The effect of water on the solid state characteristics of pharmaceutical excipients: Molecular mechanisms, measurement techniques, and quality aspects of final dosage form

PubMed Central

Szakonyi, Gergely; Zelkó, Romána

2012-01-01

In this paper we give an overview about the interaction of water molecules with pharmaceutical excipients. Most of these excipients are amorphous or partially amorphous polymers and their characteristics are very sensitive to the water content. In the course of the manufacturing processes water sorption is possible, therefore in some cases it is important to strictly control the residual moisture content of a dosage form. There are several mechanisms of water sorption, like water is able to bind to polar groups of hygroscopic excipients and could also exist in the capillary system of amorphous excipients. Several techniques are available to characterise the states of water inside the materials and the effects of residual water on polymers. For this purpose water sorption measurements, differential scanning calorimetry and the Fourier-transform infrared spectroscopy are reviewed. The importance of water content and storage conditions of pharmaceuticals on the properties of the final dosage forms are also demonstrated with practical examples. PMID:23071956

Vapor Phase Alkyne Coating of Pharmaceutical Excipients: Discrimination Enhancement of Raman Chemical Imaging for Tablets.

PubMed

Yamashita, Mayumi; Sasaki, Hiroaki; Moriyama, Kei

2015-12-01

Raman chemical imaging has become a powerful analytical tool to investigate the crystallographic characteristics of pharmaceutical ingredients in tablet. However, it is often difficult to discriminate some pharmaceutical excipients from each other by Raman spectrum because of broad and overlapping signals, limiting their detailed assessments. To overcome this difficulty, we developed a vapor phase coating method of excipients by an alkyne, which exhibits a distinctive Raman signal in the range of 2100-2300 cm(-1) . We found that the combination of two volatile reagents, propargyl bromide and triethylamine, formed a thin and nonvolatile coating on the excipient and observed the Raman signal of the alkyne at the surface. We prepared alkyne-coated cellulose by this method and formed a tablet. The Raman chemical imaging of the tablet cross-section using the alkyne peak area intensity of 2120 cm(-1) as the index showed a much clearer particle image of cellulose than using the peak area intensity of 1370 cm(-1) , which originated from the cellulose itself. Our method provides an innovative technique to analyze the solid-state characteristics of pharmaceutical excipients in tablets. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

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.

Co-processed excipients: a patent review.

PubMed

Garg, Nidhi; Dureja, Harish; Kaushik, Deepak

2013-04-01

The introduction of high speed tableting machines and the preference of direct compression as a method of tableting have increased the demands on the functionality of excipients mainly in terms of flowability and compressibility. Co-processed excipients, where in, excipients are combined by virtue of sub-particle level interaction have provided an attractive tool for developing high functionality excipients. The multifold advantages offered by co-processed excipients such as production of synergism in functionality of individual components, reduction of company's regulatory concern because of absence of chemical change during co-processing and improvement in physico-chemical properties have expanded their use in the pharmaceutical industry. In the recent years, there has been a spurt in the number of patents filed on co-processed excipients. Hence, the present review focuses on co-processed excipients and their application in pharmaceutical industry. The worldwide databases of European patent office (http://ep.espacenet.com) and United States patent office (www.uspto.gov) were employed to collect the patents and patent applications. The advantages, limitations, basis for the selection of excipients to be co-processed, methods of co-processing and regulatory perspective of co-processed excipients are also briefly discussed.

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.

Regulatory Notes on Impact of Excipients on Drug Products and the Maillard Reaction.

PubMed

Chowdhury, Dipak K; Sarker, Haripada; Schwartz, Paul

2018-02-01

In general, it is an important criterion that excipients remain inert throughout the shelf life of the formulated pharmaceutical product. However, depending on the functionality in chemical structure of active drug and excipients, they may undergo interaction. The well-known Maillard reaction occurs between a primary amine with lactose at high temperature to produce brown pigments. The reactivity of Maillard reaction may vary depending on the concentration as well as other conditions. Commercially, there are products where the active pharmaceutical ingredient is a primary amine and contains less than 75% lactose along with inactive excipients. This product does not show Maillard reaction during its shelf life of around 2 years at ambient conditions. However, when the same type of product contains more than 95 % lactose as an excipient, then there is a possibility of interactions though it is not visible in the initial year. Therefore, this regulatory note discusses involvement of different factors of a known drug-excipient interactions with case studies and provides an overview on how the concentration of lactose in the pharmaceutical product is important in addition to temperature and moisture in Maillard reaction.

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.

The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue.

PubMed

Hu, Minlu; Zhou, Tian; Dezzutti, Charlene S; Rohan, Lisa C

Pharmaceutical excipients are widely used in vaginal drug products. The epithelial integrity of the cervicovaginal tissue is important for HIV-1 prevention. However, the effects of excipients on cervicovaginal epithelium remain unknown. This study aims at assessing the effects of vaginal product excipients on the integrity of human cervicovaginal epithelium and on a lead HIV prevention antiretroviral drug, tenofovir (TFV). In the current study, nine excipients commonly used in vaginal formulations were incubated for 6 h with excised human ectocervical tissue. The effects of the excipients were examined by measuring the transepithelial electrical resistance (TEER), epithelial morphology, paracellular/transcellular permeability, and cell viability. The efficacy of TFV for preventing HIV-1 infection in the ex vivo cultured ectocervix was also tested. We found that disodium ethyl-enediaminetetraacetate (EDTA), sorbic acid, and benzoic acid had no effect on the tissue TEER. Butylated hydroxyanisole, glycerin, propylene glycol, methylparaben, and propylparaben slightly to moderately decreased tissue TEER, whereas citric acid significantly decreased the TEER in a time-dependent manner. Tissue morphology observed post-exposure strongly correlated with TEER data; however, a less strong correlation was observed between paracellular permeability and TEER data after exposure to different excipients. In addition, treatment with EDTA, methylparaben, and propylene glycol at tested levels had no effect on the efficacy of TFV in preventing tissue HIV-1 infection. In conclusion, the combined measurements of TEER, morphology, permeability, and viability using human cervicovaginal tissue represent a clinically relevant platform for safety evaluation of excipients and formulated products for HIV-1 prevention.

Comprehensive analysis of pharmaceutical products using simultaneous mixed-mode (ion-exchange/reversed-phase) and hydrophilic interaction liquid chromatography.

PubMed

Kazarian, Artaches A; Nesterenko, Pavel N; Soisungnoen, Phimpha; Burakham, Rodjana; Srijaranai, Supalax; Paull, Brett

2014-08-01

Liquid chromatographic assays were developed using a mixed-mode column coupled in sequence with a hydrophilic interaction liquid chromatography column to allow the simultaneous comprehensive analysis of inorganic/organic anions and cations, active pharmaceutical ingredients, and excipients (carbohydrates). The approach utilized dual sample injection and valve-mediated column switching and was based upon a single high-performance liquid chromatography gradient pump. The separation consisted of three distinct sequential separation mechanisms, namely, (i) ion-exchange, (ii) mixed-mode interactions under an applied dual gradient (reversed-phase/ion-exchange), and (iii) hydrophilic interaction chromatography. Upon first injection, the Scherzo SS C18 column (Imtakt) provided resolution of inorganic anions and cations under isocratic conditions, followed by a dual organic/salt gradient to elute active pharmaceutical ingredients and their respective organic counterions and potential degradants. At the top of the mixed-mode gradient (high acetonitrile content), the mobile phase flow was switched to a preconditioned hydrophilic interaction liquid chromatography column, and the standard/sample was reinjected for the separation of hydrophilic carbohydrates, some of which are commonly known excipients in drug formulations. The approach afforded reproducible separation and resolution of up to 23 chemically diverse solutes in a single run. The method was applied to investigate the composition of commercial cough syrups (Robitussin®), allowing resolution and determination of inorganic ions, active pharmaceutical ingredients, excipients, and numerous well-resolved unknown peaks. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cyclodextrins as excipients in tablet formulations.

PubMed

Conceição, Jaime; Adeoye, Oluwatomide; Cabral-Marques, Helena Maria; Lobo, José Manuel Sousa

2018-04-22

This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets. Copyright © 2018 Elsevier Ltd. All rights reserved.

Formulation Development and Evaluation of Fast Disintegrating Tablets of Salbutamol Sulphate, Cetirizine Hydrochloride in Combined Pharmaceutical Dosage Form: A New Era in Novel Drug Delivery for Pediatrics and Geriatrics

PubMed Central

Sharma, Deepak; Singh, Gurmeet; Kumar, Dinesh; Singh, Mankaran

2015-01-01

The objective of the present study was to prepare the fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form for respiratory disorders such as bronchitis, asthma, and coughing for pediatrics and geriatrics. The tablets were prepared by direct compression technique. Superdisintegrant such as Sodium Starch Glycolate was optimized as 4% on the basis of least disintegration time. Different binders such as MCC and PVP K-30 were optimized along with optimized superdisintegrant concentration. 1% MCC was selected as optimum binder concentration on the basis of least disintegration time. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and drug content uniformity. Optimized formulation was further evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. Percent weight variation and content uniformity were within the acceptable limit. The friability was less than 1%. The wetting time and disintegration time were practically good for all formulations. FTIR studies and accelerated stability study showed that there was no interaction between the drug and excipients. It was concluded that, by employing commonly available pharmaceutical excipients such as superdisintegrants, hydrophilic and swellable excipients and proper filler, a fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form, were formulated successfully with desired characteristics. PMID:25810924

Selection of solubility parameters for characterization of pharmaceutical excipients.

PubMed

Adamska, Katarzyna; Voelkel, Adam; Héberger, Károly

2007-11-09

The solubility parameter (delta(2)), corrected solubility parameter (delta(T)) and its components (delta(d), delta(p), delta(h)) were determined for series of pharmaceutical excipients by using inverse gas chromatography (IGC). Principal component analysis (PCA) was applied for the selection of the solubility parameters which assure the complete characterization of examined materials. Application of PCA suggests that complete description of examined materials is achieved with four solubility parameters, i.e. delta(2) and Hansen solubility parameters (delta(d), delta(p), delta(h)). Selection of the excipients through PCA of their solubility parameters data can be used for prediction of their behavior in a multi-component system, e.g. for selection of the best materials to form stable pharmaceutical liquid mixtures or stable coating formulation.

Effect of colloidal silica on rheological properties of common pharmaceutical excipients.

