strict regulatory laws governing the sales, manufacturing, marketing, and label claims of nutraceutical formulations currently sold in the U.S. market. Major online retail stores and Internet pharmacies aid the widespread sale of nutraceuticals. Finally, according to the literature, many of these products were found to be either counterfeit or adulterated with active pharmaceutical ingredients (API) and mislabeled as being safe and natural. Therefore, regulatory authorities along with the research community should intervene to draw attention to these products and their possible effects.

A novel method for the determination of chemical purity and assay of menaquinone-7. Comparison with the methods from the official USP monograph.

PubMed

Jedynak, Łukasz; Jedynak, Maria; Kossykowska, Magdalena; Zagrodzka, Joanna

2017-02-20

An HPLC method with UV detection and separation with the use of a C30 reversed phase analytical column for the determination of chemical purity and assay of menaquinone-7 (MK7) in one chromatographic run was developed. The method is superior to the methods published in the USP Monograph in terms of selectivity, sensitivity and accuracy, as well as time, solvent and sample consumption. The developed methodology was applied to MK7 samples of active pharmaceutical ingredient (API) purity, MK7 samples of lower quality and crude MK7 samples before purification. The comparison of the results revealed that the use of USP methodology could lead to serious overestimation (up to a few percent) of both purity and MK7 assay in menaquinone-7 samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Factors influencing the quality of Myrmecia pilosula (Jack Jumper) ant venom for use in in vitro and in vivo diagnoses of allergen sensitization and in allergen immunotherapy.

PubMed

Wanandy, T; Dwyer, H E; McLean, L; Davies, N W; Nichols, D; Gueven, N; Brown, S G A; Wiese, M D

2017-11-01

Allergen immunotherapy uses pharmaceutical preparations derived from naturally occurring source materials, which contain water-soluble allergenic components responsible for allergic reactions. The success of in vivo and in vitro diagnoses in allergen sensitization and allergen immunotherapy largely depends on the quality, composition and uniformity of allergenic materials used to produce the active ingredients, and the formulation employed to prepare finished products. We aimed to examine the factors influencing batch-to-batch consistency of Jack Jumper (Myrmecia pilosula) ant venom (JJAV) in the form of active pharmaceutical ingredient (AI) and informed whether factors such as temperature, artificial light and container materials influence the quality of JJAV AIs. We also aimed to establish handling and storage requirements of JJAV AIs to ensure preservation of allergenic activities during usage in the diagnosis of allergen sensitization and in allergen immunotherapy. The quality and consistency of JJAV AIs were analysed using a combination of bicinchoninic acid assay for total protein quantification, HPLC-UV for JJAV allergen peptides quantification, ELISA inhibition for total allergenic potency, SDS-PAGE, AU-PAGE and immunoblot for qualitative assessment of JJAV components, and Limulus Amebocyte Lysate assay for the quantification of endotoxin concentration. API-ZYM and Zymogram assays were used to probe the presence of enzymatic activities in JJAV. Pharmaceutical-grade JJAV for allergen immunotherapy has good batch-to-batch consistency. Temporary storage at 4°C and light exposure do not affect the quality of JJAV. Exposure to temperature above 40°C degrades high MW allergens in JJAV. Vials containing JJAV must be stored frozen and in upright position during long-term storage. We have identified factors, which can influence the quality and consistency of JJAV AIs, and provided a framework for appropriate handling, transporting and storage of JJAV to be used for the diagnosis of allergen sensitization and in AIT. © 2017 John Wiley & Sons Ltd.

Stability of Alprazolam, Atropine Sulfate, Glutamine, Levofloxacin, Metoprolol Tartrate, Nitrofurantoin, Ondansetron Hydrochloride, Oxandrolone, Pregabaline, and Riboflavin in SyrSpend SF pH4 Oral Suspensions.

PubMed

Ferreira, Anderson O; Polonini, Hudson C; Loures da Silva, Sharlene; Cerqueira de Melo, Victor Augusto; de Andrade, Laura; Brandão, Marcos Antônio Fernandes

2017-01-01

The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): alprazolam 1.0 mg/mL, atropine sulfate 0.1 mg/mL, glutamine 250.0 mg/mL, levofloxacin 50.0 mg/mL, metoprolol tartrate 10.0 mg/mL, nitrofurantoin 2.0 mg/mL, ondansetron hydrochloride 0.8 mg/mL, oxandrolone 3.0 mg/mL, pregabaline 20.0 mg/mL, riboflavin 10.0 mg/mL. All suspensions were stored at both controlled refrigeration (2°C to 8°C) and controlled room temperature (20°C to 25°C). Stability was assessed by measuring the percent recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredients quantification was performed by high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions with regard to both temperatures. This suggests that the vehicle is stable for compounding active pharmaceutical ingredients from different pharmacological classes. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Bioinspired co-crystals of Imatinib providing enhanced kinetic solubility.

PubMed

Reggane, Maude; Wiest, Johannes; Saedtler, Marco; Harlacher, Cornelius; Gutmann, Marcus; Zottnick, Sven H; Piechon, Philippe; Dix, Ina; Müller-Buschbaum, Klaus; Holzgrabe, Ulrike; Meinel, Lorenz; Galli, Bruno

2018-05-04

Realizing the full potential of co-crystals enhanced kinetic solubility demands a comprehensive understanding of the mechanisms of dissolution, phase conversion, nucleation and crystal growth, and of the complex interplay between the active pharmaceutical ingredient (API), the coformer and co-existing forms in aqueous media. One blueprint provided by nature to keep poorly water-soluble bases in solution is the complexation with phenolic acids. Consequently, we followed a bioinspired strategy for the engineering of co-crystals of a poorly water-soluble molecule - Imatinib - with a phenolic acid, syringic acid (SYA). The dynamics of dissolution and solution-mediated phase transformations were monitored by Nuclear Magnetic Resonance (NMR) spectroscopy, providing mechanistic insights into the 60 fold-increased long lasting concentrations achieved by the syringate co-crystals as compared to Imatinib base and Imatinib mesylate. This lasting effect was linked to SYA's ability to delay the formation and nucleation of Imatinib hydrate - the thermodynamically stable form in aqueous media - through a metastable association of SYA with Imatinib in solution. Results from permeability studies evidenced that SYA did not impact Imatinib's permeability across membranes while suggesting improved bioavailability through higher kinetic solubility at the biological barriers. These results reflect that some degree of hydrophobicity of the coformer might be key to extend the kinetic solubility of co-crystals with hydrophobic APIs. Understanding how kinetic supersaturation can be shaped by the selection of an interactive coformer may help achieving the needed performance of new forms of poorly water-soluble, slowly dissolving APIs. Copyright © 2018. Published by Elsevier B.V.

Global approach for the validation of an in-line Raman spectroscopic method to determine the API content in real-time during a hot-melt extrusion process.

PubMed

Netchacovitch, L; Thiry, J; De Bleye, C; Dumont, E; Cailletaud, J; Sacré, P-Y; Evrard, B; Hubert, Ph; Ziemons, E

2017-08-15

Since the Food and Drug Administration (FDA) published a guidance based on the Process Analytical Technology (PAT) approach, real-time analyses during manufacturing processes are in real expansion. In this study, in-line Raman spectroscopic analyses were performed during a Hot-Melt Extrusion (HME) process to determine the Active Pharmaceutical Ingredient (API) content in real-time. The method was validated based on a univariate and a multivariate approach and the analytical performances of the obtained models were compared. Moreover, on one hand, in-line data were correlated with the real API concentration present in the sample quantified by a previously validated off-line confocal Raman microspectroscopic method. On the other hand, in-line data were also treated in function of the concentration based on the weighing of the components in the prepared mixture. The importance of developing quantitative methods based on the use of a reference method was thus highlighted. The method was validated according to the total error approach fixing the acceptance limits at ±15% and the α risk at ±5%. This method reaches the requirements of the European Pharmacopeia norms for the uniformity of content of single-dose preparations. The validation proves that future results will be in the acceptance limits with a previously defined probability. Finally, the in-line validated method was compared with the off-line one to demonstrate its ability to be used in routine analyses. Copyright © 2017 Elsevier B.V. All rights reserved.

Co-milled API-lactose systems for inhalation therapy: impact of magnesium stearate on physico-chemical stability and aerosolization performance.

PubMed

Lau, Michael; Young, Paul M; Traini, Daniela

2017-06-01

Particle micronization for inhalation can impart surface disorder (amorphism) of crystalline structures. This can lead to stability issues upon storage at elevated humidity from recrystallization of the amorphous state, which can subsequently affect the aerosol performance of the dry powder formulation. The aim of this study was to investigate the impact of an additive, magnesium stearate (MGST), on the stability and aerosol performance of co-milled active pharmaceutical ingredient (API) with lactose. Blends of API-lactose with/without MGST were prepared and co-milled by the jet-mill apparatus. Samples were stored at 50% relative humidity (RH) and 75% RH for 1, 5, and 15 d. Analysis of changes in particle size, agglomerate structure/strength, moisture sorption, and aerosol performance were analyzed by laser diffraction, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), and in-vitro aerodynamic size assessment by impaction. Co-milled formulation with MGST (5% w/w) led to a reduction in agglomerate size and strength after storage at elevated humidity compared with co-milled formulation without MGST, as observed from SEM and laser diffraction. Hysteresis in the sorption/desorption isotherm was observed in the co-milled sample without MGST, which was likely due to the recrystallization of the amorphous regions of micronized lactose. Deterioration in aerosol performance after storage at elevated humidity was greater for the co-milled samples without MGST, compared with co-milled with MGST. MGST has been shown to have a significant impact on co-milled dry powder stability after storage at elevated humidity in terms of physico-chemical properties and aerosol performance.

A novel particle engineering technology to enhance dissolution of poorly water soluble drugs: spray-freezing into liquid.

PubMed

Rogers, True L; Nelsen, Andrew C; Hu, Jiahui; Brown, Judith N; Sarkari, Marazban; Young, Timothy J; Johnston, Keith P; Williams, Robert O

2002-11-01

A novel cryogenic spray-freezing into liquid (SFL) process was developed to produce microparticulate powders consisting of an active pharmaceutical ingredient (API) molecularly embedded within a pharmaceutical excipient matrix. In the SFL process, a feed solution containing the API was atomized beneath the surface of a cryogenic liquid such that the liquid-liquid impingement between the feed and cryogenic liquids resulted in intense atomization into microdroplets, which were frozen instantaneously into microparticles. The SFL micronized powder was obtained following lyophilization of the frozen microparticles. The objective of this study was to develop a particle engineering technology to produce micronized powders of the hydrophobic drug, danazol, complexed with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and to compare these SFL micronized powders to inclusion complex powders produced from other techniques, such as co-grinding of dry powder mixtures and lyophilization of bulk solutions. Danazol and HPbetaCD were dissolved in a water/tetrahydrofuran cosolvent mixture prior to SFL processing or slow freezing. Identical quantities of the API and HPbetaCD used in the solutions were co-ground in a mortar and pestle and blended to produce a co-ground physical mixture for comparison. The powder samples were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), scanning electron microscopy, surface area analysis, and dissolution testing. The results provided by DSC, XRD, and FTIR suggested the formation of inclusion complexes by both slow-freezing and SFL. However, the specific surface area was significantly higher for the latter. Dissolution results suggested that equilibration of the danazol/HPbetaCD solution prior to SFL processing was required to produce the most soluble conformation of the resulting inclusion complex following SFL. SFL micronized powders exhibited better dissolution profiles than the slowly frozen aggregate powder. Results indicated that micronized SFL inclusion complex powders dissolved faster in aqueous dissolution media than inclusion complexes formed by conventional techniques due to higher surface areas and stabilized inclusion complexes obtained by ultra-rapid freezing.

Molecular-Level Control of Ciclopirox Olamine Release from Poly(ethylene oxide)-Based Mucoadhesive Buccal Films: Exploration of Structure-Property Relationships with Solid-State NMR.

PubMed

Urbanova, Martina; Gajdosova, Marketa; Steinhart, Miloš; Vetchy, David; Brus, Jiri

2016-05-02

Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX-2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer-drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure-property relationships in these complex pharmaceutical solids.

Designing green derivatives of β-blocker Metoprolol: a tiered approach for green and sustainable pharmacy and chemistry.

PubMed

Rastogi, Tushar; Leder, Christoph; Kümmerer, Klaus

2014-09-01

The presences of micro-pollutants (active pharmaceutical ingredients, APIs) are increasingly seen as a challenge of the sustainable management of water resources worldwide due to ineffective effluent treatment and other measures for their input prevention. Therefore, novel approaches are needed like designing greener pharmaceuticals, i.e. better biodegradability in the environment. This study addresses a tiered approach of implementing green and sustainable chemistry principles for theoretically designing better biodegradable and pharmacologically improved pharmaceuticals. Photodegradation process coupled with LC-MS(n) analysis and in silico tools such as quantitative structure-activity relationships (QSAR) analysis and molecular docking proved to be a very significant approach for the preliminary stages of designing chemical structures that would fit into the "benign by design" concept in the direction of green and sustainable pharmacy. Metoprolol (MTL) was used as an example, which itself is not readily biodegradable under conditions found in sewage treatment and the aquatic environment. The study provides the theoretical design of new derivatives of MTL which might have the same or improved pharmacological activity and are more degradable in the environment than MTL. However, the in silico toxicity prediction by QSAR of those photo-TPs indicated few of them might be possibly mutagenic and require further testing. This novel approach of theoretically designing 'green' pharmaceuticals can be considered as a step forward towards the green and sustainable pharmacy field. However, more knowledge and further experience have to be collected on the full scope, opportunities and limitations of this approach. Copyright © 2014 Elsevier Ltd. All rights reserved.

A harmonization effort for acceptable daily exposure application to pharmaceutical manufacturing - Operational considerations.

PubMed

Hayes, Eileen P; Jolly, Robert A; Faria, Ellen C; Barle, Ester Lovsin; Bercu, Joel P; Molnar, Lance R; Naumann, Bruce D; Olson, Michael J; Pecquet, Alison M; Sandhu, Reena; Shipp, Bryan K; Sussman, Robert G; Weideman, Patricia A

2016-08-01

A European Union (EU) regulatory guideline came into effect for all new pharmaceutical products on June 1st, 2015, and for all existing pharmaceutical products on December 1st, 2015. This guideline centers around the use of the Acceptable Daily Exposure (ADE) [synonymous with the Permitted Daily Exposure (PDE)] and operational considerations associated with implementation are outlined here. The EU guidance states that all active pharmaceutical ingredients (API) require an ADE; however, other substances such as starting materials, process intermediates, and cleaning agents may benefit from an ADE. Problems in setting ADEs for these additional substances typically relate to toxicological data limitations precluding the ability to establish a formal ADE. Established methodologies such as occupational exposure limits or bands (OELs or OEBs) and the threshold of toxicological concern (TTC) can be used or adjusted for use as interim ADEs when only limited data are available and until a more formal ADE can be established. Once formal ADEs are derived, it is important that the documents are routinely updated and that these updates are communicated to appropriate stakeholders. Another key operational consideration related to data-poor substances includes the use of maximum daily dose (MDD) in setting cross-contamination limits. The MDD is an important part of the maximum allowable/safe concentration (MAC/MSC) calculation and there are important considerations for its use and definition. Finally, other considerations discussed include operational aspects of setting ADEs for pediatrics, considerations for large molecules, and risk management in shared facilities. Copyright © 2016 Elsevier Inc. All rights reserved.

Optical coherence tomography for non-destructive analysis of coatings in pharmaceutical tablets

NASA Astrophysics Data System (ADS)

Markl, Daniel; Hannesschläger, Günther; Sacher, Stephan; Khinast, Johannes G.; Leitner, Michael

2013-04-01

Tablet coating is a common pharmaceutical technique to apply a thin continuous layer of solid on the top of a tablet or a granule containing active pharmaceutical ingredients (APIs). Coating thickness and homogeneity are critical parameters regarding the drug release rate, and consequently a direct or indirect monitoring strategy of these critical process parameters is essential. With the aid of Optical Coherence Tomography (OCT) it is not only possible to measure the absolute coating thickness, but also to detect inhomogeneities in the coating or substrate material. In this work the possible application of OCT as in-line method for monitoring pharmaceutical tablet film coating is studied. Firstly, the feasibility of OCT for analysis tablet coating is examined. Seven different commercially available film-coated tablets with different shapes, formulations and coating thicknesses were investigated off-line. OCT images were acquired by two different spectral-domain OCT systems operating at center wavelengths of 830 and 1325 nm. Since the images of both systems allow the analysis of the coatings, the OCT system employing the shorter wavelength and thus providing a higher axial resolution was selected for the further experiments. The influence of a moving tablet bed on OCT images was analyzed by considering a static tablet bed and moving the sensor head along the tablet bed. The ability to analyze the coating homogeneity is limited to a speed up to 0.3 m/s. However, determining the coating thickness and inter-coating uniformity is still possible up to a speed of 0.7 m/s.

Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development.

PubMed

Iliou, Katerina; Malenović, Anđelija; Loukas, Yannis L; Dotsikas, Yannis

2018-02-05

A novel Liquid Chromatography-tandem mass spectrometry (LC-MS/MS) method is presented for the quantitative determination of two potential genotoxic impurities (PGIs) in rabeprazole active pharmaceutical ingredient (API). In order to overcome the analytical challenges in the trace analysis of PGIs, a development procedure supported by Quality-by-Design (QbD) principles was evaluated. The efficient separation between rabeprazole and the two PGIs in the shortest analysis time was set as the defined analytical target profile (ATP) and to this purpose utilization of a switching valve allowed the flow to be sent to waste when rabeprazole was eluted. The selected critical quality attributes (CQAs) were the separation criterion s between the critical peak pair and the capacity factor k of the last eluted compound. The effect of the following critical process parameters (CPPs) on the CQAs was studied: %ACN content, the pH and the concentration of the buffer salt in the mobile phase, as well as the stationary phase of the analytical column. D-Optimal design was implemented to set the plan of experiments with UV detector. In order to define the design space, Monte Carlo simulations with 5000 iterations were performed. Acceptance criteria were met for C 8 column (50×4mm, 5μm) , and the region having probability π≥95% to achieve satisfactory values of all defined CQAs was computed. The working point was selected with the mobile phase consisting ‎of ACN, ammonium formate 11mM at a ratio 31/69v/v with pH=6,8 for the water phase. The LC protocol was transferred to LC-MS/MS and validated according to ICH guidelines. Copyright © 2017 Elsevier B.V. All rights reserved.

Supercritical carbon dioxide processing of active pharmaceutical ingredients for polymorphic control and for complex formation.

PubMed

Moribe, Kunikazu; Tozuka, Yuichi; Yamamoto, Keiji

2008-02-14

Supercritical fluid technique have been exploited in extraction, separation and crystallization processes. In the field of pharmaceutics, supercritical carbon dioxide (scCO(2)) has been used for the purpose of micronization, polymorphic control, and preparation of solid dispersion and complexes. Particle design of active pharmaceutical ingredients is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology is required to optimize the formulation. For solubility enhancement of poorly water-soluble drugs, preparation of the solid dispersion or the complexation with proper drugs or excipients should be a promising approach. This review focuses on aspects of polymorphic control and complexation behavior of active pharmaceutical ingredients by scCO(2) processing.