PubMed

Majerová, Diana; Kulaviak, Lukáš; Růžička, Marek; Štěpánek, František; Zámostný, Petr

2016-09-01

In pharmaceutical industry, the use of lubricants is mostly based on historical experiences or trial and error methods even these days. It may be demanding in terms of the material consumption and may result in sub-optimal drug composition. Powder rheology enables more accurate monitoring of the flow properties and because the measurements need only a small sample it is perfectly suitable for the rare or expensive substances. In this work, rheological properties of four common excipients (pregelatinized maize starch, microcrystalline cellulose, croscarmellose sodium and magnesium stearate) were studied by the FT4 Powder Rheometer, which was used for measuring the compressibility index by a piston and flow properties of the powders by a rotational shear cell. After an initial set of measurements, two excipients (pregelatinized maize starch and microcrystalline cellulose) were chosen and mixed, in varying amounts, with anhydrous colloidal silicon dioxide (Aerosil 200) used as a glidant. The bulk (conditioned and compressed densities, compressibility index), dynamic (basic flowability energy) and shear (friction coefficient, flow factor) properties were determined to find an optimum ratio of the glidant. Simultaneously, the particle size data were obtained using a low-angle laser light scattering (LALLS) system and scanning electron microscopy was performed in order to examine the relationship between the rheological properties and the inner structure of the materials. The optimum of flowability for the mixture composition was found, to correspond to empirical findings known from general literature. In addition the mechanism of colloidal silicone dioxide action to improve flowability was suggested and the hypothesis was confirmed by independent test. New findings represent a progress towards future application of determining the optimum concentration of glidant from the basic characteristics of the powder in the pharmaceutical research and development. Copyright © 2016 Elsevier B.V. All rights reserved.

Managing acute pain in patients who report lactose intolerance: the safety of an old excipient re-examined

PubMed Central

Mill, Deanna; Dawson, Jessica; Johnson, Jacinta Lee

2018-01-01

Lactose intolerance is exceedingly common, reportedly affecting up to 70% of the world’s population, leading to both abdominal and systemic symptoms. Current treatment focuses predominantly on restricting dietary consumption of lactose. Given lactose is one of the most commonly used excipients in the pharmaceutical industry, consideration must be given to the lactose content and therefore safety of pharmaceutical preparations prescribed for patients with lactose intolerance. This article summarizes the current literature examining the likelihood of inducing adverse effects through the administration of lactose-containing pharmaceutical preparations in patients reporting lactose intolerance, describes how to assess this risk on an individual patient basis and reviews suitable analgesic options for this population. A case study is presented detailing a patient reporting lactose intolerance who insists on treatment with the lactose-free product codeine/ibuprofen (Nurofen Plus) rather than other codeine-free analgesics. It is important to assess the likelihood of lactose as an excipient inducing symptoms in this scenario, as reluctance to cease codeine could suggest codeine dependence, an issue that is becoming increasingly common in countries such as Australia and Canada. Given codeine dependence is associated with serious sequelae including hospitalization and death, the patient must either be reassured the lactose component in their prescribed analgesics will not induce symptoms or an alternative treatment strategy must be confirmed. General recommendations applying theory from the literature to the management of acute pain in lactose-intolerant patients are discussed and specific treatment options are outlined. Although large inter-individual variability is reported, most lactose-intolerant patients can tolerate the small quantities of lactose found in pharmaceutical preparations. Cumulative lactose exposure can be assessed in patients taking multiple medications while also consuming lactose in the diet. In those sensitive to small quantities of lactose, lactase supplements can be trailed. Additionally, for the analgesic drug classes employed for the management of acute pain, lactose-free formulations, including most oral liquids and dispersible tablets and some oral tablets and capsules, are available. PMID:29796247

Hydrolysis of the quinone methide of butylated hydroxytoluene in aqueous solutions.

PubMed

Willcockson, Maren Gulsrud; Toteva, Maria M; Stella, Valentino J

2013-10-01

Butylated hydroxytoluene or BHT is an antioxidant commonly used in pharmaceutical formulations. BHT upon oxidation forms a quinone methide (QM). QM is a highly reactive electrophilic species that can undergo nucleophilic addition. Here, the kinetic reactivity of QM with water at various apparent pH values in a 50% (v/v) water-acetonitrile solution at constant ionic strength of I = 0.5 (NaCl)4 , was studied. The hydrolysis of QM in the presence of added acid, base, sodium chloride, and phosphate buffer resulted in the formation of only one product--the corresponding 3,5-di-tert-butyl-4-hydroxybenzyl alcohol (BA). The rate of BA formation was catalyzed by the addition of acid and base, but not chloride and phosphate species. Nucleophilic excipients, used in the pharmaceutical formulation, or nucleophilic groups on active pharmaceutical ingredient molecule may form adducts with QM, the immediate oxidative product of BHT degradation, thus having implications for drug product impurity profiles. Because of these considerations, BHT should be used with caution in formulations containing drugs or excipients capable of acting as nucleophiles. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Kaolinite in pharmaceutics and biomedicine.

PubMed

Awad, Mahmoud E; López-Galindo, Alberto; Setti, Massimo; El-Rahmany, Mahmoud M; Iborra, César Viseras

2017-11-25

Kaolinite Al 2 Si 2 O 5 (OH) 4 is an abundant and inexpensive geomaterial regarded as one of the most common clay minerals in the earth's crust and the most widespread phase among the other kaolin polymorphs (halloysite, dickite and nacrite). Structurally, it is a hydrous aluminum phyllosilicate member belonging to the dioctahedral 1:1 kaolin mineral group. The particle size of the pseudohexagonal kaolinite platelets is normally <2μm (if compared to a human red blood cell of a typical diameter 6.2-8.2μm or to a virus particle of about 50nm diameter). The kaolinite platelets, either stacked together with a common booklet-like shape in a highly ordered structure (well crystallized) or disordered structure (poorly crystallized), consist of layers considered as a strong dipole of hydrophobic siloxane surface dominated by negative charges, and the other hydrophilic aluminol surface carries positive charges. Kaolinite has been used in many pharmaceutical applications as excipient or active ingredient, because it exhibits excellent physical, chemical and surface physicochemical properties. In addition to their classical pharmaceutical uses, kaolinite and its derivatives have been recently considered as a promising material in many biomedical innovation areas such as drug, protein and gene delivery based on the high interaction capacities with organic and biochemical molecules, bioadhesion and cellular uptake. Pharmaceutical kaolin grades are considerably demanded for usage as excipient in formulations of solid and semi-solid dosage forms. The most important functionalities of kaolin used as excipient are reported as diluent, binder, disintegrant, pelletizing and granulating, amorphizing, particle film coating, emulsifying and suspending agent. Because of its uninjured bioactivity, kaolinite has been also used as active agent for treatment of some common diseases. It can be topically administered as hemostatic agent, dermatological protector, anti-inflammatory agent and in pelotherapy, or orally as gastrointestinal protector, and antibacterial, antiviral, detoxification or antidiarrheal agent. With these premises, the future of kaolinite in health-care uses is strongly interesting, especially in the development of pharmaceutical and cosmetic industries. In biomedicinal investigations, it can be considered as a promising natural geomaterial for designing new derivatives that can contribute in the trials of discovering new therapeutic systems and treatment pathways of global challenge diseases such as cancer, viruses, antibiotic resistant bacteria, alzheimer, chronic skeletomuscular and geriatric diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Orientation to determine quality attributes of flavoring excipients containing volatile molecules.

PubMed

Kiene, Florian E; Pein, Miriam; Thommes, Markus

2015-06-10

Pharmaceutical excipients containing volatile odor-active molecules can be used in pharmaceutical development to increase patients' compliance. However, capturing the molecular composition of these odor-active substances is challenging. Therefore, guidance for the analytical investigation of these excipients should be developed. Using a model flavor, lead molecules were chosen and a gas chromatographic method was validated according to pharmaceutical guidelines. Changes during storage as well as batch homogeneity and conformity were investigated. The knowledge gained could be used to understand molecular differences between batches caused by aging. A suitable attempt to capture the volatile molecular composition of flavoring substance was presented and the found results could be used for the determination and interpretation of quality attributes. Copyright © 2015 Elsevier B.V. All rights reserved.

Direct estimation of the permeation of topical excipients through artificial membranes and human skin with non-invasive Terahertz time-domain techniques.

PubMed

Lopez-Dominguez, Victor; Boix-Montañes, Antoni; Redo-Sanchez, Albert; Tejada-Palacios, Javier

2016-07-01

Drug permeation through skin, or a synthetic membrane, from locally acting pharmaceutical products can be influenced by the permeation behaviour of pharmaceutical excipients. Terahertz time-domain technology is investigated as a non-invasive method for a direct and accurate measurement of excipients permeation through synthetic membranes or human skin. A series of in-vitro release and skin permeation experiments of liquid excipients (e.g. propylene glycol and polyethylene glycol 400) has been conducted with vertical diffusion cells. The permeation profiles of excipients through different synthetic membranes or skin were obtained using Terahertz pulses providing a direct measurement. Corresponding permeation flux and permeability coefficient values were calculated based on temporal changes of the terahertz pulses. The influence of different experimental conditions, such as the polarity of the membrane and the viscosity of the permeant, was assessed in release experiments. Specific transmembrane flux values of those excipients were directly calculated with statistical differences between cases. Finally, an attempt to estimate the skin permeation of propylene glycol with this technique was also achieved. All these permeation results were likely comparable to those obtained by other authors with usual analytical techniques. Terahertz time-domain technology is shown to be a suitable technique for an accurate and non-destructive measurement of the permeation of liquid substances through different synthetic membranes or even human skin. © 2016 Royal Pharmaceutical Society.

Method of tagging excipients with /sup 99m/Tc

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

Bardy, A.; Beydon, J.; Gobin, R.

1977-11-08

A method of using /sup 99m/technetium for tagging excipients in medical diagnosis by scintigraphy comprises mixing, in an aqueous solution of alkali-metal pertechnetate, an excipient and a reducing agent in the form of a complex, which complex is such that the association constant of the anion with reduced techetium is less than the association constant of the excipient with reduced technetium, thereby forming a radio-pharmaceutical substance which is a complex between the excipient and /sup 99m/technetium.

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.

In vitro metabolic stability of moisture-sensitive rabeprazole in human liver microsomes and its modulation by pharmaceutical excipients.