Development and Justification of a Risk Evaluation Matrix To Guide Chemical Testing Necessary To Select and Qualify Plastic Components Used in Production Systems for Pharmaceutical Products.

PubMed

Jenke, Dennis

2015-01-01

An accelerating trend in the pharmaceutical industry is the use of plastic components in systems used to produce an active pharmaceutical ingredient or a finished drug product. If the active pharmaceutical ingredient, the finished drug product, or any solution used to generate them (for example, a process stream such as media, buffers, eluents, and the like) is contacted by a plastic component at any time during the production process, substances leached from the component may accumulate in the active pharmaceutical ingredient or finished drug product, affecting its safety and/or efficacy. In this article the author develops and justifies a semi-quantitative risk evaluation matrix that is used to determine the amount and rigor of component testing necessary and appropriate to establish that the component is chemically suitable for its intended use. By considering key properties of the component, the contact medium, the contact conditions, and the active pharmaceutical ingredient's or finished drug product's clinical conditions of use, use of the risk evaluation matrix produces a risk score whose magnitude reflects the accumulated risk that the component will interact with the contact solution to such an extent that component-related extractables will accumulate in the active pharmaceutical ingredient or finished drug product as leachables at levels sufficiently high to adversely affect user safety. The magnitude of the risk score establishes the amount and rigor of the testing that is required to select and qualify the component, and such testing is broadly grouped into three categories: baseline assessment, general testing, and full testing (extractables profiling). Production suites used to generate pharmaceuticals can include plastic components. It is possible that substances in the components could leach into manufacturing solutions and accumulate in the pharmaceutical product. In this article the author develops and justifies a semi-quantitative risk evaluation matrix that can be used to determine the amount and rigor of component testing that may be necessary and appropriate to establish that the component is suitable for its intended use. Use of the risk evaluation matrix allows a user of a component to determine the type and amount of testing that should be performed to establish the patient safety risk associated with using that component in order to manufacture an active pharmaceutical ingredient or a finished drug product. © PDA, Inc. 2015.

Evaluation of physical and chemical changes in pharmaceuticals flown on space missions.

PubMed

Du, Brian; Daniels, Vernie R; Vaksman, Zalman; Boyd, Jason L; Crady, Camille; Putcha, Lakshmi

2011-06-01

Efficacy and safety of medications used for the treatment of astronauts in space may be compromised by altered stability in space. We compared physical and chemical changes with time in 35 formulations contained in identical pharmaceutical kits stowed on the International Space Station (ISS) and on Earth. Active pharmaceutical content (API) was determined by ultra- and high-performance liquid chromatography after returning to Earth. After stowage for 28 months in space, six medications aboard the ISS and two of matching ground controls exhibited changes in physical variables; nine medications from the ISS and 17 from the ground met the United States Pharmacopeia (USP) acceptance criteria for API content after 28 months of storage. A higher percentage of medications from each flight kit had lower API content than the respective ground controls. The number of medications failing API requirement increased as a function of time in space, independent of expiration date. The rate of degradation was faster in space than on the ground for many of the medications, and most solid dosage forms met USP standard for dissolution after storage in space. Cumulative radiation dose was higher and increased with time in space, whereas temperature and humidity remained similar to those on the ground. Exposure to the chronic low dose of ionizing radiation aboard the spacecraft as well as repackaging of solid dosage forms in flight-specific dispensers may adversely affect stability of pharmaceuticals. Characterization of degradation profiles of unstable formulations and identification of chemical attributes of stability in space analog environments on Earth will facilitate development of space-hardy medications.

Near infrared and Raman spectroscopy as Process Analytical Technology tools for the manufacturing of silicone-based drug reservoirs.

PubMed

Mantanus, J; Rozet, E; Van Butsele, K; De Bleye, C; Ceccato, A; Evrard, B; Hubert, Ph; Ziémons, E

2011-08-05

Using near infrared (NIR) and Raman spectroscopy as PAT tools, 3 critical quality attributes of a silicone-based drug reservoir were studied. First, the Active Pharmaceutical Ingredient (API) homogeneity in the reservoir was evaluated using Raman spectroscopy (mapping): the API distribution within the industrial drug reservoirs was found to be homogeneous while API aggregates were detected in laboratory scale samples manufactured with a non optimal mixing process. Second, the crosslinking process of the reservoirs was monitored at different temperatures with NIR spectroscopy. Conformity tests and Principal Component Analysis (PCA) were performed on the collected data to find out the relation between the temperature and the time necessary to reach the crosslinking endpoints. An agreement was found between the conformity test results and the PCA results. Compared to the conformity test method, PCA had the advantage to discriminate the heating effect from the crosslinking effect occurring together during the monitored process. Therefore the 2 approaches were found to be complementary. Third, based on the HPLC reference method, a NIR model able to quantify the API in the drug reservoir was developed and thoroughly validated. Partial Least Squares (PLS) regression on the calibration set was performed to build prediction models of which the ability to quantify accurately was tested with the external validation set. The 1.2% Root Mean Squared Error of Prediction (RMSEP) of the NIR model indicated the global accuracy of the model. The accuracy profile based on tolerance intervals was used to generate a complete validation report. The 95% tolerance interval calculated on the validation results indicated that each future result will have a relative error below ±5% with a probability of at least 95%. In conclusion, 3 critical quality attributes of silicone-based drug reservoirs were quickly and efficiently evaluated by NIR and Raman spectroscopy. Copyright © 2011 Elsevier B.V. All rights reserved.

Examining the production costs of antiretroviral drugs.

PubMed

Pinheiro, Eloan; Vasan, Ashwin; Kim, Jim Yong; Lee, Evan; Guimier, Jean Marc; Perriens, Joseph

2006-08-22

To present direct manufacturing costs and price calculations of individual antiretroviral drugs, enabling those responsible for their procurement to have a better understanding of the cost structure of their production, and to indicate the prices at which these antiretroviral drugs could be offered in developing country markets. Direct manufacturing costs and factory prices for selected first and second-line antiretroviral drugs were calculated based on cost structure data from a state-owned company in Brazil. Prices for the active pharmaceutical ingredients (API) were taken from a recent survey by the World Health Organization (WHO). The calculated prices for antiretroviral drugs are compared with quoted prices offered by privately-owned, for-profit manufacturers. The API represents the largest component of direct manufacturing costs (55-99%), while other inputs, such as salaries, equipment costs, and scale of production, have a minimal impact. The calculated prices for most of the antiretroviral drugs studied fall within the lower quartile of the range of quoted prices in developing country markets. The exceptions are those drugs, primarily for second-line therapy, for which the API is either under patent, in short supply, or in limited use in developing countries (e.g. abacavir, lopinavir/ritonavir, nelfinavir, saquinavir). The availability of data on the cost of antiretroviral drug production and calculation of factory prices under a sustainable business model provide benchmarks that bulk purchasers of antiretroviral drugs could use to negotiate lower prices. While truly significant price decreases for antiretroviral drugs will depend largely on the future evolution of API prices, the present study demonstrates that for several antiretroviral drugs price reduction is currently possible. Whether or not these reductions materialize will depend on the magnitude of indirect cost and profit added by each supplier over the direct production costs. The ability to achieve price reductions in line with production costs will have critical implications for sustainable treatment for HIV/AIDS in the developing world.

Determination of Bortezomib in API Samples Using HPLC: Assessment of Enantiomeric and Diastereomeric Impurities.

PubMed

Kamalzadeh, Zahra; Babanezhad, Esmaeil; Ghaffari, Solmaz; Mohseni Ezhiyeh, Alireza; Mohammadnejad, Mahdieh; Naghibfar, Mehdi; Bararjanian, Morteza; Attar, Hossein

2017-08-01

A new, normal phase high performance liquid chromatography (NP-HPLC) method was developed for separation of Bortezomib (BZB) enantiomers and quantitative determination of (1S,2R)-enantiomer of BZB in active pharmaceutical ingredient (API) samples. The developed method was validated based on International Conference on Harmonisation (ICH) guidelines and it was proved to be accurate, precise and robust. The obtained resolution (RS) between the enantiomers was more than 2. The calibration curve for (1S,2R)-enantiomer was found to be linear in the concentration range of 0.24-5.36 mg/L with regression coefficient (R2) of 0.9998. Additionally, the limit of detection (LOD) and limit of quantification (LOQ) were 0.052 and 0.16 mg/L, respectively. Also, in this study, a precise, sensitive and robust gradient reversed-phase HPLC (RP-HPLC) method was developed and validated for determination of BZB in API samples. The detector response was linear over the concentration range of 0.26-1110.5 mg/L. The values of R2, LOD and LOQ were 0.9999, 0.084 and 0.25 mg/L, respectively. For both NP-HPLC and RP-HPLC methods, all of the RSD (%) values obtained in the precision study were <1.0%. System suitability parameters in terms of tailing factor (TF), number of theoretical plates (N) and RS were TF < 2.0, N > 2,000 and RS > 2.0. The performance of two common integration methods of valley to valley and drop perpendicular for drawing the baseline between two adjacent peaks were investigated for the determination of diastereomeric impurity (Imp-D) in the BZB-API samples. The results showed that the valley to valley method outperform the drop perpendicular method for calculation of Imp-D peak areas. Therefore, valley to valley method was chosen for peak integration. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A long-term stability study of Prussian blue: A quality assessment of water content and cesium binding.

PubMed

Mohammad, Adil; Yang, Yongsheng; Khan, Mansoor A; Faustino, Patrick J

2015-01-25

Prussian blue (PB) is the active pharmaceutical ingredient (API) of Radiogardase, the first approved medical countermeasure for the treatment of radiocesium poisoning in the event of a major radiological incident such as a "dirty bomb" or nuclear attack. The purpose of this study is to assess the long-term stability of Prussian blue drug products (DPs) and APIs under laboratory storage condition by monitoring the loss in water content and the in vitro cesium binding. The water content was measured by thermal gravimetric analysis (TGA). The in-vitro cesium binding study was conducted using a surrogate model to mimic gastric residence and intestinal transport. Free cesium was analyzed using a validated flame atomic emission spectroscopy (AES) method. The binding equilibrium was reached at 24h. The Langmuir isotherm was plotted to calculate the maximum binding capacity (MBC). Comparison of the same PB samples with 2003 data samples, the water content of both APIs and DPs decreased on an average by approximately 12-24%. Consequently, the MBC of cesium was decreased from 358mg/g in 2003 to 265mg/g @ pH 7.5, a decrease of approximately 26%. The binding of cesium is also pH dependent with lowest binding at pH 1.0 and maximum binding at pH 7.5. At pH 7.5, the amount of cesium bound decreased by an average value of 7.9% for APIs and 8.9% for DPs (for 600ppm initial cesium concentration). These findings of water loss, pH dependence and decrease in cesium binding are consistent with our previously published data in 2003. Over last 10 years the stored DPs and APIs of PB have lost about 20% of water which has a negative impact on the PB cesium binding, however PB still meets the FDA specification of >150mg/g at equilibrium. The study is the first quantitative assessment of the long-term stability of PB and directs that proper long-term and short-term storage of PB is required to ensure that it is safe and efficacious at the time of an emergency situation. Published by Elsevier B.V.

75 FR 9442 - Lonza, Inc., Riverside Plant, Lonza Exclusive Synthesis Section, Custom Manufacturing Division...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-02

... competitive with cGMP intermediates and Active Pharmaceutical Ingredients from the subject facility to a..., Conshohocken, Pennsylvania, who are engaged in employment related to the production of cGMP intermediates and...GMP intermediates and Active Pharmaceutical Ingredients, who became totally or partially separated...

Characterization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids.

PubMed

Moshikur, Rahman Md; Chowdhury, Md Raihan; Wakabayashi, Rie; Tahara, Yoshiro; Moniruzzaman, Muhammad; Goto, Masahiro

2018-07-30

The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1 H and 13 C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Analysis of minimum target prices for production of entecavir to treat hepatitis B in high- and low-income countries.

PubMed

Hill, Andrew; Gotham, Dzintars; Cooke, Graham; Bhagani, Sanjay; Andrieux-Meyer, Isabelle; Cohn, Jennifer; Fortunak, Joseph

2015-04-01

In 2013, an estimated 686,000 people died from hepatitis B virus (HBV) infection worldwide. Mass treatment programmes for hepatitis B will require very low drug costs. International treatment guidelines recommend first-line monotherapy with either entecavir or tenofovir disoproxil fumarate (TDF). While the basic patent on TDF expires in 2017/8, entecavir is already generic in several countries, including the US. The chemical structure of entecavir is related to abacavir, which costs <$200 per person-year in low-income countries. The clinical efficacy, chemical structures, daily doses, routes of chemical synthesis, costs of raw materials and patent expiry dates were analysed for entecavir and TDF. Costs of sustainable, generic production were calculated for entecavir, and compared with published originator and generic prices in high- and low-income countries. With a daily dose of 0.5 mg, one year's supply of entecavir treatment requires <0.2 g of active pharmaceutical ingredient (API) per person, estimated to cost $4/year, based on quotations of API production from generic suppliers. With an additional $20 per year for formulation/packaging and a 50% profit margin, entecavir was estimated to cost a minimum of $36/person-year, substantially lower than current originator and generic prices. Entecavir is no longer under patent protection in the USA, China, Brazil and South Africa, with European expiry in 2017. Given differences in daily dosing, production volumes for entecavir would be 600 times lower than TDF (300 mg once daily) for treating the same numbers of patients. Mass treatment for hepatitis B with generic entecavir could be achieved at very low cost in all countries, provided that important projections can be met in terms of pricing for the API and finished dosage form.

Microtomographic studies of subdivision of modified-release tablets.

PubMed

Wilczyński, Sławomir; Koprowski, Robert; Duda, Piotr; Banyś, Anna; Błońska-Fajfrowska, Barbara

2016-09-25

The uniformity of dosage units within a certain batch is ensured when each unit contains the active pharmaceutical ingredient (API) within a narrow range around the label claim. For tablets containing a score-line authorised for dose reductions, the European Pharmacopoeia (Ph. Eur.) considers that the uniformity of the tablet parts may be based on weight measurements regardless of the tablet type (immediate or modified release). This is because it is up to the regulatory authorities first to assess whether the tablet may contain a score-line for such use. X-ray microtomography was applied to assess the symmetry of 36 modified release tablets, containing 300mg of theophylline. The sum of the volume and surface area of the pellets in the subdivided tablets were compared. Simulations were carried out to identify the optimal amount of pellets in the tablet mass. The maximum difference in the API content between two subdivided halves was 165.18mg vs 133.83mg. If the amount of pellets in the tablet mass would drop below 13% on the basis of the pellet surface area, then the Ph. Eur. requirements would be exceeded. The amount of pellets in the tablet halves resulting in the greatest variability in API content was 38%. The results of this study indicate that the pellets were not distributed uniformly in the tablet mass. Thus, the uniformity of the dose in both halves of a tablet containing pellets cannot be based on the weight measurements i.e. it is necessary to develop further standards for tablet subdivision. Microtomographic methods are a very interesting alternative to expensive and time-consuming pharmacokinetic studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Tailoring controlled-release oral dosage forms by combining inkjet and flexographic printing techniques.

PubMed

Genina, Natalja; Fors, Daniela; Vakili, Hossein; Ihalainen, Petri; Pohjala, Leena; Ehlers, Henrik; Kassamakov, Ivan; Haeggström, Edward; Vuorela, Pia; Peltonen, Jouko; Sandler, Niklas

2012-10-09

We combined conventional inkjet printing technology with flexographic printing to fabricate drug delivery systems with accurate doses and tailored drug release. Riboflavin sodium phosphate (RSP) and propranolol hydrochloride (PH) were used as water-soluble model drugs. Three different paper substrates: A (uncoated woodfree paper), B (triple-coated inkjet paper) and C (double-coated sheet fed offset paper) were used as porous model carriers for drug delivery. Active pharmaceutical ingredient (API) containing solutions were printed onto 1 cm × 1 cm substrate areas using an inkjet printer. The printed APIs were coated with water insoluble polymeric films of different thickness using flexographic printing. All substrates were characterized with respect to wettability, surface roughness, air permeability, and cell toxicity. In addition, content uniformity and release profiles of the produced solid dosage forms before and after coating were studied. The substrates were nontoxic for the human cell line assayed. Substrate B was smoothest and least porous. The properties of substrates B and C were similar, whereas those of substrate A differed significantly from those of B, C. The release kinetics of both printed APIs was slowest from substrate B before and after coating with the water insoluble polymer film, following by substrate C, whereas substrate A showed the fastest release. The release rate decreased with increasing polymer coating film thickness. The printed solid dosage forms showed excellent content uniformity. So, combining the two printing technologies allowed fabricating controlled-release oral dosage forms that are challenging to produce using a single technique. The approach opens up new perspectives in the manufacture of flexible doses and tailored drug-delivery systems. Copyright © 2012 Elsevier B.V. All rights reserved.

Improving the hardness of dry granulated tablets containing sodium lauryl sulfate.

PubMed

Moore, Francis; Okelo, Geoffrey; Colón, Ivelisse; Kushner, Joseph

2010-11-15

The impact of the addition of a wetting agent, the surfactant sodium lauryl sulfate (SLS), on the tablet hardness of a dry granulated, solid oral dosage form was investigated. In three batches, SLS was added concurrently with: (1) a poorly soluble, highly hydrophobic active pharmaceutical ingredient (API) and the other excipients prior to the initial blending step, (2) magnesium stearate prior to roller compaction, or (3) magnesium stearate prior to tableting. A fourth batch, which did not contain SLS, served as a control. The maximum hardness of 100 mg, 1/4″-SRC tablets for the four batches--SLS added initially, prior to roller compaction, prior to tableting, and no SLS--were 61±3, 71±3, 89±5, and 86±3N, respectively, suggesting reduced processing of SLS improves tablet hardness by ∼50%. Dissolution of the tablets in 900 ml of simulated gastric fluid with paddles at 75 rpm showed that: (1) there was no impact on the insertion point of SLS into the process on API dissolution, and (2) that the presence of SLS improved dissolution by 5% compared to the control tablets. Adding SLS just prior to tableting can improve tablet hardness and yield similar dissolution performance relative to SLS addition prior to the initial blending step. Copyright © 2010 Elsevier B.V. All rights reserved.

Controlled release from drug microparticles via solventless dry-polymer coating.

PubMed

Capece, Maxx; Barrows, Jason; Davé, Rajesh N

2015-04-01

A novel solvent-less dry-polymer coating process employing high-intensity vibrations avoiding the use of liquid plasticizers, solvents, binders, and heat treatments is utilized for the purpose of controlled release. The main hypothesis is that such process having highly controllable processing intensity and time may be effective for coating particularly fine particles, 100 μm and smaller via exploiting particle interactions between polymers and substrates in the dry state, while avoiding breakage yet achieving conformal coating. The method utilizes vibratory mixing to first layer micronized polymer onto active pharmaceutical ingredient (API) particles by virtue of van der Waals forces and to subsequently mechanically deform the polymer into a continuous film. As a practical example, ascorbic acid and ibuprofen microparticles, 50-500 μm, are coated with the polymers polyethylene wax or carnauba wax, a generally recognized as safe material, resulting in controlled release on the order of seconds to hours. As a novelty, models are utilized to describe the coating layer thickness and the controlled-release behavior of the API, which occurs because of a diffusion-based mechanism. Such modeling would allow the design and control of the coating process with application for the controlled release of microparticles, particularly those less than 100 μm, which are difficult to coat by conventional solvent coating methods. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Continuous Inkjet Printing of Enalapril Maleate onto Orodispersible Film Formulations.