PubMed

Ren, Shan; Park, Mi-Jin; Kim, Aera; Lee, Beom-Jin

2008-03-01

A reliable method to assess in vitro metabolic stability of rabeprazole and its modulation by Generally Recognized As Safe (GRAS)-listed pharmaceutical excipients was established in human liver microsomes. The metabolic stability of rabeprazole decreased as a function of incubation time, resulting in the formation of thioether rabeprazole via nonenzymatic degradation and enzymatic metabolism. Buffer type was also a determining factor for the degree of both nonenzymatic degradation and enzymatic metabolism. The net extent of enzymatic drug metabolism, obtained by calculating the difference in drug degradation between a microsome-present reaction system and a microsome-free solution, was about 9.20 +/- 0.67% in phosphate buffer and 2.27 +/- 1.76% in Tris buffer, respectively. Rabeprazole exhibited first-order kinetics in microsome-free solution but showed non-linear kinetics in the microsome-present reaction system. The maximal velocity, Vmax, in phosphate buffer was 5.07 microg mL(-1) h(-1) and the Michaelis-Menten constant, Km, was 10.39 microg mL(-1) by computer-fitting to the classical Michaelis-Menten equation for pattern of time-dependent change in the substrate concentration. The intact drug and its thioether form were well resolved and successfully identified by HPLC chromatography and liquid chromatography mass spectroscopy (LC/MS). The metabolic stability of rabeprazole was also modulated by the presence of pharmaceutical excipients. Among the five pharmaceutical excipients tested, poloxamer 188 and Gelucire 44/14 had potentially inhibitory effects on rabeprazole metabolism in human liver microsomes (p < 0.05). A greater understanding of metabolic stability and its modulation by pharmaceutical excipients would be useful for optimizing the bioavailability of rabeprazole at the early formulation stages.

Risk assessment of supply chain for pharmaceutical excipients with AHP-fuzzy comprehensive evaluation.

PubMed

Li, Maozhong; Du, Yunai; Wang, Qiyue; Sun, Chunmeng; Ling, Xiang; Yu, Boyang; Tu, Jiasheng; Xiong, Yerong

2016-01-01

As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.

Risk assessment of supply chain for pharmaceutical excipients with AHP-fuzzy comprehensive evaluation.

PubMed

Li, Maozhong; Du, Yunai; Wang, Qiyue; Sun, Chunmeng; Ling, Xiang; Yu, Boyang; Tu, Jiasheng; Xiong, Yerong

2016-04-01

As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.

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.

Pharmaceutical properties of two ethenzamide-gentisic acid cocrystal polymorphs: Drug release profiles, spectroscopic studies and theoretical calculations.

PubMed

Sokal, Agnieszka; Pindelska, Edyta; Szeleszczuk, Lukasz; Kolodziejski, Waclaw

2017-04-30

The aim of this study was to evaluate the stability and solubility of the polymorphic forms of the ethenzamide (ET) - gentisic acid (GA) cocrystals during standard technological processes leading to tablet formation, such as compression and excipient addition. In this work two polymorphic forms of pharmaceutical cocrystals (ETGA) were characterized by 13 C and 15 N solid-state nuclear magnetic resonance and Fourier transformed infrared spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of chemical shielding constants.Polymorphs of cocrystals were easily identified and characterized on the basis of solid-state spectroscopic studies. ETGA cocrystals behaviour during direct compressionand tabletting with excipient addition were tested. In order to choose the best tablet composition with suitable properties for the pharmaceutical industry dissolution profile studies of tablets containing polymorphic forms of cocrystals with selected excipients were carried out. Copyright © 2017. Published by Elsevier B.V.

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

PubMed

Desai, Kashappa Goud; Obayashi, Hirokazu; Colandene, James D; Nesta, Douglas P

2018-03-28

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Zein as a Pharmaceutical Excipient in Oral Solid Dosage Forms: State of the Art and Future Perspectives.

PubMed

Berardi, Alberto; Bisharat, Lorina; AlKhatib, Hatim S; Cespi, Marco

2018-05-07

Zein is the main storage protein of corn and it has several industrial applications. Mainly in the last 10-15 years, zein has emerged as a potential pharmaceutical excipient with unique features. Zein is a natural, biocompatible and biodegradable material produced from renewable sources. It is insoluble, yet due to its amphiphilic nature, it has self-assembling properties, which have been exploited for the formation of micromicroparticle and nanoparticle and films. Moreover, zein can hydrate so it has been used in swellable matrices for controlled drug release. Other pharmaceutical applications of zein in oral drug delivery include its incorporation in solid dispersions of poorly soluble drugs and in colonic drug delivery systems. This review describes the features of zein significant for its use as a pharmaceutical excipient for oral drug delivery, and it summaries the literature relevant to macroscopic zein-based oral dosage forms, i.e. tablets, capsules, beads and powders. Particular attention is paid to the most novel formulations and applications of zein. Moreover, gaps of knowledge as well as possible venues for future investigations on zein are highlighted.

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.

Basic principles of drug--excipients interactions.

PubMed

Vranić, Edina

2004-05-01

Excipients are generally considered inert additives included in drug formulation to help in the manufacturing, administration or absorption. Other reasons for inclusion concern product differentiation, appearance enhancement or retention of quality. Excipients can initiate, propagate or participate in chemical or physical interactions with an active substance, possibly leading to compromised quality or performance of the medication. Understanding the chemical and physical nature of excipients, the impurities or residues associated with them and how they may interact with other materials, or with each other, forewarns the pharmaceutical technologist of possibilities for undesirable developments.

Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals.

PubMed

McClements, David Julian; Xiao, Hang

2014-07-25

The oral bioavailability of many lipophilic bioactive agents (pharmaceuticals and nutraceuticals) is limited due to various physicochemical and physiological processes: poor release from food or drug matrices; low solubility in gastrointestinal fluids; metabolism or chemical transformation within the gastrointestinal tract; low epithelium cell permeability. The bioavailability of these agents can be improved by specifically designing food matrices that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract. This article discusses the impact of food composition and structure on oral bioavailability, and how this knowledge can be used to design excipient foods for improving the oral bioavailability of lipophilic bioactives. Excipient foods contain ingredients or structures that may have no bioactivity themselves, but that are able to promote the bioactivity of co-ingested bioactives. These bioactives may be lipophilic drugs in pharmaceutical preparations (such as capsules, pills, or syrups) or nutraceuticals present within food matrices (such as natural or processed foods and beverages).

Pharmaceutical spray drying: solid-dose process technology platform for the 21st century.

PubMed

Snyder, Herman E

2012-07-01

Requirement for precise control of solid-dosage particle properties created with a scalable process technology are continuing to expand in the pharmaceutical industry. Alternate methods of drug delivery, limited active drug substance solubility and the need to improve drug product stability under room-temperature conditions are some of the pharmaceutical applications that can benefit from spray-drying technology. Used widely for decades in other industries with production rates up to several tons per hour, pharmaceutical uses for spray drying are expanding beyond excipient production and solvent removal from crystalline material. Creation of active pharmaceutical-ingredient particles with combinations of unique target properties are now more common. This review of spray-drying technology fundamentals provides a brief perspective on the internal process 'mechanics', which combine with both the liquid and solid properties of a formulation to enable high-throughput, continuous manufacturing of precision powder properties.

The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan.

PubMed

Chang, Lin-Chau; Kang, Jaw-Jou; Gau, Churn-Shiouh

2015-12-01

Excipients, once considered an inert component, have been shown to greatly influence the characteristics of the drug product, such as quality and safety. Functionality-related characteristics of excipients could affect the performance of the drug product. Moreover, the impact of globalization has complicated the issue and made the supervision of supply chain highly important. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes efforts to harmonize with international regulations and to strengthen the protection of patients through regulatory controls. In order to improve the harmonization and the transparency of regulatory requirements, the aim of the present study was to investigate the regulatory framework and considerations of stringent regulatory authorities and to propose the draft regulatory requirements to the Taiwan Food and Drug Administration for jurisdiction. The proposal which was extensively discussed in the expert committee includes the regulatory considerations to ensure the safety and quality of the excipients and may serve as a platform to facilitate the communication with industries about the current thinking on related issues. Moreover, through the review of the recent guidelines published by the stringent regulatory authorities, the trend of the regulatory considerations was revealed and discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Studies of Particle Packings in Mixtures of Pharmaceutical Excipients

NASA Astrophysics Data System (ADS)

Bentham, Craig; Dutt, Meenakshi; Hancock, Bruno; Elliott, James

2005-03-01

Pharmaceutical powder blends used to generate tablets are complex multicomponent mixtures of the drug powder and excipients which facilitate the delivery of the required drug. The individual constituents of these blends can be noncohesive and cohesive powders. We study the geometric and mechanical characteristics of idealized mixtures of excipient particle packings, for a small but representative number of dry noncohesive particles, generated via gravitational compaction followed by uniaxial compaction. We discuss particle packings in 2- and 3- component mixtures of microcrystalline cellulose (MCC) & lactose and MCC, starch & lactose, respectively. We have computed the evolution of the force and stress distributions in monodisperse and polydisperse mixtures comprised of equal parts of each excipient; comparisons are made with results for particles packings of pure blends of MCC and lactose. We also compute the stress-strain relations for these mixtures. In order to obtain insight into details of the particle packings, we calculate the coordination number, packing fraction, radial distribution functions and contact angle distributions for the various mixtures. The numerical experiments have been performed on spheroidal idealizations of the excipient grains using Discrete Element Method simulations (Dutt et al., 2004 to be published).

The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.

PubMed

David, Dahlgren; Carl, Roos; Pernilla, Johansson; Christer, Tannergren; Anders, Lundqvist; Peter, Langguth; Markus, Sjöblom; Erik, Sjögren; Hans, Lennernäs

2018-05-11

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients (CPEs), or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs/CPEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME/CPE effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME/CPE evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations. Copyright © 2018. Published by Elsevier B.V.

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.

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.

Novel excipients - Regulatory challenges and perspectives - The EU insight.

PubMed

Kozarewicz, Piotr; Loftsson, Thorsteinn

2018-05-21

Novel excipients are indispensable in development of modern, advanced drug delivery systems and biotechnology-derived drugs. Although numerous novel excipients are developed for pharmaceutical use, they are not frequently seen in medicinal products due to the strict regulatory requirements and perception that their use makes new product evaluation more complex with risk of delays in the approval process. Regulators regard novel excipients as new substances and whenever new excipient is used in a formulation it must be subjected to full evaluation, similarly to the one required for new active substance. Consequently, the amount of information required in support of the regulatory approval (i.e. marketing authorization) is much more complex and comprehensive than for established excipients. This short review provides an insight into the use of novel excipients in medicinal products approved in the European Union. In addition, barriers and challenges in development of novel excipients are being discussed as well as means to overcome those barriers. Copyright © 2018 Elsevier B.V. All rights reserved.

Sucrose esters as natural surfactants in drug delivery systems--a mini-review.

PubMed

Szűts, Angéla; Szabó-Révész, Piroska

2012-08-20

Sucrose esters (SEs) are widely used in the food and cosmetic industries and there has recently been great interest in their applicability in different pharmaceutical fields. They are natural and biodegradable excipients with well-known emulsifying and solubilizing behavior. Currently the most common pharmaceutical applications of SEs are for the enhancement of drug dissolution and drug absorption/permeation, and in controlled-release systems. Although the number of articles on SEs is continuously increasing, they have not yet been widely used in the pharmaceutical industry. The aim of this review is to discuss and summarize some of the findings and applications of SEs in different areas of drug delivery. The article highlights the main properties of SEs and focuses on their use in pharmaceutical technology and on their regulatory and toxicological status. Copyright © 2012 Elsevier B.V. All rights reserved.

The use of natural and synthetic phospholipids as pharmaceutical excipients*

PubMed Central

van Hoogevest, Peter; Wendel, Armin

2014-01-01

In pharmaceutical formulations, phospholipids obtained from plant or animal sources and synthetic phospholipids are used. Natural phospholipids are purified from, e.g., soybeans or egg yolk using non-toxic solvent extraction and chromatographic procedures with low consumption of energy and minimum possible waste. Because of the use of validated purification procedures and sourcing of raw materials with consistent quality, the resulting products differing in phosphatidylcholine content possess an excellent batch to batch reproducibility with respect to phospholipid and fatty acid composition. The natural phospholipids are described in pharmacopeias and relevant regulatory guidance documentation of the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Synthetic phospholipids with specific polar head group, fatty acid composition can be manufactured using various synthesis routes. Synthetic phospholipids with the natural stereochemical configuration are preferably synthesized from glycerophosphocholine (GPC), which is obtained from natural phospholipids, using acylation and enzyme catalyzed reactions. Synthetic phospholipids play compared to natural phospholipid (including hydrogenated phospholipids), as derived from the number of drug products containing synthetic phospholipids, a minor role. Only in a few pharmaceutical products synthetic phospholipids are used. Natural phospholipids are used in oral, dermal, and parenteral products including liposomes. Natural phospholipids instead of synthetic phospholipids should be selected as phospholipid excipients for formulation development, whenever possible, because natural phospholipids are derived from renewable sources and produced with more ecologically friendly processes and are available in larger scale at relatively low costs compared to synthetic phospholipids. Practical applications: For selection of phospholipid excipients for pharmaceutical formulations, natural phospholipids are preferred compared to synthetic phospholipids because they are available at large scale with reproducible quality at lower costs of goods. They are well accepted by regulatory authorities and are produced using less chemicals and solvents at higher yields. In order to avoid scale up problems during pharmaceutical development and production, natural phospholipid excipients instead of synthetic phospholipids should be selected whenever possible. PMID:25400504

Noninvasive in situ identification and band assignments of some pharmaceutical excipients inside USP vials with FT-near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Ali, Hassan Refat H.; Edwards, Howell G. M.; Scowen, Ian J.

2009-05-01

For the manufacture of dosage forms all ingredients must be reliably identified. In this paper, the suitability of FT-NIR spectroscopy to identify potassium sorbate, sodium starch glycollate, calcium ascorbate, calcium carbonate, candelilla wax, maltosextrin, monohydrated and anhydrous lactose inside USP vials was investigated. Differentiation between the anhydrous and monohydrated forms of lactose was found to be possible by studying the regions of the near-infrared spectrum corresponding to the combination and first overtone stretching frequencies of water. The results show unequivocally the potential of FT-NIR spectroscopy for rapid, in situ and non-destructive identification of pharmaceutical excipients.

Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering.

PubMed

Labib, Gihan

2018-01-01

Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer. Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering. Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached.

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…

Effects of excipients on the tensile strength, surface properties and free volume of Klucel® free films of pharmaceutical importance

NASA Astrophysics Data System (ADS)

Gottnek, Mihály; Süvegh, Károly; Pintye-Hódi, Klára; Regdon, Géza

2013-08-01

The physicochemical properties of polymers planned to be applied as mucoadhesive films were studied. Two types of Klucel® hydroxypropylcellulose (LF and MF) were used as film-forming polymers. Hydroxypropylcellulose was incorporated in 2 w/w% with glycerol and xylitol as excipients and lidocaine base as an active ingredient at 5, 10 or 15 w/w% of the mass of the film-forming polymer. The free volume changes of the films were investigated by positron annihilation lifetime spectroscopy, the mechanical properties of the samples were measured with a tensile strength tester and contact angles were determined to assess the surface properties of the films. It was found that the Klucel® MF films had better physicochemical properties than those of the LF films. Klucel® MF as a film-forming polymer with lidocaine base and both excipients at 5 w/w% exhibited physicochemical properties and good workability. The excipients proved to exert strong effects on the physicochemical properties of the tested systems and it is very important to study them intensively in preformulation studies in the pharmaceutical technology in order to utilise their benefits and to avoid any disadvantageous effects.

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.

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method.

PubMed

Etherson, Kelly; Halbert, Gavin; Elliott, Moira

2016-09-01

The aim of this study was to determine the influence of non-ionisable excipients hydroxypropyl-β-cyclodextrin (HPβCD) and poloxamers 407 and 188 on the supersaturation and precipitation kinetics of ibuprofen, gliclazide, propranolol and atenolol induced through solution pH shifts using the CheqSol method. The drug's kinetic and intrinsic aqueous solubilities were measured in the presence of increasing excipient concentrations using the CheqSol method. Experimental data rate of change of pH with time was also examined to determine excipient-induced parachute effects and influence on precipitation rates. The measured kinetic and intrinsic solubilities provide a determination of the influence of each excipient on supersaturation index, and the area under the CheqSol curve can measure the parachute capability of excipients. The excipients influence on precipitation kinetics can be measured with novel parameters; for example, the precipitation pH or percentage ionised drug at the precipitation point, which provide further information on the excipient-induced changes in precipitation performance. This method can therefore be employed to measure the influence of non-ionisable excipients on the kinetic solubility behaviour of supersaturated solutions of ionisable drugs and to provide data, which discriminates between excipient systems during precipitation. © 2016 Royal Pharmaceutical Society.

Screening of polysaccharides from tamarind, fenugreek and jackfruit seeds as pharmaceutical excipients.

PubMed

Nayak, Amit Kumar; Pal, Dilipkumar; Santra, Kousik

2015-08-01

The paper describes the isolation and screening of plant polysaccharides namely tamarind seed polysaccharide (TSP), fenugreek seed mucilage (FSM) and jackfruit seed starch (JFSS) from tamarind (Tamarindus indica L.) seeds, fenugreek (Trigonella foenum-graecum L.) seeds and jackfruit (Artocarpus heterophyllus L.) seeds, respectively. The yields of isolated dried TSP, FSM and JFSS were 47.00%, 17.36% and 18.86%, respectively. Various physicochemical properties like colour, odour, taste, solubility in water, pH and viscosity of these isolated plant polysaccharides were assessed. Isolated polysaccharide samples were subjected to some phytochemical identification tests. FTIR and (1)H NMR analyses of isolated polysaccharides were performed, which suggest the presence of sugar residues. Isolated TSP, FSM and JFSS can be used as pharmaceutical excipients in various pharmaceutical formulations. Copyright © 2015 Elsevier B.V. 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

75 FR 22412 - Food and Drug Administration/Xavier University Global Outsourcing Conference

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-28

... relationships and supply chain control, as well as expectations from global regulators. Pharmaceutical companies...; Quality Agreement Development throughout the product and process lifecycle; Supply Chain Transparency and Pedigree; How to Audit the Supply Chain; Rx-360 and International Pharmaceutical Excipients Council...

An iterative approach for compound detection in an unknown pharmaceutical drug product: Application on Raman microscopy.

PubMed

Boiret, Mathieu; Gorretta, Nathalie; Ginot, Yves-Michel; Roger, Jean-Michel

2016-02-20

Raman chemical imaging provides both spectral and spatial information on a pharmaceutical drug product. Even if the main objective of chemical imaging is to obtain distribution maps of each formulation compound, identification of pure signals in a mixture dataset remains of huge interest. In this work, an iterative approach is proposed to identify the compounds in a pharmaceutical drug product, assuming that the chemical composition of the product is not known by the analyst and that a low dose compound can be present in the studied medicine. The proposed approach uses a spectral library, spectral distances and orthogonal projections to iteratively detect pure compounds of a tablet. Since the proposed method is not based on variance decomposition, it should be well adapted for a drug product which contains a low dose product, interpreted as a compound located in few pixels and with low spectral contributions. The method is tested on a tablet specifically manufactured for this study with one active pharmaceutical ingredient and five excipients. A spectral library, constituted of 24 pure pharmaceutical compounds, is used as a reference spectral database. Pure spectra of active and excipients, including a modification of the crystalline form and a low dose compound, are iteratively detected. Once the pure spectra are identified, multivariate curve resolution-alternating least squares process is performed on the data to provide distribution maps of each compound in the studied sample. Distributions of the two crystalline forms of active and the five excipients were in accordance with the theoretical formulation. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Solvent-free melting techniques for the preparation of lipid-based solid oral formulations.

PubMed

Becker, Karin; Salar-Behzadi, Sharareh; Zimmer, Andreas

2015-05-01

Lipid excipients are applied for numerous purposes such as taste masking, controlled release, improvement of swallowability and moisture protection. Several melting techniques have evolved in the last decades. Common examples are melt coating, melt granulation and melt extrusion. The required equipment ranges from ordinary glass beakers for lab scale up to large machines such as fluid bed coaters, spray dryers or extruders. This allows for upscaling to pilot or production scale. Solvent free melt processing provides a cost-effective, time-saving and eco-friendly method for the food and pharmaceutical industries. This review intends to give a critical overview of the published literature on experiences, formulations and challenges and to show possibilities for future developments in this promising field. Moreover, it should serve as a guide for selecting the best excipients and manufacturing techniques for the development of a product with specific properties using solvent free melt processing.