PubMed

Thabet, Yasmin; Lunter, Dominique; Breitkreutz, Joerg

2018-05-10

Piezoelectric inkjet printing onto orodispersible films (ODFs) was proven to be a successful technique applying flexible doses of active pharmaceutical ingredients (APIs) onto edible substrates. The reported API printing and ODF production was conducted in a non-continuous production approach. Within this study, drug-free and hydrochlorothiazide (HCT) containing ODFs should be imprinted in-line with enalapril maleate (EM) ink during continuous ODF production. Macrogol inks based on various solvents and solvent-water mixtures were developed providing dynamic viscosities from 7 to 17 mPa∗s. Water based inks contained 1.25%, methanol based inks up to 10% EM. Both inks could be printed (500-1000 Hz) during continuous ODF production. No EM recrystallization was observed for water-based inks. Mechanical properties were not affected by drug printing using various firing frequencies. ODF imprinted with water-based EM inks contained 0.04 mg EM / 6cm 2 . EM amount can be increased to a paediatric therapeutic dose of 0.5 mg EM utilizing methanol-based inks. These inks were successfully printed onto HCT ODFs resulting in a therapeutically relevant fixed-dose combination. No EM migration into the HCT layer could be observed. In conclusion, it was feasible to print EM doses onto drug-free and HCT ODFs during an in-line continuous manufacturing process. Copyright © 2018 Elsevier B.V. All rights reserved.

A nipple shield delivery system for oral drug delivery to breastfeeding infants: microbicide delivery to inactivate HIV.

PubMed

Gerrard, Stephen E; Baniecki, Mary Lynn; Sokal, David C; Morris, Mary K; Urdaneta-Hartmann, Sandra; Krebs, Fred C; Wigdahl, Brian; Abrams, Barbara F; Hanson, Carl V; Slater, Nigel K H; Edwards, Alexander D

2012-09-15

A new drug delivery method for infants is presented which incorporates an active pharmaceutical ingredient (API)-loaded insert into a nipple shield delivery system (NSDS). The API is released directly into milk during breastfeeding. This study investigates the feasibility of using the NSDS to deliver the microbicide sodium dodecyl sulfate (SDS), with the goal of preventing mother-to-child transmission (MTCT) of HIV during breastfeeding in low-resource settings, when there is no safer alternative for the infant but to breastfeed. SDS has been previously shown to effectively inactivate HIV in human milk. An apparatus was developed to simulate milk flow through and drug release from a NSDS. Using this apparatus milk was pulsed through a prototype device containing a non-woven fiber insert impregnated with SDS and the microbicide was rapidly released. The total SDS release from inserts ranged from 70 to 100% of the average 0.07 g load within 50 ml (the volume of a typical breastfeed). Human milk spiked with H9/HIV(IIIB) cells was also passed through the same set-up. Greater than 99% reduction of cell-associated HIV infectivity was achieved in the first 10 ml of milk. This proof of concept study demonstrates efficient drug delivery to breastfeeding infants is achievable using the NSDS. Copyright © 2012 Elsevier B.V. All rights reserved.

The influence of spray-drying parameters on phase behavior, drug distribution, and in vitro release of injectable microspheres for sustained release.

PubMed

Meeus, Joke; Lenaerts, Maité; Scurr, David J; Amssoms, Katie; Davies, Martyn C; Roberts, Clive J; Van Den Mooter, Guy

2015-04-01

For ternary solid dispersions, it is indispensable to characterize their structure, phase behavior, and the spatial distribution of the dispersed drug as this might influence the release profile and/or stability of these formulations. This study shows how formulation (feed concentration) and process (feed rate, inlet air temperature, and atomizing air pressure) parameters can influence the characteristics of ternary spray-dried solid dispersions. The microspheres considered here consist of a poly(lactic-co-glycolic acid) (PLGA) surface layer and an underlying polyvinylpyrrolidone (PVP) phase. A poorly soluble active pharmaceutical ingredient (API) was molecularly dispersed in this matrix. Differences were observed in component miscibility, phase heterogeneity, particle size, morphology, as well as API surface coverage for selected spray-drying parameters. Observed differences are likely because of changes in the droplet generation, evaporation, and thus particle formation processes. However, varying particle characteristics did not influence the drug release of the formulations studied, indicating the robustness of this approach to produce particles of consistent drug release characteristics. This is likely because of the fact that the release is dominated by diffusion from the PVP layer through pores in the PLGA surface layer and that observed differences in the latter have no influence on the release. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry.

PubMed

Hiebler, Katharina; Lichtenegger, Georg J; Maier, Manuel C; Park, Eun Sung; Gonzales-Groom, Renie; Binks, Bernard P; Gruber-Woelfler, Heidrun

2018-01-01

Within the "compartmentalised smart factory" approach of the ONE-FLOW project the implementation of different catalysts in "compartments" provided by Pickering emulsions and their application in continuous flow is targeted. We present here the development of heterogeneous Pd catalysts that are ready to be used in combination with biocatalysts for catalytic cascade synthesis of active pharmaceutical ingredients (APIs). In particular, we focus on the application of the catalytic systems for Suzuki-Miyaura cross-coupling reactions, which is the key step in the synthesis of the targeted APIs valsartan and sacubitril. An immobilised enzyme will accomplish the final product formation via hydrolysis. In order to create a large interfacial area for the catalytic reactions and to keep the reagents separated until required, the catalyst particles are used to stabilise Pickering emulsions of oil and water. A set of Ce-Sn-Pd oxides with the molecular formula Ce 0.99- x Sn x Pd 0.01 O 2-δ ( x = 0-0.99) has been prepared utilising a simple single-step solution combustion method. The high applicability of the catalysts for different functional groups and their minimal leaching behaviour is demonstrated with various Suzuki-Miyaura cross-coupling reactions in batch as well as in continuous flow employing the so-called "plug & play reactor". Finally, we demonstrate the use of these particles as the sole emulsifier of oil-water emulsions for a range of oils.

Biowaiver monograph for immediate-release solid oral dosage forms: bisoprolol fumarate.

PubMed

Charoo, Naseem A; Shamsher, Areeg A A; Lian, Lai Y; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

2014-02-01

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing bisoprolol as the sole active pharmaceutical ingredient (API) are reviewed. Bisoprolol is classified as a Class I API according to the current Biopharmaceutics Classification System (BCS). In addition to the BCS class, its therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability problems are taken into consideration. Qualitative compositions of IR tablet dosage forms of bisoprolol with a marketing authorization (MA) in ICH (International Conference on Harmonisation) countries are tabulated. It was inferred that these tablets had been demonstrated to be bioequivalent to the innovator product. No reports of failure to meet BE standards have been made in the open literature. On the basis of all these pieces of evidence, a biowaiver can currently be recommended for bisoprolol fumarate IR dosage forms if (1) the test product contains only excipients that are well known, and used in normal amounts, for example, those tabulated for products with MA in ICH countries and (2) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Evaluation of Maltose-Induced Chemical Degradation at the Interface of Bilayer Tablets.

PubMed

Matsuzaki, Naoya; Yamamoto, Yousuke; Murayama, Daisuke; Katakawa, Yoshifumi; Mimura, Hisashi; Kimura, Shin-Ichiro; Iwao, Yasunori; Itai, Shigeru

2017-01-01

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study showed that the original formulation for the tablets led to a significant increase of unknown degradants in the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.

The global biopharma industry and the rise of Indian drug multinationals: implications for Australian generics policy

PubMed Central

Löfgren, Hans

2007-01-01

This article provides a synopsis of the new dynamics of the global biopharma industry. The emergence of global generics companies with capabilities approximating those of 'big pharma' has accelerated the blurring of boundaries between the innovator and generics sectors. Biotechnology-based products form a large and growing segment of prescription drug markets and regulatory pathways for biogenerics are imminent. Indian biopharma multinationals with large-scale efficient manufacturing plants and growing R&D capabilities are now major suppliers of Active Pharmaceutical Ingredients (APIs) and generic drugs across both developed and developing countries. In response to generic competition, innovator companies employ a range of life cycle management techniques, including the launch of 'authorised generics'. The generics segment in Australia will see high growth rates in coming years but the prospect for local manufacturing is bleak. The availability of cheap generics in international markets has put pressure on Pharmaceutical Benefits Scheme (PBS) pricing arrangements, and a new policy direction was announced in November 2006. Lower generics prices will have a negative impact on some incumbent suppliers but industrial renewal policies for the medicines industry in Australia are better focused on higher value R&D activities and niche manufacturing of sophisticated products. PMID:17543115

[New drugs for horses and production animals in 2017].

PubMed

Emmerich, Ilka Ute

2018-04-01

In 2017, no new active pharmaceutical ingredients were released on the German market for horses or food-producing animals. Four established veterinary active pharmaceutical ingredients became available for additional species: the ectoparasitic Fluralaner (Exzolt®) of the isoxazoline group was additionally authorized for chickens, the macrolide antibiotics Gamithromycin (Zactran®) and Tulathromycin (Draxxin®) for sheep and the nonsteroidal anti-inflammatory drug Tolfenamic Acid (Tolfedol®) from the fenamate group for cattle and pigs. Additionally, one drug with a new combination of active ingredients, one drug with a new pharmaceutical form and one drug with a new mode of administration have been launched on the market for horses and food-producing animals. Schattauer GmbH.

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility.

PubMed

Frank, Kerstin J; Westedt, Ulrich; Rosenblatt, Karin M; Hölig, Peter; Rosenberg, Jörg; Mägerlein, Markus; Fricker, Gert; Brandl, Martin

2012-01-01

Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 μg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the surfactants besides ABT-102 as the main component. The amorphous microparticles are assumed to be the origin of the observed increase in molecular solubility ("true" supersaturation).

Microwave-assisted digestion using nitric acid for heavy metals and sulfated ash testing in active pharmaceutical ingredients.

PubMed

Pluhácek, T; Hanzal, J; Hendrych, J; Milde, D

2016-04-01

The monitoring of inorganic impurities in active pharmaceutical ingredients plays a crucial role in the quality control of the pharmaceutical production. The heavy metals and residue on ignition/sulfated ash methods employing microwave-assisted digestion with concentrated nitric acid have been demonstrated as alternatives to inappropriate compendial methods recommended in United States Pharmacopoeia (USP) and European Pharmacopoeia (Ph. Eur.). The recoveries using the heavy metals method ranged between 89% and 122% for nearly all USP and Ph. Eur. restricted elements as well as the recoveries of sodium sulfate spikes were around 100% in all tested matrices. The proposed microwave-assisted digestion method allowed simultaneous decomposition of 15 different active pharmaceutical ingredients with sample weigh up to 1 g. The heavy metals and sulfated ash procedures were successfully applied to the determination of heavy metals and residue on ignition/sulfated ash content in mycophenolate mofetil, nicergoline and silymarin.

Risk of error estimated from Palestine pharmacists' knowledge and certainty on the adverse effects and contraindications of active pharmaceutical ingredients and excipients.

PubMed

Shawahna, Ramzi; Al-Rjoub, Mohammed; Al-Horoub, Mohammed M; Al-Hroub, Wasif; Al-Rjoub, Bisan; Al-Nabi, Bashaaer Abd

2016-01-01

This study aimed to investigate community pharmacists' knowledge and certainty of adverse effects and contraindications of pharmaceutical products to estimate the risk of error. Factors influencing their knowledge and certainty were also investigated. The knowledge of community pharmacists was assessed in a cross-sectional design using a multiple-choice questions test on the adverse effects and contraindications of active pharmaceutical ingredients and excipients from May 2014 to March 2015. Self-rated certainty scores were also recorded for each question. Knowledge and certainty scores were combined to estimate the risk of error. Out of 315 subjects, 129 community pharmacists (41.0%) completed the 30 multiple-choice questions test on active ingredients and excipients. Knowledge on active ingredients was associated with the year of graduation and obtaining a licence to practice pharmacy. Knowledge on excipients was associated with the degree obtained. There was higher risk of error in items on excipients than those on ingredients (P<0.01). The knowledge of community pharmacists in Palestine was insufficient with high risk of errors. Knowledge of community pharmacists on the safety issues of active ingredients and excipients need to be improved.

Recent advances in developing ophthalmic formulations: a patent review.

PubMed

Lu, Guang Wei

2010-01-01

In an effort to improve the drug solubility, stability and/or ocular bioavailability of ophthalmic formulations,various approaches have been explored in the recent past. Additionally, different formulations have been investigated in order to seek those preservative systems that are more tolerable to the ocular tissue. Over the past ten years, inventions in ophthalmic formulations directed toward front-of-eye instillations have concentrated in the areas of new excipients' applications, novel and combined use of conventional excipients, and developments of novel dosage forms. Among these areas, applications of polymeric excipients, cyclodextrins and stabilized chloride dioxide (SCD) have been the most actively studied fields. In addition, oil-in-water (O/W) emulsions have been becoming more popular as an ophthalmic dosage form due to the potentials in increasing drug solubility, stabilizing active pharmaceutical ingredients (APIs), improving ocular tolerance, and providing palliative effects. Some of these innovations from the past decade have the capability of leading to new commercial products. This patent review has a useful knowledge in the advancement for treating various ophthalmic diseases.

Adulterated and Counterfeit Male Enhancement Nutraceuticals and Dietary Supplements Pose a Real Threat to the Management of Erectile Dysfunction: A Global Perspective.

PubMed

ElAmrawy, Fatema; ElAgouri, Ghada; Elnoweam, Ola; Aboelazayem, Samar; Farouk, ElMohanad; Nounou, Mohamed I

2016-11-01

Erectile dysfunction prevalence globally is noticeably high. This is accompanied by an increase in the use of nutraceuticals for male enhancement. However, the global market is invaded by counterfeit and adulterated nutraceuticals claimed to be of natural origin sold with a therapeutic claim. The objective of this article is to review male enhancement nutraceuticals worldwide with respect to claim, adulterants, and safety. The definition of such products is variable across countries. Thus, the registration procedures differ as well. This facilitates the manipulation of the process, which leads to widespread adulterated and counterfeit products without control. The tele-advertisement and Internet pharmacies aided the widespread sale of male enhancement nutraceuticals, unfortunately, the spurious ones. Finally, based on literature, most of these products were found to be adulterated with active pharmaceutical ingredients (API) and mislabeled as being natural. These products represent a major health hazard for consumers due to lack of clear regulations.

"Soft"or "hard" ionisation? Investigation of metastable gas temperature effect on direct analysis in real-time analysis of Voriconazole.

PubMed

Lapthorn, Cris; Pullen, Frank

2009-01-01

The performance of the direct analysis in real-time (DART) technique was evaluated across a range of metastable gas temperatures for a pharmaceutical compound, Voriconazole, in order to investigate the effect of metastable gas temperature on molecular ion intensity and fragmentation. The DART source has been used to analyse a range of analytes and from a range of matrices including drugs in solid tablet form and preparations, active ingredients in ointment, naturally occurring plant alkaloids, flavours and fragrances, from thin layer chromatography (TLC) plates, melting point tubes and biological matrices including hair, urine and blood. The advantages of this technique include rapid analysis time (as little as 5 s), a reduction in sample preparation requirements, elimination of mobile phase requirement and analysis of samples not typically amenable to atmospheric pressure ionisation (API) techniques. This technology has therefore been proposed as an everyday tool for identification of components in crude organic reaction mixtures.

Rapid interferometric imaging of printed drug laden multilayer structures

NASA Astrophysics Data System (ADS)

Sandler, Niklas; Kassamakov, Ivan; Ehlers, Henrik; Genina, Natalja; Ylitalo, Tuomo; Haeggstrom, Edward

2014-02-01

The developments in printing technologies allow fabrication of micron-size nano-layered delivery systems to personal specifications. In this study we fabricated layered polymer structures for drug-delivery into a microfluidic channel and aimed to interferometrically assure their topography and adherence to each other. We present a scanning white light interferometer (SWLI) method for quantitative assurance of the topography of the embedded structure. We determined rapidly in non-destructive manner the thickness and roughness of the structures and whether the printed layers containing polymers or/and active pharmaceutical ingredients (API) adhere to each other. This is crucial in order to have predetermined drug release profiles. We also demonstrate non-invasive measurement of a polymer structure in a microfluidic channel. It shown that traceable interferometric 3D microscopy is a viable technique for detailed structural quality assurance of layered drug-delivery systems. The approach can have impact and find use in a much broader setting within and outside life sciences.

Characterization of new eye drops with choline salicylate and assessment of their irritancy by in vitro short time exposure tests.

PubMed

Wroblewska, Katarzyna; Kucinska, Małgorzata; Murias, Marek; Lulek, Janina

2015-09-01

The aim of our study was to examine the irritation potential of new eye drops containing 2% choline salicylate (CS) as an active pharmaceutical ingredient (API) and various polymers increasing eye drop viscosity (hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone). The standard method for assessing the potential of irritating substances has been the Draize rabbit eye test. However the European Centre for Validation of Alternative Methods and the Coordinating Committee for Validation of Alternative Methods recommend, short time exposure (STE) in vitro tests as an alternative method for assessing eye irritation. The eye irritation potential was determined using cytotoxicity test methods for rabbit corneal cell line (SIRC) after 5 min exposure. The viability of cells was determined using two cytotoxicity assays: MTT and Neutral Red Uptake. According to the irritation rankings for the short time exposure test, all tested eye drops are classified as non-irritating (cell viability >70%).

Characterization of new eye drops with choline salicylate and assessment of their irritancy by in vitro short time exposure tests

PubMed Central

Wroblewska, Katarzyna; Kucinska, Małgorzata; Murias, Marek; Lulek, Janina

2014-01-01

The aim of our study was to examine the irritation potential of new eye drops containing 2% choline salicylate (CS) as an active pharmaceutical ingredient (API) and various polymers increasing eye drop viscosity (hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone). The standard method for assessing the potential of irritating substances has been the Draize rabbit eye test. However the European Centre for Validation of Alternative Methods and the Coordinating Committee for Validation of Alternative Methods recommend, short time exposure (STE) in vitro tests as an alternative method for assessing eye irritation. The eye irritation potential was determined using cytotoxicity test methods for rabbit corneal cell line (SIRC) after 5 min exposure. The viability of cells was determined using two cytotoxicity assays: MTT and Neutral Red Uptake. According to the irritation rankings for the short time exposure test, all tested eye drops are classified as non-irritating (cell viability >70%). PMID:27134543

Downstream processing from hot-melt extrusion towards tablets: A quality by design approach.

PubMed

Grymonpré, W; Bostijn, N; Herck, S Van; Verstraete, G; Vanhoorne, V; Nuhn, L; Rombouts, P; Beer, T De; Remon, J P; Vervaet, C

2017-10-05

Since the concept of continuous processing is gaining momentum in pharmaceutical manufacturing, a thorough understanding on how process and formulation parameters can impact the critical quality attributes (CQA) of the end product is more than ever required. This study was designed to screen the influence of process parameters and drug load during HME on both extrudate properties and tableting behaviour of an amorphous solid dispersion formulation using a quality-by-design (QbD) approach. A full factorial experimental design with 19 experiments was used to evaluate the effect of several process variables (barrel temperature: 160-200°C, screw speed: 50-200rpm, throughput: 0.2-0.5kg/h) and drug load (0-20%) as formulation parameter on the hot-melt extrusion (HME) process, extrudate and tablet quality of Soluplus ® -Celecoxib amorphous solid dispersions. A prominent impact of the formulation parameter on the CQA of the extrudates (i.e. solid state properties, moisture content, particle size distribution) and tablets (i.e. tabletability, compactibility, fragmentary behaviour, elastic recovery) was discovered. The resistance of the polymer matrix to thermo-mechanical stress during HME was confirmed throughout the experimental design space. In addition, the suitability of Raman spectroscopy as verification method for the active pharmaceutical ingredient (API) concentration in solid dispersions was evaluated. Incorporation of the Raman spectroscopy data in a PLS model enabled API quantification in the extrudate powders with none of the DOE-experiments resulting in extrudates with a CEL content deviating>3% of the label claim. This research paper emphasized that HME is a robust process throughout the experimental design space for obtaining amorphous glassy solutions and for tabletting of such formulations since only minimal impact of the process parameters was detected on the extrudate and tablet properties. However, the quality of extrudates and tablets can be optimized by adjusting specific formulations parameters (e.g. drug load). Copyright © 2017 Elsevier B.V. All rights reserved.

Production of cocrystals in an excipient matrix by spray drying.

PubMed

Walsh, David; Serrano, Dolores R; Worku, Zelalem Ayenew; Norris, Brid A; Healy, Anne Marie

2018-01-30

Spray drying is a well-established scale-up technique for the production of cocrystals. However, to the best of our knowledge, the effect of introducing a third component into the feed solution during the spray drying process has never been investigated. Cocrystal formation in the presence of a third component by a one-step spray drying process has the potential to reduce the number of unit operations which are required to produce a final pharmaceutical product (e.g. by eliminating blending with excipient). Sulfadimidine (SDM), a poorly water soluble active pharmaceutical ingredient (API), and 4-aminosalicylic acid (4ASA), a hydrophilic molecule, were used as model drug and coformer respectively to form cocrystals by spray drying in the presence of a third component (excipient). The solubility of the cocrystal in the excipient was measured using a thermal analysis approach. Trends in measured solubility were in agreement with those determined by calculated Hansen Solubility Parameter (HSP) values. The ratio of cocrystal components to excipient was altered and cocrystal formation at different weight ratios was assessed. Cocrystal integrity was preserved when the cocrystal components were immiscible with the excipient, based on the difference in Hansen Solubility Parameters (HSP). For immiscible systems (difference in HSP > 9.6 MPa 0.5 ), cocrystal formation occurred even when the proportion of excipient was high (90% w/w). When the excipient was partly miscible with the cocrystal components, cocrystal formation was observed post spray drying, but crystalline API and coformer were also recovered in the processed powder. An amorphous dispersion was formed when the excipient was miscible with the cocrystal components even when the proportion of excipient used as low (10% w/w excipient). For selected spray dried cocrystal-excipient systems an improvement in tableting characteristics was observed, relative to equivalent physical mixtures. Copyright © 2017 Elsevier B.V. All rights reserved.

Solid State NMR Characterization of Ibuprofen:Nicotinamide Cocrystals and New Idea for Controlling Release of Drugs Embedded into Mesoporous Silica Particles.

PubMed

Skorupska, Ewa; Kaźmierski, Sławomir; Potrzebowski, Marek J

2017-05-01

Grinding and melting methods were employed for synthesis of pharmaceutical cocrystals formed by racemic (R/S) and entiomeric (S) ibuprofen (IBU) and nicotinamide (NA) as coformer. Obtained (R/S)-IBU:NA and (S)-IBU:NA cocrystals were fully characterized by means of advanced one- and two-dimensional solid state nuclear magnetic resonance (SS NMR) techniques with very fast magic angle spinning (MAS) at 60 kHz. The distinction in molecular packing and specific hydrogen bonding pattern was clearly recognized by analysis of 1 H, 13 C, and 15 N spectra. It is concluded from these studies that both methods (grinding and melting) provide exactly the same, specific forms of cocrystals. Thermal solvent-free (TSF) approach was used for loading of (R/S)-IBU:NA and (S)-IBU:NA into the pores of MCM-41 mesoporous silica particle (MSP). The progress and efficiency of this process was analyzed by NMR spectroscopy. It has been confirmed that TSF method is an effective and safe technique of filling the MSP pores with active pharmaceutical ingredients (APIs). By analyzing the NMR results, it has been further proved that excess of IBU and NA components, which are not embedded into the pores during melting and cooling, crystallize on the MCM-41 walls preserving very specific arrangement, characteristic for crystalline samples. By investigating kinetic of release for (R/S)-IBU/MCM-41, (S)-IBU:NA/MCM-41, and (R/S)-IBU:NA/MCM-41 samples containing active components exclusively inside of the pores, it was revealed that release of IBU is much faster for the first of the samples compared to those containing IBU and NA inside the pores. The hypothesis that the rate of release of API can be controlled by specific composition of cocrystal embedded into the MSP pore was further supported by study of (R/S)-IBU:BA/MCM-41 sample with benzoic acid (BA) as coformer.

Evaluation of P-Listed Pharmaceutical Residues in Empty Pharmaceutical Containers

EPA Science Inventory

Under the Resource Conservation and Recovery Act (RCRA), some pharmaceuticals are considered acute hazardous wastes because their sole active pharmaceutical ingredients are P-listed commercial chemical products (40 CFR 261.33). Hospitals and other healthcare facilities have stru...

A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

PubMed Central

2013-01-01

Background Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as β-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of β-artemether and lumefantrine FDC products. Methods Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. β-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 μl injection volume. Quantification was performed at 210 nm and 335 nm for β-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®. Results Both β-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (± RSD) of 99.7 % (± 0.7%) for β-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified β-artemether-related impurities were predicted in Derek Nexus v2.0® to have toxicity risks similar to β-artemether active pharmaceutical ingredient (API) itself. Conclusions A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of β-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus® indicated that the overall toxicity risk for β-artemether-related impurities is comparable to that of β-artemether API. PMID:23631682

21 CFR Appendix C to Subpart A of... - Indicative List of Products Covered by Subpart A

Code of Federal Regulations, 2012 CFR

2012-04-01

... vaccines, and immunologicals; —veterinary pharmaceuticals, including prescription and nonprescription drugs...); —intermediate products and active pharmaceutical ingredients or bulk pharmaceuticals (United States)/starting...

APT drug R&D: the right active ingredient in the right presentation for the right therapeutic use.

PubMed

Cavalla, David

2009-11-01

Drug repurposing, in which an established active pharmaceutical ingredient is applied in a new way - for example, for a new indication, and often combined with an alternative method of presentation, such as a novel delivery route - is an evolving strategy for pharmaceutical R&D. This article discusses examples of the success of this strategy, and presents an analysis of sales of US pharmaceutical products that suggests that this low-risk approach to new product development retains substantial commercial value.

Impact of data base structure in a successful in vitro-in vivo correlation for pharmaceutical products.

PubMed

Roudier, B; Davit, B; Schütz, H; Cardot, J-M

2015-01-01

The in vitro-in vivo correlation (IVIVC) (Food and Drug Administration 1997) aims to predict performances in vivo of a pharmaceutical formulation based on its in vitro characteristics. It is a complex process that (i) incorporates in a gradual and incremental way a large amount of information and (ii) requires information from different properties (formulation, analytical, clinical) and associated dedicated treatments (statistics, modeling, simulation). These results in many studies that are initiated and integrated into the specifications (quality target product profile, QTPP). This latter defines the appropriate experimental designs (quality by design, QbD) (Food and Drug Administration 2011, 2012) whose main objectives are determination (i) of key factors of development and manufacturing (critical process parameters, CPPs) and (ii) of critical points of physicochemical nature relating to active ingredients (API) and critical quality attribute (CQA) which may have implications in terms of efficiency, safety, and inoffensiveness for the patient, due to their non-inclusion. These processes generate a very large amount of data that is necessary to structure. In this context, the storage of information in a database (DB) and the management of this database (database management system, DBMS) become an important issue for the management of projects and IVIVC and more generally for development of new pharmaceutical forms. This article describes the implementation of a prototype object-oriented database (OODB) considered as a tool, which is helpful for decision taking, responding in a structured and consistent way to the issues of project management of IVIVC (including bioequivalence and bioavailability) (Food and Drug Administration 2003) necessary for the implementation of QTPP.

76 FR 51401 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-18

... a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana... ingredients (APIs) for distribution to its customers. In reference to drug code 7360 (Marihuana), the company...

Characterisation of dry powder inhaler formulations using atomic force microscopy.

PubMed

Weiss, Cordula; McLoughlin, Peter; Cathcart, Helen

2015-10-15

Inhalation formulations are a popular way of treating the symptoms of respiratory diseases. The active pharmaceutical ingredient (API) is delivered directly to the site of action within the deep lung using an inhalation device such as the dry powder inhaler (DPI). The performance of the formulation and the efficiency of the treatment depend on a number of factors including the forces acting between the components. In DPI formulations these forces are dominated by interparticulate interactions. Research has shown that adhesive and cohesive forces depend on a number of particulate properties such as size, surface roughness, crystallinity, surface energetics and combinations of these. With traditional methods the impact of particulate properties on interparticulate forces could be evaluated by examining the bulk properties. Atomic force microscopy (AFM), however, enables the determination of local surface characteristics and the direct measurement of interparticulate forces using the colloidal probe technique. AFM is considered extremely useful for evaluating the surface topography of a substrate (an API or carrier particle) and even allows the identification of crystal faces, defects and polymorphs from high-resolution images. Additionally, information is given about local mechanical properties of the particles and changes in surface composition and energetics. The assessment of attractive forces between two bodies is possible by using colloidal probe AFM. This review article summarises the application of AFM in DPI formulations while specifically focussing on the colloidal probe technique and the evaluation of interparticulate forces. Copyright © 2015 Elsevier B.V. All rights reserved.

Sensitive detection of oversulfated chondroitin sulfate in heparin sodium or crude heparin with a colorimetric microplate based assay.

PubMed

Sommers, Cynthia D; Mans, Daniel J; Mecker, Laura C; Keire, David A

2011-05-01

In this work we describe a 96-well microplate assay for oversulfated chondroitin sulfate A (OSCS) in heparin, based on a water-soluble cationic polythiophene polymer (3-(2-(N-(N'-methylimidazole))ethoxy)-4-methylthiophene (LPTP)) and heparinase digestion of heparin. The assay takes advantage of several unique properties of heparin, OSCS, and LPTP, including OSCS inhibition of heparinase I and II activity, the molecular weight dependence of heparin-LPTP spectral shifts, and the distinct association of heparin fragments and OSCS to LPTP. These factors combine to enable detection of the presence of 0.003% w/w spiked OSCS in 10 μg of heparin sodium active pharmaceutical ingredient (API) using a plate reader and with visual detection to 0.1% levels. The same detection limit for OSCS was observed in the presence of 10% levels of dermatan sulfate (DS) or chondroitin sulfate A (CSA) impurities. In addition, we surveyed a selection of crude heparin samples received by the agency in 2008 and 2009 to determine average and extreme DS, CSA, and galactosamine weight percent levels. In the presence of these impurities and the variable heparin content in the crude heparin samples, spiked OSCS was reliably detected to the 0.1% w/w level using a plate reader. Finally, authentically OSCS contaminated heparin sodium API and crude samples were distinguished visually by color from control samples using the LPTP/heparinase test.

A Novel 3D Label-Free Monitoring System of hES-Derived Cardiomyocyte Clusters: A Step Forward to In Vitro Cardiotoxicity Testing

PubMed Central

Jahnke, Heinz-Georg; Steel, Daniella; Fleischer, Stephan; Seidel, Diana; Kurz, Randy; Vinz, Silvia; Dahlenborg, Kerstin; Sartipy, Peter; Robitzki, Andrea A.

2013-01-01

Unexpected adverse effects on the cardiovascular system remain a major challenge in the development of novel active pharmaceutical ingredients (API). To overcome the current limitations of animal-based in vitro and in vivo test systems, stem cell derived human cardiomyocyte clusters (hCMC) offer the opportunity for highly predictable pre-clinical testing. The three-dimensional structure of hCMC appears more representative of tissue milieu than traditional monolayer cell culture. However, there is a lack of long-term, real time monitoring systems for tissue-like cardiac material. To address this issue, we have developed a microcavity array (MCA)-based label-free monitoring system that eliminates the need for critical hCMC adhesion and outgrowth steps. In contrast, feasible field potential derived action potential recording is possible immediately after positioning within the microcavity. Moreover, this approach allows extended observation of adverse effects on hCMC. For the first time, we describe herein the monitoring of hCMC over 35 days while preserving the hCMC structure and electrophysiological characteristics. Furthermore, we demonstrated the sensitive detection and quantification of adverse API effects using E4031, doxorubicin, and noradrenaline directly on unaltered 3D cultures. The MCA system provides multi-parameter analysis capabilities incorporating field potential recording, impedance spectroscopy, and optical read-outs on individual clusters giving a comprehensive insight into induced cellular alterations within a complex cardiac culture over days or even weeks. PMID:23861955

Development and Validation of a Stability-indicating Reversed-phase UPLC-UV Method for the Assay of Imidacloprid and Estimation of its Related Compounds.

PubMed

Tian, Jingzhi; Rustum, Abu

2018-02-01

Imidacloprid is used as an active pharmaceutical ingredient (API) in veterinary drugs to control fleas and ticks for dogs and cats. Here we are reporting for the first time a validated stability-indicating reversed-phase UPLC-UV method for the assay of imidacloprid and estimation of its related compounds. The stability-indicating capability of this method has been demonstrated by a forced degradation study. All related compounds including processing impurities, imidacloprid API and degradates from stressed samples were well separated from each other. Structures of major degradates from forced degradation study were elucidated through UPLC-MS/MS and key degradation pathways were proposed from the proposed chemical structures of major degradates. The UPLC-UV method is carried out using an HSS T3 column (C18, 2.1 × 30 mm, 1.8 μm particle size) maintained at 30°C with mobile phase A (0.05% v/v of phosphoric acid in water) and mobile phase B (methanol/acetonitrile 75/25 v/v). Analytes are separated by a gradient elution and detected at 270 nm. The UPLC method is green and fast with only 6.5 min run time and about 3.5 ml mobile phase consumption for each sample analysis. The UPLC-UV method was validated according to ICH guidelines. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A custom tailored model to investigate skin penetration in porcine skin and its comparison with human skin.

PubMed

Herbig, Michael E; Houdek, Pia; Gorissen, Sascha; Zorn-Kruppa, Michaela; Wladykowski, Ewa; Volksdorf, Thomas; Grzybowski, Stephan; Kolios, Georgios; Willers, Christoph; Mallwitz, Henning; Moll, Ingrid; Brandner, Johanna M

2015-09-01

Reliable models for the determination of skin penetration and permeation are important for the development of new drugs and formulations. The intention of our study was to develop a skin penetration model which (1) is viable and well supplied with nutrients during the period of the experiment (2) is mimicking human skin as far as possible, but still is independent from the problems of supply and heterogeneity, (3) can give information about the penetration into different compartments of the skin and (4) considers specific inter-individual differences in skin thickness. In addition, it should be quick and inexpensive (5) and without ethical implications (6). Using a chemically divers set of four topically approved active pharmaceutical ingredients (APIs), namely diclofenac, metronidazole, tazarotene, and terbinafine, we demonstrated that the model allows reliable determination of drug concentrations in different layers of the viable epidermis and dermis. For APIs susceptible for skin metabolism, the extent of metabolic transformation in epidermis and dermis can be monitored. Furthermore, a high degree of accordance in the ability for discrimination of skin concentrations of the substances in different layers was found in models derived from porcine and human skin. Viability, proliferation, differentiation and markers for skin barrier function were surveyed in the model. This model, which we call 'Hamburg model of skin penetration' is particularly suited to support a rational ranking and selection of dermatological formulations within drug development projects. Copyright © 2015 Elsevier B.V. All rights reserved.

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

PubMed Central

Hiebler, Katharina; Lichtenegger, Georg J; Maier, Manuel C; Park, Eun Sung; Gonzales-Groom, Renie

2018-01-01

Within the “compartmentalised smart factory” approach of the ONE-FLOW project the implementation of different catalysts in “compartments” provided by Pickering emulsions and their application in continuous flow is targeted. We present here the development of heterogeneous Pd catalysts that are ready to be used in combination with biocatalysts for catalytic cascade synthesis of active pharmaceutical ingredients (APIs). In particular, we focus on the application of the catalytic systems for Suzuki–Miyaura cross-coupling reactions, which is the key step in the synthesis of the targeted APIs valsartan and sacubitril. An immobilised enzyme will accomplish the final product formation via hydrolysis. In order to create a large interfacial area for the catalytic reactions and to keep the reagents separated until required, the catalyst particles are used to stabilise Pickering emulsions of oil and water. A set of Ce–Sn–Pd oxides with the molecular formula Ce0.99− xSnxPd0.01O2−δ (x = 0–0.99) has been prepared utilising a simple single-step solution combustion method. The high applicability of the catalysts for different functional groups and their minimal leaching behaviour is demonstrated with various Suzuki–Miyaura cross-coupling reactions in batch as well as in continuous flow employing the so-called “plug & play reactor”. Finally, we demonstrate the use of these particles as the sole emulsifier of oil–water emulsions for a range of oils. PMID:29623127

Study of quality and stability of ursodeoxycholic acid formulations for oral pediatric administration.

PubMed

Santoveña, A; Sánchez-Negrín, E; Charola, L; Llabrés, M; Fariña, J B

2014-12-30

This paper describes a rational method of characterizing the biopharmaceutical stability of two oral suspensions of ursodeoxycholic acid (UDCA) used in pediatrics. Because there is no commercial presentation of UDCA that can administer appropriate doses for infants and children, an active pharmaceutical ingredient (API) formulation is required. Due to its very low solubility and low dose in the formula (1.5%), two different suspensions with minimal use of excipients were studied, avoiding the use of complex additives and those not recommended by the European Medicines Agency (EMA). Adherence to Standard Operating Procedure (SOP) allows the preparation of formulations with appropriately sized and stable particles, and suitable rheological behavior in withdrawing the dose after stirring. Dose uniformity, expressed as mass and content variability, was determined using the criteria of the European and the United States Pharmacopoeia. Additionally, dose content variation of every mass determined was studied. A rational method was developed for determining the dose uniformity of UDCA in suspensions, whether freshly prepared or after storage under different conditions for 30 and 60 days. This method permits detection of differences between doses taken at different heights in the vessel at various times and storage conditions. UDCA was stable under all conditions studied, requiring the presence of glycerol in the formulation to obtain the declared API value after stirring. Storage of UDCA suspensions in a refrigerator increased variability between doses. Copyright © 2014 Elsevier B.V. All rights reserved.

Quantitative determination of cesium binding to ferric hexacyanoferrate: Prussian blue.