Recently Investigated Natural Gums and Mucilages as Pharmaceutical Excipients: An Overview

PubMed Central

Choudhary, Pritam Dinesh; Pawar, Harshal Ashok

2014-01-01

Due to advances in drug delivery technology, currently, excipients are included in novel dosage forms to fulfil specific functions and in some cases they directly or indirectly influence the extent and/or rate of drug release and drug absorption. Recent trends towards use of plant based and natural products demand the replacement of synthetic additives with natural ones. Today, the whole world is increasingly interested in natural drugs and excipients. These natural materials have many advantages over synthetic ones as they are chemically inert, nontoxic, less expensive, biodegradable, and widely available. This review discusses majority of the plant-derived polymeric compounds (gums and mucilage's), their sources, chemical constituents, uses, and some recent investigations as excipients in novel drug delivery systems. PMID:26556189

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

PubMed

Kendall, Richard; Lenoir, Joke; Gerrard, Stephen; Scheuerle, Rebekah L; Slater, Nigel K H; Tuleu, Catherine

2017-04-01

Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

Study of interaction of hypericin and its pharmaceutical preparation by fluorescence techniques.

PubMed

Liu, Jun; Saw, Constance Lay Lay; Olivo, Malini; Sudhaharan, Thankiah; Ahmed, Sohail; Heng, Paul Wan Sia; Wohland, Thorsten

2009-01-01

We report the detection of interactions between a photosensitizer, hypericin (HY), and its solvent system prepared with a formulation additive, polyvinylpyrrolidone (PVP), a commonly used pharmaceutical excipient. Fluorescence correlation spectroscopy (FCS) and fluorescence lifetime imaging microscopy (FLIM) were used to study aggregation and binding of HY in the presence of PVP. Digitized fluorescence endoscopic imaging (DFEI) was used to study the effect of the pharmaceutical formulation in the in vivo tumor implanted chick chorioallantoic membrane (CAM) model. The results presented reveal the coordination of HY-PVP binding, HY disaggregation in the presence of PVP, and strengthened HY tumor uptake selectivity. PVP is thus suggested as a potential adjuvant to previously investigated N-methyl pyrrolidone (NMP) in the HY delivery system as well as a replacement for the conventionally used albumin in the HY bladder instillation fluids preparation for clinical use.

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.

Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing.

PubMed

Li, Qijun; Guan, Xiaoying; Cui, Mengsuo; Zhu, Zhihong; Chen, Kai; Wen, Haoyang; Jia, Danyang; Hou, Jian; Xu, Wenting; Yang, Xinggang; Pan, Weisan

2018-01-15

Three dimensional (3D) extrusion-based printing is a paste-based rapid prototyping process, which is capable of building complex 3D structures. The aim of this study was to explore the feasibility of 3D extrusion-based printing as a pharmaceutical manufacture technique for the fabrication of gastro-floating tablets. Novel low-density lattice internal structure gastro-floating tablets of dipyridamole were developed to prolong the gastric residence time in order to improve drug release rate and consequently, improve bioavailability and therapeutic efficacy. Excipients commonly employed in the pharmaceutical study could be efficiently applied in the room temperature 3D extrusion-based printing process. The tablets were designed with three kinds of infill percentage and prepared by hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15) as hydrophilic matrices and microcrystalline cellulose (MCC PH101) as extrusion molding agent. In vitro evaluation of the 3D printed gastro-floating tablets was performed by determining mechanical properties, content uniformity, and weight variation. Furthermore, re-floating ability, floating duration time, and drug release behavior were also evaluated. Dissolution profiles revealed the relationship between infill percentage and drug release behavior. The results of this study revealed the potential of 3D extrusion-based printing to fabricate gastro-floating tablets with more than 8h floating process with traditional pharmaceutical excipients and lattice internal structure design. Copyright © 2017. Published by Elsevier B.V.

Hospitalised neonates in Estonia commonly receive potentially harmful excipients

PubMed Central

2012-01-01

Background Information on the neonatal exposure to excipients is limited. Our aim was to describe the extent of excipient intake by Estonian neonates; to classify the excipients according to potential neonatal toxicity and thereby to measure the extent of exposure of neonates to potentially harmful excipients. Methods A prospective cohort study that recorded all medicines prescribed to patients aged below 28 days admitted to Tartu University Hospital from 01.02-01.08 2008 and to Tallinn Children’s Hospital from 01.02- 01.08 2009 was conducted. Excipients were identified from Summaries of Product Characteristics and classified according to toxicity following a literature review. Results 1961 prescriptions comprising 107 medicines were written for 348/490 neonates admitted. A total of 123 excipients were found in 1620 (83%) prescriptions and 93 (87%) medicines. 47 (38%) of these excipients were classified as potentially or known to be harmful to neonates. Most neonates (97%) received at least one medicine (median number 2) with potentially or known to be harmful excipient. Parabens were the most commonly used known to be harmful excipients and sodium metabisulphite the most commonly used potentially harmful excipient, received by 343 (99%) and 297 (85%) of treated neonates, respectively. Conclusions Hospitalised neonates in Estonia are commonly receiving a wide range of excipients with their medication. Quantitative information about excipients should be made available to pharmacists and neonatologists helping them to take into account excipient issues when selecting medicines and to monitor for adverse effects if administration of medicines containing excipients is unavoidable. PMID:22931304

Pharmaceutical Applications of Ion-Exchange Resins

ERIC Educational Resources Information Center

Elder, David

2005-01-01

The historical uses of ion-exchanged resins and a summary of the basic chemical principles involved in the ion-exchanged process are discussed. Specific applications of ion-exchange are provided that include drug stabilization, pharmaceutical excipients, taste-masking agents, oral sustained-release products, topical products for local application…

Influence of intestinal efflux pumps on the absorption and transport of furosemide

PubMed Central

Al-Mohizea, Abdullah M.

2010-01-01

Purpose Furosemide is a commonly used diuretic which is used in the treatment of edema, congestive heart failure, hypertension and renal failure. Its absorption exhibits inter- and intra-subject variability that can be attributed to many factors including the intestinal efflux pumps such as the P-glycoprotein (P-gp). This study was done due to the great disagreement between what is published in the literature regarding the influence of P-gp on furosemide and at the same time due to the importance of this drug in the treatment of different conditions as described above. In addition, an investigation of the effect of two of the commonly used pharmaceutical excipients (hydroxypropyl β-cyclodextrin [HPβCD] and Tween 80) and also a P-gp inhibitor (verapamil hydrochloride) on the intestinal absorption of this drug were also done. Methods The study utilized the everted intestinal sacs technique to investigate both the effect of the efflux transporter (P-gp) on furosemide absorption and also the effect of the chosen excipients. Results The absorption of furosemide was significantly influenced by the P-gp as confirmed by the everted vis the non-everted sacs together with the verapamil study in which the transport of furosemide was inhibited by verapamil. In addition, Tween 80 was also shown to inhibit the P-gp pump whereas the HPβCD did not significantly influence the efflux of furosemide in this study. Conclusions P-glycoprotein and some of the used excipients in the formulation play a very important role in the transport of furosemide and other drugs. Thus excipients that affect the activity of P-gp should be avoided when formulating drugs that are substrate for the P-gp or other efflux pumps. PMID:23960725

A new tablet brittleness index.

PubMed

Gong, Xingchu; Sun, Changquan Calvin

2015-06-01

Brittleness is one of the important material properties that influences the success or failure of powder compaction. We have discovered that the reciprocal of diametrical elastic strain at fracture is the most suitable tablet brittleness indices (TBIs) for quantifying brittleness of pharmaceutical tablets. The new strain based TBI is supported by both theoretical considerations and a systematic statistical analysis of friability data. It is sufficiently sensitive to changes in both tablet compositions and compaction parameters. For all tested materials, it correctly shows that tablet brittleness increases with increasing tablet porosity for the same powder. In addition, TBI increases with increasing content of a brittle excipient, lactose monohydrate, in the mixtures with a plastic excipient, microcrystalline cellulose. A probability map for achieving less than 1% tablet friability at various combinations of tablet tensile strength and TBI was constructed. Data from marketed tablets validate this probability map and a TBI value of 150 is recommended as the upper limit for pharmaceutical tablets. This TBI can be calculated from the data routinely obtained during tablet diametrical breaking test, which is commonly performed for assessing tablet mechanical strength. Therefore, it is ready for adoption for quantifying tablet brittleness to guide tablet formulation development since it does not require additional experimental work. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Influence of excipients in comilling on mitigating milling-induced amorphization or structural disorder of crystalline pharmaceutical actives.

PubMed

Balani, Prashant N; Ng, Wai Kiong; Tan, Reginald B H; Chan, Sui Yung

2010-05-01

The feasibility of using excipients to suppress the amorphization or structural disorder of crystalline salbutamol sulphate (SS) during milling was investigated. SS was subjected to ball-milling in the presence of alpha-lactose monohydrate (LAC), adipic acid (AA), magnesium stearate (MgSt), or polyvinyl pyrrolidone (PVP). X-ray powder diffraction, dynamic vapor sorption (DVS), high sensitivity differential scanning calorimetry (HSDSC) were used to analyze the crystallinity of the milled mixtures. Comilling with crystalline excipients, LAC, AA, and MgSt proved effective in reducing the amorphization of SS. LAC, AA, or MgSt acting as seed crystals to induce recrystallization of amorphous SS formed by milling. During comilling, both SS and LAC turned predominantly amorphous after 45 min but transformed back to a highly crystalline state after 60 min. Amorphous content was below the detection limits of DVS (0.5%) and HSDSC (5%). Comilled and physical mixtures of SS and ALM were stored under normal and elevated humidity conditions. This was found to prevent subsequent changes in crystallinity and morphology of comilled SS:LAC as compared to significant changes in milled SS and physical mixture. These results demonstrate a promising application of comilling with crystalline excipients in mitigating milling induced amorphization of pharmaceutical actives.

The influence of selected excipients on the rheological behaviour of chitosan based ocular pharmaceutical systems

NASA Astrophysics Data System (ADS)

Budai, L.; Szabadi, E.; Hajdú, M.; Budai, M.; Klebovich, I.; Antal, I.

2015-04-01

Aims: Chitosan, a modified natural carbohydrate polymer, has received great attention in diverse scientific fields including pharmaceutical and biomedical research areas. Besides its low toxicity, mucoadhesiveness and biodegradability its special favourable rheological feature makes it a unique gelling agent for the design of ocular systems. Chitosan based (2.0 w/v %) ocular systems containing selected excipients were formulated in order to investigate the rheological influence of applied auxiliary materials. Rotational and oscillatory rheological properties of propylene glycol (1.0-20.0 w/v %), glycerin (1.0-5.0 w/v %) and castor oil (1.0-5.0 w/v %) containing chitosan gels were evaluated. The rheological behaviour of formulated ocular gels were compared before and after steam sterilization. Methods: Rotational and oscillatory rheological measurements were carried out with Kinexus Pro Rheometer. Comparison of flow curves and oscillatory frequency sweep measurements in the linear viscoelastic region made possible the evaluation of rheological effect of selected excipients. Results: In the applied concentration range the effect of propylene glycol among the selected excipients presents the most significant impact on rheology of chitosan formulations. Steam sterilization results in reduced viscosity in most of chitosan gels. However, the presence of polyols appears to prevent the degradation of chitosan after steam sterilization.