PubMed

Faustino, Patrick J; Yang, Yongsheng; Progar, Joseph J; Brownell, Charles R; Sadrieh, Nakissa; May, Joan C; Leutzinger, Eldon; Place, David A; Duffy, Eric P; Houn, Florence; Loewke, Sally A; Mecozzi, Vincent J; Ellison, Christopher D; Khan, Mansoor A; Hussain, Ajaz S; Lyon, Robbe C

2008-05-12

Ferric hexacyanoferrate (Fe4III[FeII(CN)6]3), also known as insoluble Prussian blue (PB) is the active pharmaceutical ingredient (API) of the drug product, Radiogardase. Radiogardase is the first FDA approved medical countermeasure for the treatment of internal contamination with radioactive cesium (Cs) or thallium in the event of a major radiological incident such as a "dirty bomb". A number of pre-clinical and clinical studies have evaluated the use of PB as an investigational decorporation agent to enhance the excretion of metal cations. There are few sources of published in vitro data that detail the binding capacity of cesium to insoluble PB under various chemical and physical conditions. The study objective was to determine the in vitro binding capacity of PB APIs and drug products by evaluating certain chemical and physical factors such as medium pH, particle size, and storage conditions (temperature). In vitro experimental conditions ranged from pH 1 to 9, to cover the range of pH levels that PB may encounter in the gastrointestinal (GI) tract in humans. Measurements of cesium binding were made between 1 and 24h, to cover gastric and intestinal tract residence time using a validated atomic emission spectroscopy (AES) method. The results indicated that pH, exposure time, storage temperature (affecting moisture content) and particle size play significant roles in the cesium binding to both the PB API and the drug product. The lowest cesium binding was observed at gastric pH of 1 and 2, whereas the highest cesium binding was observed at physiological pH of 7.5. It was observed that dry storage conditions resulted in a loss of moisture from PB, which had a significant negative effect on the PB cesium binding capacity at time intervals consistent with gastric residence. Differences were also observed in the binding capacity of PB with different particle sizes. Significant batch to batch differences were also observed in the binding capacity of some PB API and drug products. Our results suggest that certain physiochemical properties affect the initial binding capacity and the overall binding capacity of PB APIs and drug products during conditions that simulated gastric and GI residence time. These physiochemical properties can be utilized as quality attributes to monitor and predict drug product quality under certain manufacturing and storage conditions and may be utilized to enhance the clinical efficacy of PB.

40 CFR 439.41 - Special definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... STANDARDS (CONTINUED) PHARMACEUTICAL MANUFACTURING POINT SOURCE CATEGORY Mixing/Compounding and Formulation § 439.41 Special definitions. For the purpose of this subpart: (a) Mixing, compounding, and formulating... pharmaceutical product manufactured by blending, mixing, compounding, and formulating pharmaceutical ingredients...

77 FR 52368 - Manufacturer of Controlled Substances; Notice of Registration; Austin Pharma, LLC.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-29

... a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana... ingredients (APIs) for distribution to its customers. In reference to drug code 7360 (Marihuana), the company...

Stable Isotope Profiling of Internet-Sourced Viagra® and 'generic- Viagra' Tablets

NASA Astrophysics Data System (ADS)

Kemp, Helen; Meier-Augenstein, Wolfram

2013-04-01

Viagra® manufactured by Pfizer was the first prescription drug for the treatment of erectile dysfunction (ED), a condition that is estimated to affect 1 in 10 men at some stage in their lives (1). Viagra® contains the active pharmaceutical ingredient (API) sildenafil, as the citrate salt. Sildenafil, along with Tadalafil and Vardenafil belong to a class of drugs known as phosphodiesterase type 5 (PDE5) inhibitors. Since its first production in 1998, Viagra® has generated well in excess of 10 billion US dollars in sales (2) and with Pfizers' patent extended to April 2020 (3) it still remains the only sildenafil-based treatment option for sufferers of ED in the US. There are no legal 'generic-Viagra' formulations available in the US. However, formulations containing sildenafil citrate as API are widely available over the internet and often sold as 'generic Viagra'. These cheaper alternatives are often manufactured under less than ideal conditions with little or no QA/QC procedures in place. The World Health Organisation recognised the scale of the problem in its 2010 bulletin "Growing threat from counterfeit medicines" (4) and quotes a Dutch study cited in the International Journal of Clinical Practice in which from a cohort of 370 seized Viagra® samples, only 10 were genuine. We sourced a variety of tablets sold for the treatment of ED which claimed to have sildenafil citrate as API. Viagra®, 'generic-Viagra', Kamagra, Silagra and Filagra tablets were ordered via the internet and supplied from both UK-based pharmacies as well as overseas suppliers (Hong Kong, India, Vanuata). In this small-scale pilot study, we present results from bulk 2H/18O and 13C/15N stable isotope analysis performed on crushed tablets from 23 samples of internet-sourced tablets sold for the treatment of ED and purported to contain sildenafil citrate as API. References 1. www.healthcare.org.uk 2. www.moneynews.com 3. US Patent & trademark office (www.uspto.gov) 4. WHO bulletin 2010; 88:247-248

[Effects of Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats].

PubMed

Tong, Hai-Ying; Wu, Jisiguleng; Bai, Liang-Feng; Bao, Wu-Ye; Hu, Rilebagen; Li, Jing; Zhang, Yue

2014-05-01

To observe the effects of Mongolian pharmaceutical Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats. Sixty male Wistar rats were randomly divided into six groups according to the sugar consumption test (10 rats in each group), normal control group,model group,fluoxetine group (3.3 mg x kg(-1)) and low dose, medium dose and high dose group (0.25, 0.5, 1 g x kg(-1)) of Betel shisanwei ingredients pill. Except the normal control,the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely raising for 28 days. 10 mL x kg(-1) of drugs were given to each rat once daily,continuously for 28 days. The AC activity of the hippocampus and prefrontal cortex were determined by radiation immunity analysis (RIA), while cAMP and PKA quantity were determinated by Enzyme-linked immunosorbent (ELISA). The AC activity, cAMP and PKA quantity of hippocampus and prefrontal of mouse model of Chronic stress depression decreased significantly than those of control group (P < 0.05 or P < 0.01). However, the AC activity, cAMP and PKA quantity of rat hippocampus and prefrontal cortex in the fluoxetine group and the Mongolian pharmaceutical Betel shisanwei ingredients pill group indecreased significantly than those of model group (P < 0.01 or P < 0.05). Especially for the high dose group of Mongolian pharmaceutical Betel shisanwei ingredients pill. The AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depression model of rats is down-regulated, whereas Mongolian pharmaceutical Betel shisanwei ingredients pill could up-regulated it to resist depression.

Selected Pharmaceuticals Entering an Estuary: Concentrations, Temporal Trends, Partitioning and Fluxes

EPA Science Inventory

In many coastal watersheds and ecosystems, rivers discharging to estuaries receive waters from domestic wastewater-treatment plants resulting in the release and distribution of pharmaceuticals to the marine environment. In the present study, 15 active pharmaceutical ingredients w...

Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development

PubMed Central

Gadade, Dipak Dilip; Pekamwar, Sanjay Sudhakar

2016-01-01

Cocrystal is a concept of the supramolecular chemistry which is gaining the extensive interest of researchers from pharmaceutical and chemical sciences and of drug regulatory agencies. The prominent reason of which is its ability to modify physicochemical properties of active pharmaceutical ingredients. During the development of the pharmaceutical product, formulators have to optimize the physicochemical properties of active pharmaceutical ingredients. Pharmaceutical cocrystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. It is advantageous being a green synthesis approach for production of pharmaceutical compounds. The formation polymorphic forms, solvates, hydrates and salts of cocrystals during the synthesis reported in the literature which can be a potential issue in the development of pharmaceutical cocrystals. The approaches like hydrogen bonding rules, solubility parameters, screening through the CSD database or thermodynamic characteristics can be utilized for the rational design of cocrystals and selection of coformers for synthesis multi-component cocrystals. Considering the significance of pharmaceutical cocrystals pharmaceutical regulatory authorities in the United States and Europe issued guidance documents which may be helpful for pharmaceutical product registration in these regions. In this article, we deal with the design, synthesis, strategic aspects and characteristics of cocrystals along perspectives on its regulatory and intellectual property considerations. PMID:28101455

Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development.

PubMed

Gadade, Dipak Dilip; Pekamwar, Sanjay Sudhakar

2016-12-01

Cocrystal is a concept of the supramolecular chemistry which is gaining the extensive interest of researchers from pharmaceutical and chemical sciences and of drug regulatory agencies. The prominent reason of which is its ability to modify physicochemical properties of active pharmaceutical ingredients. During the development of the pharmaceutical product, formulators have to optimize the physicochemical properties of active pharmaceutical ingredients. Pharmaceutical cocrystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. It is advantageous being a green synthesis approach for production of pharmaceutical compounds. The formation polymorphic forms, solvates, hydrates and salts of cocrystals during the synthesis reported in the literature which can be a potential issue in the development of pharmaceutical cocrystals. The approaches like hydrogen bonding rules, solubility parameters, screening through the CSD database or thermodynamic characteristics can be utilized for the rational design of cocrystals and selection of coformers for synthesis multi-component cocrystals. Considering the significance of pharmaceutical cocrystals pharmaceutical regulatory authorities in the United States and Europe issued guidance documents which may be helpful for pharmaceutical product registration in these regions. In this article, we deal with the design, synthesis, strategic aspects and characteristics of cocrystals along perspectives on its regulatory and intellectual property considerations.

Quality of antimalarial drugs and antibiotics in Papua New Guinea: a survey of the health facility supply chain.

PubMed

Hetzel, Manuel W; Page-Sharp, Madhu; Bala, Nancy; Pulford, Justin; Betuela, Inoni; Davis, Timothy M E; Lavu, Evelyn K

2014-01-01

Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing.

Quality of Antimalarial Drugs and Antibiotics in Papua New Guinea: A Survey of the Health Facility Supply Chain

PubMed Central

Hetzel, Manuel W.; Page-Sharp, Madhu; Bala, Nancy; Pulford, Justin; Betuela, Inoni; Davis, Timothy M. E.; Lavu, Evelyn K.

2014-01-01

Background Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. Methods and Findings Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. Conclusions This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing. PMID:24828338

Manufacturing of a Secretoneurin Drug Delivery System with Self-Assembled Protamine Nanoparticles by Titration

PubMed Central

Scheicher, Bernhard; Lorenzer, Cornelia; Gegenbauer, Katrin; Partlic, Julia; Andreae, Fritz; Kirsch, Alexander H.; Rosenkranz, Alexander R.; Werzer, Oliver

2016-01-01

Since therapeutic peptides and oligonucleotides are gathering interests as active pharmaceutical ingredients (APIs), nanoparticulate drug delivery systems are becoming of great importance. Thereby, the possibility to design drug delivery systems according to the therapeutic needs of APIs enhances clinical implementation. Over the last years, the focus of our group was laid on protamine-oligonucleotide-nanoparticles (so called proticles), however, the possibility to modify the size, zeta potential or loading efficiencies was limited. Therefore, at the present study we integrated a stepwise addition of protamine (titration) into the formation process of proticles loaded with the angiogenic neuropeptide secretoneurin (SN). A particle size around 130 nm was determined when proticles were assembled by the commonly used protamine addition at once. Through application of the protamine titration process it was possible to modify and adjust the particle size between approx. 120 and 1200 nm (dependent on mass ratio) without influencing the SN loading capacity. Dynamic light scattering pointed out that the difference in particle size was most probably the result of a secondary aggregation. Initially-formed particles of early stages in the titration process aggregated towards bigger assemblies. Atomic-force-microscopy images also revealed differences in morphology along with different particle size. In contrast, the SN loading was only influenced by the applied mass ratio, where a slight saturation effect was observable. Up to 65% of deployed SN could be imbedded into the proticle matrix. An in-vivo biodistribution study (i.m.) showed a retarded distribution of SN from the site of injection after the application of a SN-proticle formulation. Further, it was demonstrated that SN loaded proticles can be successfully freeze-dried and resuspended afterwards. To conclude, the integration of the protamine titration process offers new possibilities for the formulation of proticles in order to address key parameters of drug delivery systems as size, API loading or modified drug release. PMID:27828968

Morphological and Crystalline Transitions in Monohydrous and Anhydrous Aripiprazole for a Long-Acting Injectable Suspension.

PubMed

Tan, Xinyi; Zhong, Yue; He, Luying; Zhang, Yuanyuan; Jing, Guanghui; Li, Song; Wang, Jing; He, Haibing; Tang, Xing

2017-05-01

Many formulation and manufacturing processes can lead to morphological and crystalline transitions in many polycrystalline drugs, changing the properties of active pharmaceutical ingredients (APIs) such as solubility and physical stability which influence their therapeutic effects and safety and so limit their usefulness. Here, we report significant changes in crystal forms and morphology, including the shape and size of particles during the manufacture of off-white aripiprazole (APZ) dry powders used for long-acting and injectable suspensions. With the optimal top-down approach, powders were prepared by recrystallizing uniform monohydrous APZ (MA) and polycrystalline anhydrous APZ (AA) form III, characterized by thermal analysis, PXRD, and FT-IR. However, powders involving MA (MAP) with a lower mean size (2.126 μm), narrower distribution (span = 1.90), and higher stability compared with AA dry powders (AAP) were found to exhibit dehydration behavior and morphological changes after completion of the preparation processes based on the results of thermal analysis. In the case of APZ powders, we wished to obtain more information to guide in the industrial production and experimental design of suspensions in the future.

Design of CGMP Production of 18F- and 68Ga-Radiopharmaceuticals

PubMed Central

Chu, Pei-Chun; Chao, Hao-Yu; Shieh, Wei-Chen; Chen, Chuck C.

2014-01-01

Objective. Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals. Methods. The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for 68Ga-DOTATATE and 18F-FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of 68Ga-DOTATATE and 18F-FDG were established. Results. CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of 68Ga-DOTATATE and 18F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free. Conclusion. CGMP compliance of radiopharmaceuticals has been reviewed. 68Ga-DOTATATE and 18F-FDG were synthesized with high radiochemical yield under CGMP process. PMID:25276810

Reflectance infrared spectroscopy for in-line monitoring of nicotine during a coating process for an oral thin film.

PubMed

Hammes, Florian; Hille, Thomas; Kissel, Thomas

2014-02-01

A process analytical method using reflectance infrared spectrometry was developed for the in-line monitoring of the amount of the active pharmaceutical ingredient (API) nicotine during a coating process for an oral thin film (OTF). In-line measurements were made using a reflectance infrared (RI) sensor positioned after the last drying zone of the coating line. Real-time spectra from the coating process were used for modelling the nicotine content. Partial least squares (PLS1) calibration models with different data pre-treatments were generated. The calibration model with the most comparable standard error of calibration (SEC) and the standard error of cross validation (SECV) was selected for an external validation run on the production coating line with an independent laminate. Good correlations could be obtained between values estimated from the reflectance infrared data and the reference HPLC test method, respectively. With in-line measurements it was possible to allow real-time adjustments during the production process to keep product specifications within predefined limits hence avoiding loss of material and batch. Copyright © 2013 Elsevier B.V. All rights reserved.

Development of a stability-indicating UPLC method for determining olanzapine and its associated degradation products present in active pharmaceutical ingredients and pharmaceutical dosage forms.

PubMed

Krishnaiah, Ch; Vishnu Murthy, M; Kumar, Ramesh; Mukkanti, K

2011-03-25

A simple, sensitive and reproducible ultra performance liquid chromatography (UPLC) coupled with a photodiode array detector method was developed for the quantitative determination of olanzapine (OLN) in API and pharmaceutical dosage forms. The method is applicable to the quantification of related substances and assays of drug substances. Chromatographic separation was achieved on Acquity UPLC BEH 100-mm, 2.1-mm, and 1.7-μm C-18 columns, and the gradient eluted within a short runtime, i.e., within 10.0 min. The eluted compounds were monitored at 250 nm, the flow rate was 0.3 mL/min, and the column oven temperature was maintained at 27°C. The resolution of OLN and eight (potential, bi-products and degradation) impurities was greater than 2.0 for all pairs of components. The high correlation coefficient (r(2)>0.9991) values indicated clear correlations between the investigated compound concentrations and their peak areas within the test ranges. The repeatability and intermediate precision, expressed by the RSD, were less than 2.4%. The accuracy and validity of the method were further ascertained by performing recovery studies via a spike method. The accuracy of the method expressed as relative error was satisfactory. No interference was observed from concomitant substances normally added to the tablets. The drug was subjected to the International Conference on Harmonization (ICH)-prescribed hydrolytic, oxidative, photolytic and thermal stress conditions. The performance of the method was validated according to the present ICH guidelines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness and robustness. Copyright © 2010 Elsevier B.V. All rights reserved.

Investigation of pharmaceutical drugs and caffeine-containing foods using Fourier and terahertz time-domain spectroscopy

NASA Astrophysics Data System (ADS)

KaraliÅ«nas, Mindaugas; Venckevičius, Rimvydas; Kašalynas, Irmantas; Puc, Uroš; Abina, Andreja; Jeglič, Anton; Zidanšek, Aleksander; Valušis, Gintaras

2015-08-01

Several pharmaceutical drugs, such as alprazolam, ibuprofen, acetaminophen, activated carbon and others, and caffeine-containing foods were tested using terahertz (THz) time domain spectroscopy in the range from 0.3 to 2 THz. The dry powder of pharmaceutical drugs was mixed with HDPE and pressed into the pellets using hydraulic press. The coffee grounds were also pressed into the pellets after ball-milling and mixing with HDPE. The caffeine containing liquid foods were dried out on the paper strips of various stacking. Experiments allow one to determine characteristic spectral signatures of the investigated substances within THz range caused by active pharmaceutical ingredients, like in the case of caffeine, as well as supporting pharmaceutical ingredients. Spectroscopic THz imaging approach is considered as a possible option to identify packaged pharmaceutical drugs. The caffeine spectral features in the tested caffeine containing foods are difficult to observed due to the low caffeine concentration and complex caffeine chemical surrounding.

Atmospheric Pressure Ionization Using a High Voltage Target Compared to Electrospray Ionization.

PubMed

Lubin, Arnaud; Bajic, Steve; Cabooter, Deirdre; Augustijns, Patrick; Cuyckens, Filip

2017-02-01

A new atmospheric pressure ionization (API) source, viz. UniSpray, was evaluated for mass spectrometry (MS) analysis of pharmaceutical compounds by head-to-head comparison with electrospray ionization (ESI) on the same high-resolution MS system. The atmospheric pressure ionization source is composed of a grounded nebulizer spraying onto a high voltage, cylindrical stainless steel target. Molecules are ionized in a similar fashion to electrospray ionization, predominantly producing protonated or deprotonated species. Adduct formation (e.g., proton and sodium adducts) and in-source fragmentation is shown to be almost identical between the two sources. The performance of the new API source was compared with electrospray by infusion of a mix of 22 pharmaceutical compounds with a wide variety of functional groups and physico-chemical properties (molecular weight, logP, and pKa) in more than 100 different conditions (mobile phase strength, solvents, pH, and flow rate). The new API source shows an intensity gain of a factor 2.2 compared with ESI considering all conditions on all compounds tested. Finally, some hypotheses on the ionization mechanism, similarities, and differences with ESI, are discussed. Graphical Abstract ᅟ.

Atmospheric Pressure Ionization Using a High Voltage Target Compared to Electrospray Ionization

NASA Astrophysics Data System (ADS)

Lubin, Arnaud; Bajic, Steve; Cabooter, Deirdre; Augustijns, Patrick; Cuyckens, Filip

2017-02-01

A new atmospheric pressure ionization (API) source, viz. UniSpray, was evaluated for mass spectrometry (MS) analysis of pharmaceutical compounds by head-to-head comparison with electrospray ionization (ESI) on the same high-resolution MS system. The atmospheric pressure ionization source is composed of a grounded nebulizer spraying onto a high voltage, cylindrical stainless steel target. Molecules are ionized in a similar fashion to electrospray ionization, predominantly producing protonated or deprotonated species. Adduct formation (e.g., proton and sodium adducts) and in-source fragmentation is shown to be almost identical between the two sources. The performance of the new API source was compared with electrospray by infusion of a mix of 22 pharmaceutical compounds with a wide variety of functional groups and physico-chemical properties (molecular weight, logP, and pKa) in more than 100 different conditions (mobile phase strength, solvents, pH, and flow rate). The new API source shows an intensity gain of a factor 2.2 compared with ESI considering all conditions on all compounds tested. Finally, some hypotheses on the ionization mechanism, similarities, and differences with ESI, are discussed.

Stability of Allopurinol, Amitriptyline Hydrochloride, Carbamazepine, Domperidone, Isoniazid, Ketoconazole, Lisinopril, Naproxen, Paracetamol (Acetaminophen), and Sertraline Hydrochloride in SyrSpend SF PH4 Oral Suspensions.

PubMed

Polonini, Hudson C; Loures, Sharlene; de Araujo, Edson Peter; Brandão, Marcos Antônio F; Ferreira, Anderson O

2016-01-01

Oral liquids are safe alternatives to solid dosage forms, notably for elderly and pediatric patients that present dysphagia. The use of ready-to-use suspending vehicles such as SyrSpend SF PH4 is a suitable resource for pharmacists as they constitute a safe and timesaving option that has been studied often. The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients (allopurinol 20 mg/mL; amitriptyline hydrochloride 10 mg/mL; carbamazepine 25 mg/mL; domperidone 5 mg/mL; isoniazid 10 mg/mL; ketoconazole 20 mg/mL; lisinopril 1 mg/mL; naproxen 25 mg/mL; paracetamol [acetaminophen] 50 mg/mL; and sertraline hydrochloride 10 mg/mL) compounded in oral suspensions using SyrSpend SF PH4 as the vehicle throughout the study period and stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by means of measuring the percent recovery at varying time points throughout a 90-day period. The quantification of the active pharmaceutical ingredients was performed by high-performance liquid chromatography through a stability-indicating method. Methods were adequately validated. Forced-degradation studies showed that at least one parameter influenced the stability of the active pharmaceutical ingredients. All suspensions were assayed and showed active pharmaceutical ingredient contents between 90% and 110% during the 90-day study period. Although the forced-degradation experiments led to visible fluctuations in the chromatographic responses, the final preparations were stable in the storage conditions. The beyond-use dates of the preparations were found to be at least 90 days for all suspensions, both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients for different medical usages. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

[New drugs for small animals in 2017].

PubMed

Emmerich, Ilka Ute

2018-04-01

In 2017 the active pharmaceutical ingredient Lokivetmab (Cytopoint®), a caninized anti-canine Interleukin 31 monoclonal antibody, was released on the German market for small animals. One substance was authorized for an additional species. Sarolaner, an ectoparasiticide of the isoxazoline group, is now authorized for use in combination with Selamectin (Stronghold® Plus) additionally for cats. The testosterone derivate Nandrolone (Nandrosol®) and the combination of the benzodiazepine Zolazepam with the "dissociative anesthetic" Tiletamine (Zoletil®) were once again authorized. Furthermore, two veterinary drugs with a new combination of active ingredients, one drug with a new active ingredient and two veterinary drugs with a new pharmaceutical form have been launched on the market for small animals. Schattauer GmbH.

Development of a binary carrier system consisting polyethylene glycol 4000 - ethyl cellulose for ibuprofen solid dispersion

PubMed Central

Alagdar, Gada Sulaiman A.; Oo, May Kyaw; Sengupta, Pinaki; Mandal, Uttam Kumar; Jaffri, Julian Md.; Chatterjee, Bappaditya

2017-01-01

Background and Objective: One of the established strategies to improve solubility and dissolution rate of poorly water-soluble drugs is solid dispersion (SD). Polyethylene glycol (PEG) is used as common carrier despite its stability problem which may be overcome by the addition of hydrophobic polymer. The present research aimed to develop an SD formulation with ibuprofen, a poor water-soluble BCS Class II drug as active pharmaceutical ingredient (API) and PEG 4000-ethyl cellulose (EC) as binary carrier. Methods: Melt mixing SD method was employed using a ratio of API: binary carrier (1:3.5 w/w) (SDPE). Another SD was prepared using only PEG (SDP) as a carrier for comparative study. The developed formulation was evaluated using optical microscopy, scanning electron microscopy (SEM), determination of moisture content, differential scanning calorimetry (DSC), in vitro dissolution test, attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and flow properties. Results: SEM and DSC indicated the conversion of crystalline ibuprofen to fine partly amorphous solid dispersion, which was responsible for the increase in dissolution rate of SD than a physical mixture. The release characteristics within 1 h from the higher to the lower value were the SDPE> SDP> physical mixture. Flow property evaluation using the angle of repose showed no difference between SD and PM. However, by Carr index and Hausner ratio, the flow properties of SDPE was excellent. Conclusion: The SD formulation with the PEG 4000-EC carrier can be effective to enhance in vitro dissolution of ibuprofen immediate release dosage form. PMID:29184827

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion.

PubMed

Albadarin, Ahmad B; Potter, Catherine B; Davis, Mark T; Iqbal, Javed; Korde, Sachin; Pagire, Sudhir; Paradkar, Anant; Walker, Gavin

2017-10-30

The aim of this study was to evaluate a novel combination of hydroxypropyl methylcellulose phthalate (HPMCP-HP-50) and Soluplus ® polymers for enhanced physicochemical stability and solubility of the produced amorphous solid dispersions (ASDs). This was achieved using hot melt extrusion (HME) to convert the crystalline active pharmaceutical ingredient (API) into a more soluble amorphous form within the ternary systems. Itraconazole (ITZ), a Biopharmaceutics Classification System class II (BCS II) API, was selected as the model drug. The ASDs were characterized by Powder X-Ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) spectroscopy, Solid State Nuclear Magnetic Resonance (ssNMR) and dissolution studies. The data showed that the ASDs were physically and chemically stable at 20°C and 50% RH over 12 months. PXRD results indicated that the ITZ in the ASDs was in the amorphous state and no recrystallization occurred. DSC scans confirmed that each formulation exhibited a single intermediate glass transition (T g ), around 96.4°C, indicating that ITZ was completely miscible in the polymeric blends of HPMCP and Soluplus ® at up to 30% (w/w) drug loading and that the two polymers were miscible with each other in the presence of ITZ. The FTIR analysis indicated the formation of strong hydrogen bonding between ITZ, HPMCP and Soluplus ® . The dissolution end-point of the ASDs was determined to be approximately 10 times greater than that of the crystalline ITZ. Copyright © 2017 Elsevier B.V. All rights reserved.

Dielectric relaxation studies in super-cooled liquid and glassy phases of anti-cancerous alkaloid: Brucine

NASA Astrophysics Data System (ADS)

Afzal, Aboothahir; Shahin Thayyil, M.; Sulaiman, M. K.; Kulkarni, A. R.

2018-05-01

Brucine has good anti-tumor effects, on both liver cancer and breast cancer. It has bioavailability of 40.83%. Since the bioavailability of the drug is low, an alternative method to increase its bioavailability and solubility is by changing the drug into glassy form. We used Differential Scanning Calorimetry (DSC) for studying the glass forming ability of the drug. Brucine was found to be a very good glass former glass transition temperature 365 K. Based on the DSC analysis we have used broadband dielectric spectroscopy (BDS) for studying the drug in the super cooled and glassy state. BDS is an effective tool to probe the molecular dynamics in the super cooled and glassy state. Molecular mobility is found to be present even in the glassy state of this active pharmaceutical ingredient (API) which is responsible for the instability. Our aim is to study the factors responsible for instability of this API in amorphous form. Cooling curves for dielectric permittivity and dielectric loss revealed the presence of structural (α) and secondary relaxations (β and γ). Temperature dependence of relaxation time is fitted by Vogel-Fulcher-Tammann equation and found the values of activation energy of the α relaxation, fragility and glass transition temperature. Paluch's anti correlation is also verified, that the width of the α-loss peak at or near the glass transition temperature Tg is strongly anticorrelated with the polarity of the molecule. The larger the dielectric relaxation strength Δɛ (Tg) of the system, the narrower is the α-loss peak (higher value of βKWW).

Understanding the effect of lactose particle size on the properties of DPI formulations using experimental design.

PubMed

Guenette, Estelle; Barrett, Andrew; Kraus, Debbie; Brody, Rachel; Harding, Ljiljana; Magee, Gavin

2009-10-01

Medicines for delivering therapeutic agents to the lung as dry powders primarily consist of a carrier and a micronised active pharmaceutical ingredient (API). The performance of an inhaled formulation will depend on a number of factors amongst which the particle size distribution (PSD) plays a key role. It is suggested that increasing the number of fine particles in the carrier can improve the aerosolisation of the API. In addition the effect of PSD upon a bulk powder is also broadly understood in terms of powder flow. Other aspects of functionality that different size fractions of the carrier affect are not clearly understood; for example, it is not yet clearly known how different size fractions contribute to the different functionalities of the carrier. It is the purpose of this investigation to examine the effects of different lactose size fractions on fine particle dose, formulation stability and the ability to process and fill the material in the preferred device. In order to understand the true impact of the size fractions of lactose on the performance of dry powder inhaled (DPI) products, a statistically designed study has been conducted. The study comprised various DPI blend formulations prepared using lactose monohydrate carrier systems consisting of mixtures of four size fractions. Interactive mixtures were prepared containing 1% (w/w) salbutamol sulphate. The experimental design enabled the evaluation of the effect of lactose size fractions on processing and performance attributes of the formulation. Furthermore, the results of the study demonstrate that an experimental design approach can be used successfully to support dry powder formulation development.

To Study Capping or Lamination Tendency of Tablets Through Evaluation of Powder Rheological Properties and Tablet Mechanical Properties of Directly Compressible Blends.

PubMed

Dudhat, Siddhi M; Kettler, Charles N; Dave, Rutesh H

2017-05-01

Air entrapment efficiency of the powders is one of the main factors leading to occurrence of capping or lamination tendency of tablets manufactured from the directly compressible powder blends. The purpose of the current research was to study this underlying cause leading to occurrence of capping or lamination of tablets through evaluation of powder rheological properties. Powder blends were prepared by addition of 0% w/w to 100% w/w of individual active pharmaceutical ingredient (API) [two model API: acetaminophen (APAP) and ibuprofen (IBU)] with microcrystalline cellulose without and with 0.5% w/w Magnesium Stearate as lubricant. Powder rheological properties were analyzed using FT4 Powder Rheometer for dynamic, bulk, and shear properties. Tablet mechanical properties of the respective blends were studied by determining the ability of the material to form tablet of specific strength under applied compaction pressure through tabletability profile. The results showed that powder rheometer distinguished the powder blends based on their ability to relieve entrapped air along with the distinctive flow characteristics. Powder blend prepared with increasing addition of APAP displayed low powder permeability as compared to IBU blends with better powder permeability, compressibility and flow characteristics. Also, lubrication of the APAP blends did not ease their ability to relieve air. Tabletability profiles revealed the potential occurrence of capping or lamination in tablets prepared from the powder blends with high APAP content. This study can help scientist to understand tableting performance at the early-developmental stages and can avoid occurrence capping and lamination of tablets.

Development of a simple method for quantitation of methanesulfonic acid at low ppm level using hydrophilic interaction chromatography coupled with ESI-MS.

PubMed

Huang, Zongyun; Francis, Robert; Zha, Yan; Ruan, Joan

2015-01-01

A simple, sensitive and robust method using HILIC-ESI-MS has been developed for the determination of methane sulfonic acid (MSA) at low ppm level in order to verify the effectiveness of controlling the formation of genotoxic sulfonate esters in the downstream synthetic step, by which produces active pharmaceutical ingredient (API). Stationary phases with positively charged functional groups such as triazole and amino phases were evaluated for the retention of alkyl sulfonic acids. The MSA was quantitated at 1-10 ppm relative to the API using a Cosmosil column (triazole stationary phase) in HILIC mode and the control of MSA can be monitored effectively using the HILIC-ESI-MS methodology. In addition, to provide general guidance for the HILIC-ESI-MS method development, the retention behavior of propanesulfonic acid (PSA) in HILIC mode was investigated using a Unison UK-Amino column to have a better understanding of the HILIC separation mechanism. The results showed reasonable evidence that the combined effect of surface adsorption and ion-exchange played a dominant role for sulfonic acids when using a mobile phase within typical HILIC operation range (0.05-0.20 aqueous volume fraction) while the ion-exchange effect becomes increasingly important in a mobile phase with higher water content. The advantage of using ESI-MS detection in HILIC mode was also demonstrated by the observation that the sensitivity of PSA increased substantially with increasing acetonitrile fraction in mobile phase from 0.80 to 0.95. Copyright © 2014 Elsevier B.V. All rights reserved.

Internet-ordered viagra (sildenafil citrate) is rarely genuine.

PubMed

Campbell, Neil; Clark, John P; Stecher, Vera J; Goldstein, Irwin

2012-11-01

Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). Pfizer monitored top search results for the query "buy Viagra" on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal "generic Viagra." Cost per tablet ranged from $3.28-$33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet. © 2012 International Society for Sexual Medicine.

Transient swelling, spreading, and drug delivery by a dissolved anti-HIV microbicide-bearing film

NASA Astrophysics Data System (ADS)

Tasoglu, Savas; Rohan, Lisa C.; Katz, David F.; Szeri, Andrew J.

2013-03-01

There is a widespread agreement that more effective drug delivery vehicles with more alternatives, as well as better active pharmaceutical ingredients (APIs), must be developed to improve the efficacy of microbicide products. For instance, in tropical regions, films are more appropriate than gels due to better stability of drugs at extremes of moisture and temperature. Here, we apply fundamental fluid mechanical and physicochemical transport theory to help better understand how successful microbicide API delivery depends upon properties of a film and the human reproductive tract environment. Several critical components of successful drug delivery are addressed. Among these are: elastohydrodynamic flow of a dissolved non-Newtonian film; mass transfer due to inhomogeneous dilution of the film by vaginal fluid contacting it along a moving boundary (the locally deforming vaginal epithelial surface); and drug absorption by the epithelium. Local rheological properties of the film are dependent on local volume fraction of the vaginal fluid. We evaluated this experimentally, delineating the way that constitutive parameters of a shear-thinning dissolved film are modified by dilution. To develop the mathematical model, we integrate the Reynolds lubrication equation with a mass conservation equation to model diluting fluid movement across the moving vaginal epithelial surface and into the film. This is a complex physicochemical phenomenon that is not well understood. We explore time- and space-varying boundary flux model based upon osmotic gradients. Results show that the model produces fluxes that are comparable to experimental data. Further experimental characterization of the vaginal wall is required for a more precise set of parameters and a more sophisticated theoretical treatment of epithelium.

Triboelectrification of active pharmaceutical ingredients: week acids and their salts.

PubMed

Fujinuma, Kenta; Ishii, Yuji; Yashihashi, Yasuo; Yonemochi, Estuo; Sugano, Kiyohiko; Tarada, Katsuhide

2015-09-30

The effect of salt formulation on the electrostatic property of active pharmaceutical ingredients was investigated. The electrostatic property of weak acids (carboxylic acids and amide-enole type acid) and their sodium salts was evaluated by a suction-type Faraday cage meter. Free carboxylic acids showed negative chargeability, whereas their sodium salts showed more positive chargeability than the free acids. However, no such trend was observed for amide-enole type acids. Copyright © 2015 Elsevier B.V. All rights reserved.

Quality of anthelminthic medicines available in Jimma Ethiopia.

PubMed

Belew, Sileshi; Suleman, Sultan; Wynendaele, Evelien; D'Hondt, Matthias; Kosgei, Anne; Duchateau, Luc; De Spiegeleer, Bart

2018-01-01

Soil-transmitted helminthiasis and schistosomiasis are major public health problems in Ethiopia. Mass deworming of at-risk population using a single dose administration of 400mg albendazole (ABZ) or 500mg mebendazole (MBZ) for treatment of common intestinal worms and 40mg of praziquantel (PZQ) per kg body weight for treatment of schistosomiasis is one of the strategies recommended by World Health Organization (WHO) in order to control the morbidity of soil-transmitted helminthiasis and schistosomiasis. Since storage condition, climate, way of transportation and distribution route could all affect the quality of medicines, regular assessment by surveys is very critical to ensure the therapeutic outcome, to minimize risk of toxicity to the patient and resistance of parasites. Therefore, this study was conducted to assess the pharmaceutical quality of ABZ, MBZ and PZQ tablet brands commonly available in Jimma town (south west Ethiopia). Retail pharmacies (n=10) operating in Jimma town were selected using simple random sampling method. Samples of anthelminthic medicines available in the selected pharmacies were collected. Sample information was recorded and encompassed trade name, active ingredient name, manufacturer's name and full address, labeled medicine strength, dosage form, number of units per container, dosage statement, batch/lot number, manufacturing and expiry dates, storage information and presence of leaflets/package insert. Moreover, a first visual inspection was performed encompassing uniformity of color, uniformity of size, breaks, cracks, splits, embedded surface spots or visual contaminations. Finally, physico-chemical quality attributes investigated encompassed mass uniformity, quantity of active pharmaceutical ingredient (API), disintegration and dissolution, all following Pharmacopoeial test methods The physical characteristics of dosage form, packaging and labeling information of all samples complied with criteria given in the WHO checklists. The mass uniformity of tablets of each brand of ABZ, MBZ and PZQ complied with the pharmacopoeial specification limits, i.e no more than 2 individual masses >5% of average tablet weight, and none deviate by more than 10%. The quantity of APIs in all investigated tablet brands were within the 90-110% label claim (l.c.) limits, ranging between 95.05 and 110.09% l.c. Disintegration times were in line with the pharmacopoeial specification limit for immediate release (IR) tablets, ranging between 0.5 and 13min. However, the dissolution results (mean±SD, n=6) of one ABZ brand (i.e. Wormin ® , Q=59.21±0.99% at 30min) and two PZQ brands (i.e. Bermoxel ® , Q=63.43%±0.7 and Distocide ® , Q=62.43%±1.67, at 75min) showed poor dissolution, failing the United States Pharmacopoeia (USP) dissolution specification limit. Copyright © 2017 Elsevier B.V. All rights reserved.

77 FR 36997 - Foreign-Trade Zone 61-San Juan, PR; Notification of Proposed Production Activity; Pfizer...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

...; Notification of Proposed Production Activity; Pfizer Pharmaceuticals LLC (Subzone 61A); (Ibuprofen...). Pfizer is now requesting to produce ibuprofen pharmaceutical products in bulk mixture or dosage form... to the ibuprofen pharmaceutical products (duty-free) for foreign-status ibuprofen active ingredient...