Inverse gas chromatographic determination of solubility parameters of excipients.

PubMed

Adamska, Katarzyna; Voelkel, Adam

2005-11-04

The principle aim of this work was an application of inverse gas chromatography (IGC) for the estimation of solubility parameter for pharmaceutical excipients. The retention data of number of test solutes were used to calculate Flory-Huggins interaction parameter (chi1,2infinity) and than solubility parameter (delta2), corrected solubility parameter (deltaT) and its components (deltad, deltap, deltah) by using different procedures. The influence of different values of test solutes solubility parameter (delta1) over calculated values was estimated. The solubility parameter values obtained for all excipients from the slope, from Guillet and co-workers' procedure are higher than that obtained from components according Voelkel and Janas procedure. It was found that solubility parameter's value of the test solutes influences, but not significantly, values of solubility parameter of excipients.

IDENTIFICATION OF PHARMACEUTICAL EXCIPIENT BEHAVIOR OF CHICKPEA (CICER ARIETINUM) STARCH IN GLICLAZIDE IMMEDIATE RELEASE TABLETS.

PubMed

Meka, Venkata Srikanth; Yee, Phung; Sheshala, Ravi

2016-01-01

In the past few years, there are number of researchers carrying out their research on the excipients derived from polysaccharides and some of these researches show that natural excipients are comparable and can serve as an alternative to the synthetic excipients. Hence, the objectives of this research are to characterize the naturally sourced chickpea starch powder and to study the pharmaceutical excipient behavior of chickpea starch in gliclazide immediate release (IR) tablets. In this research, the binding properties of chickpea starch were compared to that of povidone, whereas the disintegrant properties of chickpea starch were compared to those of crospovidone, croscarmellose sodium and sodium starch glycolate. Flow property of chickpea starch was assessed with the measurement of bulk density, tapped density, compressibility index and angle of repose. Calibration curve for gliclazide in phosphate buffer pH 7.4 was developed. Gliclazide IR tablets were then produced with direct compression method. Physicochemical characteristics of the tablets, including thickness, tablet weight uniformity, hardness, disintegration time and friability were evaluated. Then, in vitro dissolution studies were performed by following United States Pharmacopeia (USP) dissolution method. The dissolution results were analyzed and compared with t30, t50, dissolution efficiency (DE). Lastly, drug-excipient compatibility studies, including Fourier transform infrared (FTIR) spectroscopic analysis and differential scanning calorimetric (DSC) analysis were carried out. Fair flow property was observed in the chickpea starch powder. Furthermore, the tablets produced passed all the tests in physicochemical characteristics evaluation except hardness and disintegration test. Additionally, in vitro dissolution studies show that chickpea starch acted as a disintegrant instead of a binder in gliclazide IR tablets and its disintegrant properties were comparable to those of crospovidone, croscarmellose sodium and sodium starch glycolate. Besides that, gliclazide was also compatible with the excipients used. Chickpea starch acted as a disintegrant in gliclazide IR tablets, instead of a binder. Therefore, chickpea starch can be a promising disintegrant in gliclazide IR tablets.

Excipient-assisted vinpocetine nanoparticles: experiments and molecular dynamic simulations.

PubMed

Li, Cai-Xia; Wang, Hao-Bo; Oppong, Daniel; Wang, Jie-Xin; Chen, Jian-Feng; Le, Yuan

2014-11-03

Hydrophilic excipients can be used to increase the solubility and bioavailability of poorly soluble drugs. In this work, the conventional water-soluble pharmaceutical excipients hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and lactose (LAC) were used as solid supports to prevent drug nanoparticles from aggregation and enhance drug dissolution. Excipient-assisted vinpocetine (VIN) nanoparticles were prepared by reactive precipitation. The analysis results indicated that HPMC was a suitable excipient to prepare VIN nanoparticles. VIN/HPMC nanoparticles had a mean size of 130 nm within a narrow distribution. The dissolution rate of VIN nanoparticles was significantly faster than those of a physical mixture of VIN/HPMC and raw VIN. VIN/HPMC nanoparticles had a higher dissolution profile than VIN/PVP and VIN/LAC nanoparticles. Besides, molecular dynamics (MD) simulation was applied to investigate the molecular interactions between VIN and excipients. The calculated results revealed that VIN interacted with excipients by Coulomb and Lennard-Jones (LJ) interactions. Few hydrogen bonds were formed between VIN and excipients. The HPMC affording smaller particle size may be a result of the stronger interactions between VIN and HPMC (mainly LJ interaction) and the property of HPMC. These characteristics may greatly influence the adsorption behavior and may be the crucial parameter for the better performance of HPMC.

Application of ion chromatography in pharmaceutical and drug analysis.

PubMed

Jenke, Dennis

2011-08-01

Ion chromatography (IC) has developed and matured into an important analytical methodology in a number of diverse applications and industries, including pharmaceuticals. This manuscript provides a review of IC applications for the determinations of active and inactive ingredients, excipients, degradation products, and impurities relevant to pharmaceutical analyses and thus serves as a resource for investigators looking for insights into the use of the IC methodology in this field of application.

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.

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.

Potentially harmful excipients in neonatal medicines: a pan-European observational study.

PubMed

Nellis, Georgi; Metsvaht, Tuuli; Varendi, Heili; Toompere, Karolin; Lass, Jana; Mesek, Inge; Nunn, Anthony J; Turner, Mark A; Lutsar, Irja

2015-07-01

We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure. All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Fast determination of diphenhydramine hydrochloride in reconstitutable syrups by CWT, PLS AND PCR methods.

PubMed

Devrim, Burcu; Dinç, Erdal; Bozkir, Asuman

2014-01-01

Diphenhydramine hydrochloride (DPH), a histamine H1-receptor antagonist, is widely used as antiallergic, antiemetic and antitussive drug found in many pharmaceutical preparations. In this study, a new reconstitutable syrup formulation of DPH was prepared because it is more stable in solid form than that in liquid form. The quantitative estimation of the DPH content of a reconstitutable syrup formulation in the presence of pharmaceutical excipients, D-sorbitol, sodium citrate, sodium benzoate and sodium EDTA is not possible by the direct absorbance measurement. Therefore, a signal processing approach based on continuous wavelet transform was used to determine the DPH in the reconstitutable syrup formulations and to eliminate the effect of excipients on the analysis. The absorption spectra of DPH in the range of 5.0-40.0 μg/mL were recorded between 200-300 nm. Various wavelet families were tested and Biorthogonal1.1 continuous wavelet transform (BIOR1.1-CWT) was found to be optimal signal processing family to get fast and desirable determination results and to overcome excipient interference effects. For a comparison of the experimental results obtained by partial least squares (PLS) and principal component regression (PCR) methods were applied to the quantitative prediction of DPH in the mentioned samples. The validity of the proposed BIOR1.1-CWT, PLS and PCR methods were achieved analyzing the prepared samples containing the mentioned excipients and using standard addition technique. It was observed that the proposed graphical and numerical approaches are suitable for the quantitative analysis of DPH in samples including excipients.

Application of halloysite clay nanotubes as a pharmaceutical excipient.

PubMed

Yendluri, Raghuvara; Otto, Daniel P; De Villiers, Melgardt M; Vinokurov, Vladimir; Lvov, Yuri M

2017-04-15

Halloysite nanotubes, a biocompatible nanomaterial of 50-60nm diameter and ca. 15nm lumen, can be used for loading, storage and sustained release of drugs either in its pristine form or with additional polymer complexation for extended release time. This study reports the development composite tablets based on 50wt.% of the drug loaded halloysite mixed with 45wt.% of microcrystalline cellulose. Powder flow and compressibility properties of halloysite (angle of repose, Carr's index, Hausner ratio, Brittle Fracture Index, tensile strength) indicate that halloysite is an excellent tablet excipient. Halloysite tubes can also be filled with nifedipine with ca. 6wt.% loading efficiency and sustained release from the nanotubes. Tablets prepared with drug loaded halloysite allowed for almost zero order nifedipine release for up to 20h. Nifedipine trapped in the nanotubes also protect the drug against light and significantly increased the photostability of the drug. All of these demonstrate that halloysite has the potential to be an excellent pharmaceutical excipient that is also an inexpensive, natural and abundantly available material. Copyright © 2017 Elsevier B.V. All rights reserved.

Formation, Physicochemical Characterization, and Thermodynamic Stability of the Amorphous State of Drugs and Excipients.

PubMed

Martino, Piera Di; Magnoni, Federico; Peregrina, Dolores Vargas; Gigliobianco, Maria Rosa; Censi, Roberta; Malaj, Ledjan

2016-01-01

Drugs and excipients used for pharmaceutical applications generally exist in the solid (crystalline or amorphous) state, more rarely as liquid materials. In some cases, according to the physicochemical nature of the molecule, or as a consequence of specific technological processes, a compound may exist exclusively in the amorphous state. In other cases, as a consequence of specific treatments (freezing and spray drying, melting and co-melting, grinding and compression), the crystalline form may convert into a completely or partially amorphous form. An amorphous material shows physical and thermodynamic properties different from the corresponding crystalline form, with profound repercussions on its technological performance and biopharmaceutical properties. Several physicochemical techniques such as X-ray powder diffraction, thermal methods of analysis, spectroscopic techniques, gravimetric techniques, and inverse gas chromatography can be applied to characterize the amorphous form of a compound (drug or excipient), and to evaluate its thermodynamic stability. This review offers a survey of the technologies used to convert a crystalline solid into an amorphous form, and describes the most important techniques for characterizing the amorphous state of compounds of pharmaceutical interest.

Sulfite-containing Canadian pharmaceutical products available in 1991.