Temporal and spatial behavior of pharmaceuticals in Narragansett Bay, Rhode Island, United States.

EPA Science Inventory

The behavior and fate of pharmaceutical ingredients in coastal marine ecosystems are not well understood. To address this, the spatial and temporal distribution of 15 high-volume pharmaceuticals were measured over a 1-yr period in Narragansett Bay (RI, USA) to elucidate factors a...

77 FR 63290 - Foreign-Trade Zone 121-Albany, NY; Notification of Proposed Production Activity; Albany Molecular...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-16

...; Notification of Proposed Production Activity; Albany Molecular Research, Inc., Subzone 121A, (Pharmaceutical... pharmaceutical chemicals and intermediates under FTZ procedures at the former Sanofi Winthrop L.P. plant located...). AMRI is now requesting to produce an active pharmaceutical ingredient, dexpramipexole dihydrochloride...

[New drugs for small animals in 2010].

PubMed

Emmerich, I U

2011-01-01

In 2010, no active pharmaceutical ingredients were released on the German market for small animals. Furthermore, no additional substances were authorized for additional species. Only one drug with an interesting new pharmaceutical form, two products with a new strength and one drug, which is interesting because of other criteria, were added to the market for small animals. In addition, nine active pharmaceutical ingredients with approval for use in human medicine, which are of potential interest for veterinary medicine, entered the market in 2010. Those are the analgesic Tapentadol, the antiallergicum Bilastine, the antiarrhythmics Dronedarone and Vernakalant, the antihaemorrhagic Eltrombopag, the bronchodilator Roflumilast, the hormone Corifollitropin alfa, the laxative Prucalopride and the cytostatic Mifamurtide.

Supramolecular hydrogen-bonding patterns in 1:1 cocrystals of 5-fluorouracil with 4-methylbenzoic acid and 3-nitrobenzoic acid.

PubMed

Mohana, Marimuthu; Muthiah, Packianathan Thomas; McMillen, Colin D

2017-03-01

The design of a pharmaceutical cocrystal is based on the identification of specific hydrogen-bond donor and acceptor groups in active pharmaceutical ingredients (APIs) in order to choose a `complementary interacting' molecule that can act as an efficient coformer. 5-Fluorouracil (5FU) is a pyrimidine derivative with two N-H donors and C=O acceptors and shows a diversity of hydrogen-bonding motifs. Two 1:1 cocrystals of 5-fluorouracil (5FU), namely 5-fluorouracil-4-methylbenzoic acid (5FU-MBA), C 4 H 3 FN 2 O 2 ·C 8 H 8 O 2 , (I), and 5-fluorouracil-3-nitrobenzoic acid (5FU-NBA), C 4 H 3 FN 2 O 2 ·C 7 H 5 NO 4 , (II), have been prepared and characterized by single-crystal X-ray diffraction. In (I), the MBA molecules form carboxylic acid dimers [R 2 2 (8) homosynthon]. Similarly, the 5FU molecules form two types of base pair via a pair of N-H...O hydrogen bonds [R 2 2 (8) homosynthon]. In (II), 5FU interacts with the carboxylic acid group of NBA via N-H...O and O-H...O hydrogen bonds, generating an R 2 2 (8) ring motif (heterosynthon). Furthermore, the 5FU molecules form base pairs [R 2 2 (8) homosynthon] via N-H...O hydrogen bonds. Both of the crystal structures are stabilized by C-H...F interactions.

Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives.

PubMed

Breda, Susana A; Jimenez-Kairuz, Alvaro F; Manzo, Ruben H; Olivera, María E

2009-04-17

The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.

Solubility of lovastatin in a family of six alcohols: Ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, and 1-octanol.

PubMed

Nti-Gyabaah, J; Chmielowski, R; Chan, V; Chiew, Y C

2008-07-09

Accurate experimental determination of solubility of active pharmaceutical ingredients (APIs) in solvents and its correlation, for solubility prediction, is essential for rapid design and optimization of isolation, purification, and formulation processes in the pharmaceutical industry. An efficient material-conserving analytical method, with in-line reversed HPLC separation protocol, has been developed to measure equilibrium solubility of lovastatin in ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, and 1-octanol between 279 and 313K. Fusion enthalpy DeltaH(fus), melting point temperature, Tm, and the differential molar heat capacity, DeltaC(P), were determined by differential scanning calorimetry (DSC) to be 43,136J/mol, 445.5K, and 255J/(molK), respectively. In order to use the regular solution equation, simplified assumptions have been made concerning DeltaC(P), specifically, DeltaC(P)=0, or DeltaC(P)=DeltaS. In this study, we examined the extent to which these assumptions influence the magnitude of the ideal solubility of lovastatin, and determined that both assumptions underestimate the ideal solubility of lovastatin. The solubility data was used with the calculated ideal solubility to obtain activity coefficients, which were then fitted to the van't Hoff-like regular solution equation. Examination of the plots indicated that both assumptions give erroneous excess enthalpy of solution, H(infinity), and hence thermodynamically inconsistent activity coefficients. The order of increasing ideality, or solubility of lovastatin was butanol>1-propanol>1-pentanol>1-hexanol>1-octanol.

Amino acids as co-amorphous stabilizers for poorly water soluble drugs--Part 1: preparation, stability and dissolution enhancement.

PubMed

Löbmann, Korbinian; Grohganz, Holger; Laitinen, Riikka; Strachan, Clare; Rades, Thomas

2013-11-01

Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water soluble. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissolution rate and solubility of these drugs is the conversion of a crystalline form of the drug into its respective amorphous form, usually by incorporation into hydrophilic polymers, forming glass solutions. However, this strategy only led to a small number of marketed products usually because of inadequate physical stability of the drug (crystallization). In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small molecular weight excipients that form specific molecular interactions with the drug resulting in co-amorphous forms. The two poorly water soluble drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biological receptors of these drugs. Mixtures of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepared by vibrational ball milling. Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepared as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temperature (Tg) in the DSC measurements. In addition, the Tgs of the co-amorphous mixtures were significantly increased over those of the individual drugs. The drugs remained chemically stable during the milling process and the co-amorphous formulations were generally physically stable over at least 6 months at 40 °C under dry conditions. The dissolution rate of all co-amorphous drug-amino acid mixtures was significantly increased over that of the respective crystalline and amorphous pure drugs. Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissolution of amorphous drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Therapeutic Equivalence Requires Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Identities: True Bioequivalence of a Generic Product of Intravenous Metronidazole

PubMed Central

Agudelo, M.

2012-01-01

Animal models of infection have been used to demonstrate the therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR2] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials. PMID:22330928

Investigation into process-induced de-aggregation of cohesive micronised API particles.

PubMed

Hoffmann, Magnus; Wray, Patrick S; Gamble, John F; Tobyn, Mike

2015-09-30

The aim of this study was to assess the impact of unit processes on the de-aggregation of a cohesive micronised API within a pharmaceutical formulation using near-infrared chemical imaging. The impact on the primary API particles was also investigated using an image-based particle characterization system with integrated Raman analysis. The blended material was shown to contain large, API rich domains which were distributed in-homogeneously across the sample, suggesting that the blending process was not aggressive enough to disperse aggregates of micronised drug particles. Cone milling, routinely used to improve the homogeneity of such cohesive formulations, was observed to substantially reduce the number and size of API rich domains; however, several smaller API domains survived the milling process. Conveyance of the cone milled formulation through the Alexanderwerk WP120 powder feed system completely dispersed all remaining aggregates. Importantly, powder feed transmission of the un-milled formulation was observed to produce an equally homogeneous API distribution. The size of the micronised primary drug particles remained unchanged during powder feed transmission. These findings provide further evidence that this powder feed system does induce shear, and is in fact better able to disperse aggregates of a cohesive micronised API within a blend than the blend-mill-blend step. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

40 CFR 439.41 - Special definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... STANDARDS PHARMACEUTICAL MANUFACTURING POINT SOURCE CATEGORY Mixing/Compounding and Formulation § 439.41 Special definitions. For the purpose of this subpart: (a) Mixing, compounding, and formulating operations... product manufactured by blending, mixing, compounding, and formulating pharmaceutical ingredients. The...

40 CFR 439.41 - Special definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... product manufactured by blending, mixing, compounding, and formulating pharmaceutical ingredients. The... STANDARDS PHARMACEUTICAL MANUFACTURING POINT SOURCE CATEGORY Mixing/Compounding and Formulation § 439.41 Special definitions. For the purpose of this subpart: (a) Mixing, compounding, and formulating operations...

Terahertz Tools Advance Imaging for Security, Industry

NASA Technical Reports Server (NTRS)

2010-01-01

Picometrix, a wholly owned subsidiary of Advanced Photonix Inc. (API), of Ann Arbor, Michigan, invented the world s first commercial terahertz system. The company improved the portability and capabilities of their systems through Small Business Innovation Research (SBIR) agreements with Langley Research Center to provide terahertz imaging capabilities for inspecting the space shuttle external tanks and orbiters. Now API s systems make use of the unique imaging capacity of terahertz radiation on manufacturing floors, for thickness measurements of coatings, pharmaceutical tablet production, and even art conservation.

Bioactive sterols from marine resources and their potential benefits for human health.

PubMed

Kim, Se-Kwon; Van Ta, Quang

2012-01-01

Bioactive agents from marine resources have shown their valuable health beneficial effects. Therefore, increase knowledge on novel functional ingredients with biological activities from marine animal and microbe has gained much attention. Sterols are recognized as potential in development functional food ingredients and pharmaceutical agents. Marine resources, with a great diversity, can be a very interesting natural resource of sterols. This chapter focuses on biological activities of marine animal and microbe sterols with potential health beneficial applications in functional foods and pharmaceuticals. Copyright © 2012 Elsevier Inc. All rights reserved.

Illicit Drugs: Contaminants in the Environment and Utility in Forensic Epidemiology

EPA Science Inventory

The published literature surrounding the origin, occurrence, fate, and effects of illicit drug ingredients (IDIs) in the environment is examined. Similarities exist with medical pharmaceuticals, particularly with regard to the basic processes by which these ingredients enter the ...

PharmEcovigilance and the Environmental Footprint of Pharmaceuticals

EPA Science Inventory

The prescribing and usage of medications have ramifications extending far beyond conventional medical care. The healthcare industry has an environmental footprint because the active ingredients from pharmaceuticals enter the environment as pollutants by a variety of routes, prima...

40 CFR 439.21 - Special definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... STANDARDS PHARMACEUTICAL MANUFACTURING POINT SOURCE CATEGORY Extraction Products § 439.21 Special definitions. For the purpose of this subpart: (a) Extraction means process operations that derive pharmaceutically active ingredients from natural sources such as plant roots and leaves, animal glands, and...

40 CFR 439.21 - Special definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... STANDARDS PHARMACEUTICAL MANUFACTURING POINT SOURCE CATEGORY Extraction Products § 439.21 Special definitions. For the purpose of this subpart: (a) Extraction means process operations that derive pharmaceutically active ingredients from natural sources such as plant roots and leaves, animal glands, and...

Gamma sterilization of pharmaceuticals--a review of the irradiation of excipients, active pharmaceutical ingredients, and final drug product formulations.

PubMed

Hasanain, Fatima; Guenther, Katharina; Mullett, Wayne M; Craven, Emily

2014-01-01

Sterilization by gamma irradiation has shown a strong applicability for a wide range of pharmaceutical products. Due to the requirement for terminal sterilization where possible in the pharmaceutical industry, gamma sterilization has proven itself to be an effective method as indicated by its acceptance in the European Pharmacopeia and the United States Pharmacopeia ( ). Some of the advantages of gamma over competitive procedures include high penetration power, isothermal character (small temperature rise), and no residues. It also provides a better assurance of product sterility than aseptic processing, as well as lower validation demands. Gamma irradiation is capable of killing microorganisms by breaking their chemical bonds, producing free radicals that attack the nucleic acid of the microorganism. Sterility by gamma irradiation is achieved mainly by the alteration of nucleic acid and preventing the cellular division. This review focuses on the extensive application of gamma sterilization to a wide range of pharmaceutical components including active pharmaceutical ingredients, excipients, final drug products, and combination drug-medical devices. A summary of the published literature for each class of pharmaceutical compound or product is presented. The irradiation conditions and various quality control characterization methodologies that were used to determine final product quality are included, in addition to a summary of the investigational outcomes. Based on this extensive literature review and in combination with regulatory guidelines and other published best practices, a decision tree for implementation of gamma irradiation for pharmaceutical products is established. This flow chart further facilitates the implementation of gamma irradiation in the pharmaceutical development process. The summary therefore provides a useful reference to the application and versatility of gamma irradiation for pharmaceutical sterilization. Many pharmaceutical products require sterilization to ensure their safe and effective use. Sterility is therefore a critical quality attribute and is essential for direct injection products. Due to the requirement for terminal sterilization, where possible in the pharmaceutical industry sterilization by gamma irradiation has been commonly used as an effective method to sterilize pharmaceutical products as indicated by its acceptance in the European Pharmacopeia. Gamma sterilization is a very attractive terminal sterilization method in view of its ability to attain 10(-6) probability of microbial survival without excessive heating of the product or exposure to toxic chemicals. However, radiation compatibility of a product is one of the first aspects to evaluate when considering gamma sterilization. Gamma radiation consists of high-energy photons that result in the generation of free radicals and the subsequent ionization of chemical bonds, leading to cleavage of DNA in microorganisms and their subsequent inactivation. This can result in a loss of active pharmaceutical ingredient potency, the creation of radiolysis by-products, a reduction of the molecular weight of polymer excipients, and influence drug release from the final product. There are several strategies for mitigating degradation effects, including optimization of the irradiation dose and conditions. This review will serve to highlight the extensive application of gamma sterilization to a broad spectrum of pharmaceutical components including active pharmaceutical ingredients, excipients, final drug products, and combination drug-medical devices.

WHO Expert Committee on specifications for pharmaceutical preparations.

PubMed

2010-01-01

The Expert Committee on Specifications for Pharmaceutical Preparations works towards clear, independent and practical standards and guidelines for the quality assurance of medicines. Standards are developed by the Committee through worldwide consultation and an international consensus-building process. The following new guidelines were adopted and recommended for use: good practices for pharmaceutical quality control laboratories; supplementary guidelines for active pharmaceutical ingredients; good manufacturing practices for pharmaceutical products containing hazardous substances; good manufacturing practices for sterile pharmaceutical products; good distribution practices for pharmaceutical products; guidelines on the requalification of prequalified dossiers: and guidelines for the preparation of a contract research organization master file.

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules.

PubMed

Higashi, Taishi; Iohara, Daisuke; Motoyama, Keiichi; Arima, Hidetoshi

2018-01-01

Supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences because various physiological reactions and drug activities are based on supramolecular chemistry. However, it is not a major domain in the pharmaceutical field. In this review, we propose a new concept in pharmaceutical sciences termed "supramolecular pharmaceutical sciences," which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences. Herein, we focus on cyclodextrin (CyD)-based supermolecules, because CyDs have been used not only as pharmaceutical excipients or active pharmaceutical ingredients but also as components of supermolecules.

Nanomedicinal products: a survey on specific toxicity and side effects

PubMed Central

Giannakou, Christina; De Jong, Wim H; Kooi, Myrna W; Park, Margriet VDZ; Vandebriel, Rob J; Bosselaers, Irene EM; Scholl, Joep HG; Geertsma, Robert E

2017-01-01

Due to their specific properties and pharmacokinetics, nanomedicinal products (NMPs) may present different toxicity and side effects compared to non-nanoformulated, conventional medicines. To facilitate the safety assessment of NMPs, we aimed to gain insight into toxic effects specific for NMPs by systematically analyzing the available toxicity data on approved NMPs in the European Union. In addition, by comparing five sets of products with the same active pharmaceutical ingredient (API) in a conventional formulation versus a nanoformulation, we aimed to identify any side effects specific for the nano aspect of NMPs. The objective was to investigate whether specific toxicity could be related to certain structural types of NMPs and whether a nanoformulation of an API altered the nature of side effects of the product in humans compared to a conventional formulation. The survey of toxicity data did not reveal nanospecific toxicity that could be related to certain types of structures of NMPs, other than those reported previously in relation to accumulation of iron nanoparticles (NPs). However, given the limited data for some of the product groups or toxicological end points in the analysis, conclusions with regard to (a lack of) potential nanomedicine-specific effects need to be considered carefully. Results from the comparison of side effects of five sets of drugs (mainly liposomes and/or cytostatics) confirmed the induction of pseudo-allergic responses associated with specific NMPs in the literature, in addition to the side effects common to both nanoformulations and regular formulations, eg, with liposomal doxorubicin, and possibly liposomal daunorubicin. Based on the available data, immunotoxicological effects of certain NMPs cannot be excluded, and we conclude that this end point requires further attention. PMID:28883724

Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment

PubMed Central

Hill, Andrew; Gotham, Dzintars; Fortunak, Joseph; Meldrum, Jonathan; Erbacher, Isabelle; Martin, Manuel; Shoman, Haitham; Levi, Jacob; Powderly, William G; Bower, Mark

2016-01-01

Objective To calculate sustainable generic prices for 4 tyrosine kinase inhibitors (TKIs). Background TKIs have proven survival benefits in the treatment of several cancers, including chronic myeloid leukaemia, breast, liver, renal and lung cancer. However, current high prices are a barrier to treatment. Mass production of low-cost generic antiretrovirals has led to over 13 million people being on HIV/AIDS treatment worldwide. This analysis estimates target prices for generic TKIs, assuming similar methods of mass production. Methods Four TKIs with patent expiry dates in the next 5 years were selected for analysis: imatinib, erlotinib, lapatinib and sorafenib. Chemistry, dosing, published data on per-kilogram pricing for commercial transactions of active pharmaceutical ingredient (API), and quotes from manufacturers were used to estimate costs of production. Analysis included costs of excipients, formulation, packaging, shipping and a 50% profit margin. Target prices were compared with current prices. Global numbers of patients eligible for treatment with each TKI were estimated. Results API costs per kg were $347–$746 for imatinib, $2470 for erlotinib, $4671 for lapatinib, and $3000 for sorafenib. Basing on annual dose requirements, costs of formulation/packaging and a 50% profit margin, target generic prices per person-year were $128–$216 for imatinib, $240 for erlotinib, $1450 for sorafenib, and $4020 for lapatinib. Over 1 million people would be newly eligible to start treatment with these TKIs annually. Conclusions Mass generic production of several TKIs could achieve treatment prices in the range of $128–$4020 per person-year, versus current US prices of $75161–$139 138. Generic TKIs could allow significant savings and scaling-up of treatment globally, for over 1 million eligible patients. PMID:26817636

Patents and profits: A disparity of manufacturing margins in the tenofovir value chain.

PubMed

Walwyn, David

2013-03-01

Registered in 2001, tenofovir disoproxil fumarate (TDF) has quickly become a mainstay of first line regimens for the treatment of HIV. Initially only available in developed countries at a cost of US$5 000 per person per year (ppy), Gilead's Access Programme (GAP) has extended the use of the product to 2.4 million patients in low and middle income countries. The programme has two components: distribution of the branded product at reduced prices and licensing partnerships with generic manufacturers. The licensing partnerships now supply 75% of the market by volume, at a treatment cost of US$57 ppy (1% of the branded cost). From Gilead's perspective, GAP must be considered a huge success. It has enabled the company to maintain high prices in developed countries whilst reducing its input costs and deflecting criticism of its failure to provide essential medicines for the poor, hence risking the possibility of compulsory licensing. Over the period 2001 to 2011, TDF in its various forms has generated for Gilead more than US$31 billion revenue at a gross margin of 80%, equivalent to a gross profit of US$25 billion. Analysis of the TDF value chain, from preparation of the active pharmaceutical ingredient (API) to sale of the formulated product, shows that manufacturing margins are highly skewed in favour of the originator, with the latter's profit being US$3.2 billion vs. US$4 million for API manufacturers and US$39 million for formulators (2011). The data argues for a more rational approach to drug pricing including possible regulation in developed countries and more sustainable margins for the generic producers.

The effect of local/topical analgesics on incisional pain in a pig model.

PubMed

Castel, David; Sabbag, Itai; Meilin, Sigal

2017-01-01

Interest in the development of new topical/local drug administration for blocking pain at peripheral sites, with maximum drug activity and minimal systemic effects, is on the rise. In the review article by Kopsky and Stahl, four critical barriers in the process of research and development of topical analgesics were indicated. The active pharmaceutical ingredient (API) and the formulation are among the major challenges. The road to the development of such drugs passes through preclinical studies. These studies, if planned correctly, should serve as guidance for choosing the right API and formulation. Although rodent models for pain continue to provide valuable data on the mechanisms driving pain, their use in developing topical and localized treatment approaches is limited for technical (intraplate injection area is small) as well as mechanical reasons (non-similarity to human skin and innervation). It has been previously shown that pigs are comparable to humans in ways that make them a better choice for evaluating topical and local analgesics. The aim of this study was to summarize several experiments that used pigs for testing postoperative pain in an incisional pain model (skin incision [SI] and skin and muscle incision [SMI]). At the end of the surgery, the animals were treated with different doses of bupivacaine solution (Marcaine ® ), bupivacaine liposomal formulation (Exparel ® ) or ropivacaine solution (Naropin). Von Frey testing demonstrated a decrease in the animals' sensitivity to mechanical stimulation expressed as an increase in the withdrawal force following local treatment. These changes reflect the clinical condition in the level as well as in the duration of the response. These data indicate a good resemblance between pig and human skin and suggest that use of these animals in the preclinical phase of developing topical analgesics can, to some extent, release the bottleneck.

Detection of Lipitor counterfeits: a comparison of NIR and Raman spectroscopy in combination with chemometrics.

PubMed

de Peinder, P; Vredenbregt, M J; Visser, T; de Kaste, D

2008-08-05

Research has been carried on the feasibility of near infrared (NIR) and Raman spectroscopy as rapid screening methods to discriminate between genuine and counterfeits of the cholesterol-lowering medicine Lipitor. Classification, based on partial least squares discriminant analysis (PLS-DA) models, appears to be successful for both spectroscopic techniques, irrespective of whether atorvastatine or lovastatine has been used as the active pharmaceutical ingredient (API). The discriminative power of the NIR model, in particular, largely relies on the spectral differences of the tablet matrix. This is due to the relative large sample volume that is probed with NIR and the strong spectroscopic activity of the excipients. PLS-DA models based on NIR or Raman spectra can also be applied to distinguish between atorvastatine and lovastatine as the API used in the counterfeits tested in this study. A disadvantage of Raman microscopy for this type of analysis is that it is primarily a surface technique. As a consequence spectra of the coating and the tablet core might differ. Besides, spectra may change with the position of the laser in case the sample is inhomogeneous. However, the robustness of the PLS-DA models turned out to be sufficiently large to allow a reliable discrimination. Principal component analysis (PCA) of the spectra revealed that the conditions, at which tablets have been stored, affect the NIR data. This effect is attributed to the adsorption of water from the atmosphere after unpacking from the blister. It implies that storage conditions should be taken into account when the NIR technique is used for discriminating purposes. However, in this study both models based on NIR spectra and Raman data enabled reliable discrimination between genuine and counterfeited Lipitor tablets, regardless of their storage conditions.

Tilmicosin- and florfenicol-loaded hydrogenated castor oil-solid lipid nanoparticles to pigs: Combined antibacterial activities and pharmacokinetics.

PubMed

Ling, Z; Yonghong, L; Junfeng, L; Li, Z; Xianqiang, L

2018-04-01

The combined antibacterial effects of tilmicosin (TIL) and florfenicol (FF) against Actinobacillus pleuropneumoniae (APP) (n = 2), Streptococcus suis (S. suis) (n = 2), and Haemophilus parasuis (HPS) (n = 2) were evaluated by chekerboard test and time-kill assays. The pharmacokinetics (PKs) of TIL- and FF-loaded hydrogenated castor oil (HCO)-solid lipid nanoparticles (SLN) were performed in healthy pigs. The results indicated that TIL and FF showed synergistic or additive antibacterial activities against APP, S. suis and HPS with the fractional inhibitory concentration (FIC) ranging from 0.375 to 0.75. The time-kill assays showed that 1/2 minimum inhibitory concentration (MIC) TIL combined with 1/2 MIC FF had a stronger ability to inhibit the growth of APP, S. suis, and HPS than 1 MIC TIL or 1 MIC FF, respectively. After oral administration, plasma TIL and FF concentrations could maintain about 0.1 μg/ml for 192 and 176 hr. The SLN prolonged the last time point with detectable concentrations (T last ), area under the concentration-time curve (AUC 0-t ), elimination half-life (T ½ke ), and mean residence time (MRT) by 3.1, 5.6, 12.7, 3.4-fold of the active pharmaceutical ingredient (API) of TIL and 11.8, 16.5, 18.1, 12.1-fold of the API of FF, respectively. This study suggests that the TIL-FF-SLN could be a useful oral formulation for the treatment of APP, S. suis, and HPS infection in pigs. © 2017 John Wiley & Sons Ltd.

Mechanisms by which moisture generates cocrystals.

PubMed

Jayasankar, Adivaraha; Good, David J; Rodríguez-Hornedo, Naír

2007-01-01

The purpose of this study is to determine the mechanisms by which moisture can generate cocrystals when solid particles of cocrystal reactants are exposed to deliquescent conditions (when moisture sorption forms an aqueous solution). It is based on the hypothesis that cocrystallization behavior during water uptake can be derived from solution chemistry using models that describe cocrystal solubility and reaction crystallization of molecular complexes. Cocrystal systems were selected with active pharmaceutical ingredients (APIs) that form hydrates and include carbamazepine, caffeine, and theophylline. Moisture uptake and crystallization behavior were studied by gravimetric vapor sorption, X-ray powder diffraction, and on-line Raman spectroscopy. Results indicate that moisture uptake generates cocrystals of carbamazepine-nicotinamide, carbamazepine-saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with cocrystal reactants deliquesce. Microscopy studies revealed that the transformation mechanism to cocrystal involves (1) moisture uptake, (2) dissolution of reactants, and (3) cocrystal nucleation and growth. Studies of solid blends of reactants in a macro scale show that the rate and extent of cocrystal formation are a function of relative humidity, moisture uptake, deliquescent material, and dissolution rates of reactants. It is shown that the interplay between moisture uptake and dissolution determines the liquid phase composition, supersaturation, and cocrystal formation rates. Differences in the behavior of deliquescent additives (sucrose and fructose) are associated with moisture uptake and composition of the deliquesced solution. Our results show that deliquescence can transform API to cocrystal or reverse the reaction given the right conditions. Key indicators of cocrystal formation and stability are (1) moisture uptake, (2) cocrystal aqueous solubility, (3) solubility and dissolution of cocrystal reactants, and (4) transition concentration.

Amide-N-oxide heterosynthon and amide dimer homosynthon in cocrystals of carboxamide drugs and pyridine N-oxides.

PubMed

Babu, N Jagadeesh; Reddy, L Sreenivas; Nangia, Ashwini

2007-01-01

The carboxamide-pyridine N-oxide heterosynthon is sustained by syn(amide)N-H...O-(oxide) hydrogen bond and auxiliary (N-oxide)C-H...O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide-N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide-N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine.quinoxaline N,N'-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N-H...O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius(2), COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 degrees C up to four weeks. Amide-N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H(2)O functional groups.

A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy.

PubMed

Ugaonkar, Shweta R; Wesenberg, Asa; Wilk, Jolanta; Seidor, Samantha; Mizenina, Olga; Kizima, Larisa; Rodriguez, Aixa; Zhang, Shimin; Levendosky, Keith; Kenney, Jessica; Aravantinou, Meropi; Derby, Nina; Grasperge, Brooke; Gettie, Agegnehu; Blanchard, James; Kumar, Narender; Roberts, Kevin; Robbiani, Melissa; Fernández-Romero, José A; Zydowsky, Thomas M

2015-09-10

Women urgently need a self-initiated, multipurpose prevention technology (MPT) that simultaneously reduces their risk of acquiring HIV-1, HSV-2, and HPV (latter two associated with increased risk of HIV-1 acquisition) and prevents unintended pregnancy. Here, we describe a novel core-matrix intravaginal ring (IVR), the MZCL IVR, which effectively delivered the MZC combination microbicide and a contraceptive. The MZCL IVR contains four active pharmaceutical ingredients (APIs): MIV-150 (targets HIV-1), zinc acetate (ZA; targets HIV-1 and HSV-2), carrageenan (CG; targets HPV and HSV-2), and levonorgestrel (LNG; targets unintended pregnancy). The elastomeric IVR body (matrix) was produced by hot melt extrusion of the non-water swellable elastomer, ethylene vinyl acetate (EVA-28), containing the hydrophobic small molecules, MIV-150 and LNG. The solid hydrophilic core, embedded within the IVR by compression, contained the small molecule ZA and the macromolecule CG. Hydrated ZA/CG from the core was released by diffusion via a pore on the IVR while the MIV-150/LNG diffused from the matrix continuously for 94 days (d) in vitro and up to 28 d (study period) in macaques. The APIs released in vitro and in vivo were active against HIV-1ADA-M, HSV-2, and HPV16 PsV in cell-based assays. Serum LNG was at levels associated with local contraceptive effects. The results demonstrate proof-of-concept of a novel core-matrix IVR for sustained and simultaneous delivery of diverse molecules for the prevention of HIV, HSV-2 and HPV acquisition, as well as unintended pregnancy. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

A framework for multi-scale simulation of crystal growth in the presence of polymers.

PubMed

Mandal, Taraknath; Huang, Wenjun; Mecca, Jodi M; Getchell, Ashley; Porter, William W; Larson, Ronald G

2017-03-01

We present a multi-scale simulation method for modeling crystal growth in the presence of polymer excipients. The method includes a coarse-grained (CG) model for small molecules of known crystal structure whose force field is obtained using structural properties from atomistic simulations. This CG model is capable of stabilizing the molecular crystal structure and capturing the crystal growth from the melt for a wide range of small organic molecules, as demonstrated by application of our method to the molecules isoniazid, urea, sulfamethoxazole, prilocaine, oxcarbazepine, and phenytoin. This CG model can also be used to study the effect of additives, such as polymers, on the inhibition of crystal growth by polymers, as exemplified by our simulation of suppression of the rate of crystal growth of phenytoin, an active pharmaceutical ingredient (API), by a cellulose excipient, functionalized with acetate (Ac), hydroxy-propyl (Hp) and succinate (Su) groups. We show that the efficacy of the cellulosic polymers in slowing crystal growth of small molecules strongly depends on the functional group substitution on the cellulose backbone, with the acetate substituent group slowing crystal growth more than does the deprotonated succinate group, which we confirm by experimental drug supersaturation studies.

QR encoded smart oral dosage forms by inkjet printing.

PubMed

Edinger, Magnus; Bar-Shalom, Daniel; Sandler, Niklas; Rantanen, Jukka; Genina, Natalja

2018-01-30

The use of inkjet printing (IJP) technology enables the flexible manufacturing of personalized medicine with the doses tailored for each patient. In this study we demonstrate, for the first time, the applicability of IJP in the production of edible dosage forms in the pattern of a quick response (QR) code. This printed pattern contains the drug itself and encoded information relevant to the patient and/or healthcare professionals. IJP of the active pharmaceutical ingredient (API)-containing ink in the pattern of QR code was performed onto a newly developed porous and flexible, but mechanically stable substrate with a good absorption capacity. The printing did not affect the mechanical properties of the substrate. The actual drug content of the printed dosage forms was in accordance with the encoded drug content. The QR encoded dosage forms had a good print definition without significant edge bleeding. They were readable by a smartphone even after storage in harsh conditions. This approach of efficient data incorporation and data storage combined with the use of smart devices can lead to safer and more patient-friendly drug products in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

A simple dilute and shoot methodology for the identification and quantification of illegal insulin.

PubMed

Vanhee, Celine; Janvier, Steven; Moens, Goedele; Deconinck, Eric; Courselle, Patricia

2016-10-01

The occurrence of illegal medicines is a well-established global problem and concerns mostly small molecules. However, due to the advances in genomics and recombinant expression technologies there is an increased development of polypeptide therapeutics. Insulin is one of the best known polypeptide drug, and illegal versions of this medicine led to lethal incidents in the past. Therefore, it is crucial for the public health sector to develop reliable, efficient, cheap, unbiased and easily applicable active pharmaceutical ingredient (API) identification and quantification strategies for routine analysis of suspected illegal insulins. Here we demonstrate that our combined label-free full scan approach is not only able to distinguish between all those different versions of insulin and the insulins originating from different species, but also able to chromatographically separate human insulin and insulin lispro in conditions that are compatible with mass spectrometry (MS). Additionally, we were also able to selectively quantify the different insulins, including human insulin and insulin lispro according to the validation criteria, put forward by the United Nations (UN), for the analysis of seized illicit drugs. The proposed identification and quantification method is currently being used in our official medicines control laboratory to analyze insulins retrieved from the illegal market.

Carrier-Based Drug Delivery System for Treatment of Acne

PubMed Central

Vyas, Amber; Kumar Sonker, Avinesh

2014-01-01

Approximately 95% of the population suffers at some point in their lifetime from acne vulgaris. Acne is a multifactorial disease of the pilosebaceous unit. This inflammatory skin disorder is most common in adolescents but also affects neonates, prepubescent children, and adults. Topical conventional systems are associated with various side effects. Novel drug delivery systems have been used to reduce the side effect of drugs commonly used in the topical treatment of acne. Topical treatment of acne with active pharmaceutical ingredients (API) makes direct contact with the target site before entering the systemic circulation which reduces the systemic side effect of the parenteral or oral administration of drug. The objective of the present review is to discuss the conventional delivery systems available for acne, their drawbacks, and limitations. The advantages, disadvantages, and outcome of using various carrier-based delivery systems like liposomes, niosomes, solid lipid nanoparticles, and so forth, are explained. This paper emphasizes approaches to overcome the drawbacks and limitations associated with the conventional system and the advances and application that are poised to further enhance the efficacy of topical acne formulations, offering the possibility of simplified dosing regimen that may improve treatment outcomes using novel delivery system. PMID:24688376

A novel method for the investigation of liquid/liquid distribution coefficients and interface permeabilities applied to the water-octanol-drug system.

PubMed

Stein, Paul C; di Cagno, Massimiliano; Bauer-Brandl, Annette

2011-09-01

In this work a new, accurate and convenient technique for the measurement of distribution coefficients and membrane permeabilities based on nuclear magnetic resonance (NMR) is described. This method is a novel implementation of localized NMR spectroscopy and enables the simultaneous analysis of the drug content in the octanol and in the water phase without separation. For validation of the method, the distribution coefficients at pH = 7.4 of four active pharmaceutical ingredients (APIs), namely ibuprofen, ketoprofen, nadolol, and paracetamol (acetaminophen), were determined using a classical approach. These results were compared to the NMR experiments which are described in this work. For all substances, the respective distribution coefficients found with the two techniques coincided very well. Furthermore, the NMR experiments make it possible to follow the distribution of the drug between the phases as a function of position and time. Our results show that the technique, which is available on any modern NMR spectrometer, is well suited to the measurement of distribution coefficients. The experiments present also new insight into the dynamics of the water-octanol interface itself and permit measurement of the interface permeability.

An Integrated Approach to Thermal Analysis of Pharmaceutical Solids

ERIC Educational Resources Information Center

Riley, Shelley R. Rabel

2015-01-01

A three-tiered experiment for undergraduate Instrumental Analysis students is presented in which students characterize the solid-state thermal behavior of an active pharmaceutical ingredient (acetaminophen) and excipient (a-lactose hydrate) using differential scanning calorimetry, thermogravimetric analysis, and thermal microscopy. Students are…

Accelerated aging: prediction of chemical stability of pharmaceuticals.

PubMed

Waterman, Kenneth C; Adami, Roger C

2005-04-11

Methods of rapidly and accurately assessing the chemical stability of pharmaceutical dosage forms are reviewed with respect to the major degradation mechanisms generally observed in pharmaceutical development. Methods are discussed, with the appropriate caveats, for accelerated aging of liquid and solid dosage forms, including small and large molecule active pharmaceutical ingredients. In particular, this review covers general thermal methods, as well as accelerated aging methods appropriate to oxidation, hydrolysis, reaction with reactive excipient impurities, photolysis and protein denaturation.

Quality of the antimalarial medicine artemether - lumefantrine in eight cities of the Democratic Republic of the Congo.

PubMed

Mufusama, Jean-Pierre; Ioset, Karine Ndjoko; Feineis, Doris; Hoellein, Ludwig; Holzgrabe, Ulrike; Bringmann, Gerhard

2018-06-12

In the context of post-marketing surveillance supporting public-health authorities to take evidence-based decisions to fight the spread of poor-quality medicines, the quality of antimalarial artemether-lumefantrine (AL) medicines was assessed in the Democratic Republic of the Congo (DRC). A total of 150 samples of AL containing products was collected from private pharmaceutical outlets in eight main cities: Goma, Kikwit, Kinshasa, Kisangani, Lubumbashi, Matadi, Mbandaka, and Mbuji-Mayi. All drug samples were successively analyzed by visual inspection, thin-layer chromatography (TLC), and high-performance liquid chromatography (HPLC) following The International Pharmacopoeia. Out of the 150 collected drug samples, three (2%) failed the visual inspection as they had shelf lives different from those of other samples with the same brand name. Four samples (2.7%) did not pass the TLC test as they contained only one or even none of the two declared active pharmaceutical ingredients (APIs). HPLC assays showed that 46 (30.7%) samples had artemether contents below 90% and 17 (11.3%) above 110% of the content claimed on the label. For lumefantrine, 32 (21.7%) samples had contents below 90%, and eight (5.3%) had contents above 110%. This survey in DRC gives evidence that poor-quality antimalarial medicines are widely present. Based on three detection techniques, the study shows the necessity to equip developing countries with modern techniques such as HPLC, which, if combined with affordable techniques like TLC, could provide a pertinent analytical strategy to combat drug counterfeiting and poor manufacturing. This article is protected by copyright. All rights reserved.

Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol.

PubMed

David Christopher, J; Patel, Rajni B; Mitchell, Jolyon P; Tougas, Terrence P; Goodey, Adrian P; Quiroz, Jorge; Andersson, Patrik U; Lyapustina, Svetlana

2017-11-01

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.