PubMed Central

Miyata, M; Schuster, B; Schellenberg, R

1992-01-01

OBJECTIVE: To compile an inclusive list of Canadian pharmaceutical products available in 1991 that contained sulfites. DATA SOURCES: Written and oral responses from 94 pharmaceutical companies selected from the 1989 Compendium of Pharmaceuticals and Specialties. RESULTS: A list of sulfite-containing pharmaceutical products was compiled from data supplied by the 90 responding companies. Companies whose products contained no sulfites were separately identified. CONCLUSIONS: Sulfites are present in many pharmaceutical products and are one of many excipients and additives that have been reported to cause severe adverse reactions. The provided list should be a useful aid for health care practitioners when prescribing pharmaceutical products for sulfite-sensitive patients. PMID:1483237

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.

Glycation of polyclonal IgGs: Effect of sugar excipients during stability studies.

PubMed

Leblanc, Y; Bihoreau, N; Jube, M; Andre, M-H; Tellier, Z; Chevreux, G

2016-05-01

A number of intravenous immunoglobulin preparations are stabilized with sugar additives that may lead over time to undesirable glycation reactions especially in liquid formulation. This study aimed to evaluate the reactivity of sugar excipients on such preparations in condition of temperature, formulation and concentration commonly used for pharmaceutical products. Through an innovative LC-MS method reported to characterize post-translational modifications of IgGs Fc/2 fragments, a stability study of IVIg formulated with reducing and non-reducing sugars has been undertaken. The rate of polyclonal IgGs glycation was investigated during 6months at 5, 25, 30 and 40°C. High levels of glycation were observed with reducing sugars such as glucose and maltose in the first months of the stability study from 25°C. Non-reducing sugars presented a low reactivity even at the highest tested temperature (40°C). Furthermore, a site by site analysis was performed by MS/MS to determine the glycation sites which were mainly identified at Lys246, Lys248 and Lys324. This work points out the high probability of glycation reactions in some commercialized products and describes a useful method to characterize IVIg glycated products issued from reducing sugar excipients. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

3D printing of tablets containing multiple drugs with defined release profiles.

PubMed

Khaled, Shaban A; Burley, Jonathan C; Alexander, Morgan R; Yang, Jing; Roberts, Clive J

2015-10-30

We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This 'polypill' made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and 'dial up' this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug-excipient interaction. The printed formulations were evaluated for drug release using USP dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer-Peppas release kinetics dependent upon the active/excipient ratio used. Copyright © 2015. Published by Elsevier B.V.

Dehydration of trehalose dihydrate at low relative humidity and ambient temperature.

PubMed

Jones, Matthew D; Hooton, Jennifer C; Dawson, Michelle L; Ferrie, Alan R; Price, Robert

2006-04-26

The physico-chemical behaviour of trehalose dihydrate during storage at low relative humidity and ambient temperature was investigated, using a combination of techniques commonly employed in pharmaceutical research. Weight loss, water content determinations, differential scanning calorimetry and X-ray powder diffraction showed that at low relative humidity (0.1% RH) and ambient temperature (25 degrees C) trehalose dihydrate dehydrates forming the alpha-polymorph. Physical examination of trehalose particles by scanning electron microscopy and of the dominant growth faces of trehalose crystals by environmentally controlled atomic force microscopy revealed significant changes in surface morphology upon partial dehydration, in particular the formation of cracks. These changes were not fully reversible upon complete rehydration at 50% RH. These findings should be considered when trehalose dihydrate is used as a pharmaceutical excipient in situations where surface properties are key to behaviour, for example as a carrier in a dry powder inhalation formulations, as morphological changes under common processing or storage conditions may lead to variations in formulation performance.

Predicting the tensile strength of compacted multi-component mixtures of pharmaceutical powders.

PubMed

Wu, Chuan-Yu; Best, Serena M; Bentham, A Craig; Hancock, Bruno C; Bonfield, William

2006-08-01

Pharmaceutical tablets are generally produced by compacting a mixture of several ingredients, including active drugs and excipients. It is of practical importance if the properties of such tablets can be predicted on the basis of the ones for constituent components. The purpose of this work is to develop a theoretical model which can predict the tensile strength of compacted multi-component pharmaceutical mixtures. The model was derived on the basis of the Ryshkewitch-Duckworth equation that was originally proposed for porous materials. The required input parameters for the model are the relative density or solid fraction (ratio of the volume of solid materials to the total volume of the tablets) of the multi-component tablets and parameters associated with the constituent single-component powders, which are readily accessible. The tensile strength of tablets made of various powder blends at different relative density was also measured using diametrical compression. It has been shown that the tensile strength of the multi-component powder compacts is primarily a function of the solid fraction. Excellent agreement between prediction and experimental data for tablets of binary, ternary and four-component blends of some widely used pharmaceutical excipients was obtained. It has been demonstrated that the proposed model can well predict the tensile strength of multi-component pharmaceutical tablets. Thus, the model will be a useful design tool for formulation engineers in the pharmaceutical industry.

Effect of Moisture Content of Chitin-Calcium Silicate on Rate of Degradation of Cefotaxime Sodium.

PubMed

Al-Nimry, Suhair S; Alkhamis, Khouloud A

2018-04-01

Assessment of incompatibilities between active pharmaceutical ingredient and pharmaceutical excipients is an important part of preformulation studies. The objective of the work was to assess the effect of moisture content of chitin calcium silicate of two size ranges (two specific surface areas) on the rate of degradation of cefotaxime sodium. The surface area of the excipient was determined using adsorption method. The effect of moisture content of a given size range on the stability of the drug was determined at 40°C in the solid state. The moisture content was determined at the beginning and the end of the kinetic study using TGA. The degradation in solution was studied for comparison. Increasing the moisture content of the excipient of size range 63-180 μm (surface area 7.2 m 2 /g) from 3.88 to 8.06% increased the rate of degradation of the drug more than two times (from 0.0317 to 0.0718 h -1 ). While an opposite trend was observed for the excipient of size range < 63 μm (surface area 55.4 m 2 /g). The rate of degradation at moisture content < 3% was 0.4547 h -1 , almost two times higher than that (0.2594 h -1 ) at moisture content of 8.54%, and the degradation in solid state at both moisture contents was higher than that in solution (0.0871 h -1 ). In conclusion, the rate of degradation in solid should be studied taking into consideration the specific surface area and moisture content of the excipient at the storage condition and it may be higher than that in solution.

[Pharmaceutical drugs containing lactose can as a rule be used by persons with lactose intolerance].

PubMed

Vinther, Siri; Rumessen, Jöri Johannes; Christensen, Mikkel

2015-03-09

Lactose is often used as an excipient in pharmaceutical drugs. Current evidence indicates that the amount of lactose in most drugs is not sufficient to cause symptoms in persons with lactose intolerance, although interindividual differences in sensitivity probably exist. Patient preferences and/or suboptimal treatment adherence could be reasons for considering lactose-free drug alternatives.

[Galenic forms for oral medication].

PubMed

El Semman, Ousseid; Certain, Agnès; Bouziane, Faouzia; Arnaud, Philippe

2012-10-01

Galenic science is interested in the art and the way of formulating an active principle with an excipient in order for it to be administered to the patient. The pharmaceutical forms envisage different administration routes, including by mouth. Nurses need to handle and sometimes modify the pharmaceutical form of a drug to make it easier for the patient to take. This requires vigilance.

Development and Validation of a Chromatography Method Using Tandem UV/Charged Aerosol Detector for Simultaneous Determination of Amlodipine Besylate and Olmesartan Medoxomil: Application to Drug-Excipient Compatibility Study

PubMed Central

Brondi, Ariadne M.; Garcia, Jerusa S.

2017-01-01

A study was carried out to investigate compatibility of amlodipine besylate and olmesartan medoxomil with a variety of pharmaceutical excipients. Both drugs are antihypertensive agents that can be administered alone, in monotherapy, or in pharmaceutical association. The studies were performed using binary and ternary mixtures, and samples were stored for 3 and 6 months at 40°C under 75% relative humidity and dry conditions. For this study, a method based on high-performance liquid chromatography (HPLC) was developed and validated for the simultaneous determination of amlodipine besylate and olmesartan medoxomil in samples from pharmaceutical preformulation studies using diode array detector (DAD) and charged aerosol detector (CAD). The runtime per sample was 10 min with retention time of 7.926 min and 4.408 min for amlodipine and olmesartan, respectively. The validation was performed according to ICH guidelines. The calibration curve presents linear dynamic range from 12 to 250 μg mL−1 for amlodipine and from 25 to 500 μg mL−1 for olmesartan with coefficient of determination (R2 ≥ 0.9908) while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.0%. The excipients such as corn starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, polyvinylpyrrolidone, lactose monohydrate, and polyethylene glycol showed potential incompatibilities after accelerated stability testing. PMID:29391967

A toxicity assessment of 30 pharmaceuticals using Aliivibrio fischeri: a comparison of the acute effects of different formulations.

PubMed

Jacob, Raquel Sampaio; Santos, Lucilaine Valéria de Souza; de Souza, Ana Flávia Rodrigues; Lange, Liséte Celina

2016-11-01

Considerable quantities of different classes of drugs are consumed annually worldwide. These drugs, once disposed, often remain stable, even after conventional or advanced treatments. Although there have been a number of studies on the potential harm caused by drugs when released into the environment, few studies have investigated the toxicity of pharmaceutical excipients. In the present study, the acute toxicity of 30 drugs was tested to Aliivibrio fischeri. Ten different active ingredients were investigated, each in three distinct formulations: generic, similar and reference (brand drug). The aim of the study was to evaluate the harmful potential of drugs frequently sold in drugstores and to assess the contribution of excipients towards the observed acute toxicity. Within the 10 drugs evaluated, only one, dexchlorpheniramine maleate, was not toxic in any formulation. The toxicities of the three formulations were often different, even though the active ingredient has been the same. For some drugs, such as diazepam, glibenclamide, metformin, nimesulide, hydrochlorothiazide and simvastatin, only one or two of the three formulations tested were toxic to A. fischeri. These results highlight the toxicological potential of drug excipients, but not exclusively the toxicity of the active ingredients.

Modulation of the wettability of excipients by surfactant and its impacts on the disintegration and release of tablets.

PubMed

Yang, Baixue; Xu, Lu; Wang, Qiuxiao; Li, Sanming

2016-12-01

To investigate the modulation of the wettability of excipients by different types of surfactants and its impacts on the disintegration of tablets and drug release. The critical micelle concentration (CMC) of surfactants, including sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS), dodecyl trimethyl ammonium bromide (DTAB), cetyltrimethyl ammonium bromide (CTAB) and polysorbate (Tween-20 and Tween-80), was obtained using the platinum ring method. Contact angles of surfactant solutions on the excipient compacts and double-distilled water on the mixture of surfactant and the other excipient (magnesium stearate (MgSt) or sodium alginate (SA)) were measured by the sessile drop technique. Besides, surface free energy of excipients was calculated by the Owens method. Finally, the disintegration of tablets and in vitro dissolution testing were performed according to the method described in USP. The wettability of excipients could be enhanced to different extent with low concentration of surfactant solutions and maintained stable basically after CMC. For MgSt (hydrophobic excipient), the shorter the hydrophobic chain (C 12 , including SDS and DTAB), the better the wettability with the addition of surfactant in the formulation, leading to the shorter disintegration time of tablets and higher drug release rate. In contrast, the wettability of SA (hydrophilic excipient) was reduced by adding surfactant, resulting in the longer disintegration time of tablets and lower release rate. The modulation of the wetting of pharmaceutical excipients by surfactant had changed the disintegration time of tablets and drug release rate to a greater extent.

Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design.

PubMed

Vandecruys, Roger; Peeters, Jef; Verreck, Geert; Brewster, Marcus E

2007-09-05

Assessing the effect of excipients on the ability to attain and maintain supersaturation of drug-based solution may provide useful information for the design of solid formulations. Judicious selection of materials that affect either the extent or stability of supersaturating drug delivery systems may be enabling for poorly soluble drug candidates or other difficult-to-formulate compounds. The technique suggested herein is aimed at providing a screening protocol to allow preliminary assessment of these factors based on small to moderate amounts of drug substance. A series of excipients were selected that may, by various mechanisms, affect supersaturation including pharmaceutical polymers such as HMPC and PVP, surfactants such as Polysorbate 20, Cremophor RH40 and TPGS and hydrophilic cyclodextrins such as HPbetaCD. Using a co-solvent based method and 25 drug candidates, the data suggested, on the whole, that the surfactants and the selected cyclodextrin seemed to best augment the extent of supersaturation but had variable benefits as stabilizers, while the pharmaceutical polymers had useful effect on supersaturation stability but were less helpful in increasing the extent of supersaturation. Using these data, a group of simple solid dosage forms were prepared and tested in the dog for one of the drug candidates. Excipients that gave the best extent and stability for the formed supersaturated solution in the screening assay also gave the highest oral bioavailability in the dog.

[Analysis of generic drug supply in France].

PubMed

Taboulet, F; Haramburu, F; Latry, Ph

2003-09-01

The list of generic medicines (LGM), published since 1997 by the Agence Française de Sécurité Sanitaire des Produits de Santé (AFFSSaPS), the French Medicine Agency, concerns a special part of the medicines reimbursed by the National Health Insurance (Social Security). The objectives of the present study were: i) to describe the components of this list, based on pharmaceutical, economical and therapeutic characteristics, ii) to study differences between generic and reference products (formulations, excipients, prices, etc.), iii) to analyze information on excipients provided to health care professionals. The 21st version of the LGM (April 2001) was used. Therapeutic value was retrieved from the 2001 AFSSaPS report on the therapeutic value of 4490 reimbursed medicines. Information on excipients in the LGM and the Vidal dictionary (reference prescription book in France) was compared. The products included in the LGM represent 20% of all reimbursed medicines. The mean price differences between generics and their reference products vary between 30 and 50% for more than two thirds of the generic groups. The therapeutic value of the products of the LGM was judged important in 71% of cases (vs 63% for the 4409 assessed medicines) and insufficient in 13% of cases (vs 19%). Information on excipients is often missing and sometimes erroneous. Although the LGM is regularly revised and thus the generic market in perpetual change, the 2001 cross description of this pharmaceutical market provides much informations and raises some concern.

Structural changes of polymer-coated microgranules and excipients on tableting investigated by microtomography using synchrotron X-ray radiation.

PubMed

Kajihara, Ryusuke; Noguchi, Shuji; Iwao, Yasunori; Suzuki, Yoshio; Terada, Yasuko; Uesugi, Kentaro; Itai, Shigeru

2015-03-15

Multiple-unit tablets consisting of polymer-coated microgranules and excipients have a number of advantageous pharmaceutical properties. Polymer-coated microgranules are known to often lose their functionality because of damage to the polymer coating caused by tableting, and the mechanism of polymer coating damage as well as the structural changes of excipients upon tableting had been investigated but without in-situ visualization and quantitative analysis. To elucidate the mechanism of coating damage, the internal structures of multiple-unit tablets were investigated by X-ray computed microtomography using synchrotron X-rays. Cross sectional images of the tablets with sub-micron spatial resolution clearly revealed that void spaces remained around the compressed excipient particles in the tablets containing an excipient composed of cellulose and lactose (Cellactose(®) 80), whereas much smaller void spaces remained in the tablets containing an excipient made of sorbitol (Parteck(®) SI 150). The relationships between the void spaces and the physical properties of the tablets such as hardness and disintegration were investigated. Damage to the polymer coating in tablets was found mainly where polymer-coated microgranules were in direct contact with each other in both types of tablets, which could be attributed to the difference in hardness of excipient particles and the core of the polymer-coated microgranules. Copyright © 2015 Elsevier B.V. All rights reserved.

From conventional towards new - natural surfactants in drug delivery systems design: current status and perspectives.

PubMed

Savić, Snezana; Tamburić, Slobodanka; Savić, Miroslav M

2010-03-01

Surfactants play an important role in the development of both conventional and advanced (colloidal) drug delivery systems. There are several commercial surfactants, but a proportionally small group of them is approved as pharmaceutical excipients, recognized in various pharmacopoeias and therefore widely accepted by the pharmaceutical industry. The review covers some of the main categories of natural, sugar-based surfactants (alkyl polyglucosides and sugar esters) as prospective pharmaceutical excipients. It provides analysis of the physicochemical characteristics of sugar-based surfactants and their possible roles in the design of conventional or advanced drug delivery systems for different routes of administration. Summary and analysis of recent data on functionality, applied concentrations and formulation improvements produced by alkyl polyglucosides and sugar esters in different conventional and advanced delivery systems could be of interest to researchers dealing with drug formulation. Recent FDA certification of an alkyl polyglucoside surfactant for topical formulation presents a significant step in the process of recognition of this relatively new group of surfactants. This could trigger further research into the potential benefits of naturally derived materials in both conventional and new drug delivery systems.

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

Spectrofluorometric determination of furosemide in some pharmaceutical product using acriflavine as a reagent

NASA Astrophysics Data System (ADS)

Qader, Aryan F.; Fakhre, Nabil A.

2017-09-01

Simple, inexpensive, rapid and sensitive determination of furosemide spectrofluorometrically was suggested using acriflavine as a new reagent. The method based on the quantitative quenching effect of furosemide on the native fluorescence of acriflavine in presence of Britton-Robinson buffer medium due to the reaction of furosemide with acriflavine to form an ion associated complex. The decrease of acriflavine fluorescence was observed at 505 nm after excitation at 265 nm. the florescence - concentration plot is rectilinear over the range of 2.0-10 µg/ml with correlation coefficient 0.9991 and detection limit 0.2 µg/ml. No interference was observed from the excipients that are commonly present in pharmaceutical formulations. The proposed method was determination of furosemide in some commercial tablets. The results were compared with that of HPLC method revealed with good agreements and no significant differences in the accuracy and precision.

Extractive-spectrophotometric determination of disopyramide and irbesartan in their pharmaceutical formulation

NASA Astrophysics Data System (ADS)

Abdellatef, Hisham E.

2007-04-01

Picric acid, bromocresol green, bromothymol blue, cobalt thiocyanate and molybdenum(V) thiocyanate have been tested as spectrophotometric reagents for the determination of disopyramide and irbesartan. Reaction conditions have been optimized to obtain coloured comoplexes of higher sensitivity and longer stability. The absorbance of ion-pair complexes formed were found to increases linearity with increases in concentrations of disopyramide and irbesartan which were corroborated by correction coefficient values. The developed methods have been successfully applied for the determination of disopyramide and irbesartan in bulk drugs and pharmaceutical formulations. The common excipients and additives did not interfere in their determination. The results obtained by the proposed methods have been statistically compared by means of student t-test and by the variance ratio F-test. The validity was assessed by applying the standard addition technique. The results were compared statistically with the official or reference methods showing a good agreement with high precision and accuracy.

Amorphization of itraconazole by inorganic pharmaceutical excipients: comparison of excipients and processing methods.

PubMed

Grobelny, Pawel; Kazakevich, Irina; Zhang, Dan; Bogner, Robin

2015-01-01

The aim of this study was to investigate the effects of solid carriers and processing routes on the properties of amorphous solid dispersions of itraconazole. Three solid carriers with a range of surface properties were studied, (1) a mesoporous silicate, magnesium aluminum silicate (Neusilin US2), (2) a nonporous silicate of corresponding composition (Veegum) and (3) a non-silicate, inorganic excipient, calcium phosphate dibasic anhydrous (A-TAB). The drug was incorporated via either solvent-deposition or ball milling. Both the maximum drug deposited by solvent-based method that produced an amorphous composite and the time for complete amorphization by co-milling was determined by X-ray powder diffraction (XRPD). Changes in the drug and excipients were monitored by nitrogen adsorption and wettability of the powder. The ability of the excipients to amorphize the drug and enhance its dissolution was related to the powder characteristics. Neusilin provided the fastest amorphization time in the mill and highest drug loading by solvent-deposition, compared with the other two excipients. Solvent-deposition provided greater dissolution enhancement than milling, due to the reduction in Neusilin porosity during high energy milling.This study confirms that substrates as well as the processing routes have notable influence on the drug deposition, amorphization, physical stability and drug in vitro release.

Final product analysis in the e-beam and gamma radiolysis of aqueous solutions of metoprolol tartrate

NASA Astrophysics Data System (ADS)

Slegers, Catherine; Tilquin, Bernard

2006-09-01

The radiostability of metoprolol tartrate aqueous solutions and the influence of the absorbed dose (0-50 kGy), dose rate (e-beam (EB) vs. gamma ( γ)) and radioprotectors (pharmaceutical excipients) are investigated by HPLC-UV analyses and through computer simulations. The use of radioprotecting excipients is more promising than an increase in the dose rate to lower the degradation of metoprolol tartrate aqueous solutions for applications such as radiosterilization. The decontamination of metoprolol tartrate from waste waters by EB processing appears highly feasible.

Quality control of the paracetamol drug by chemometrics and imaging spectroscopy in the near infrared region

NASA Astrophysics Data System (ADS)

Baptistao, Mariana; Rocha, Werickson Fortunato de Carvalho; Poppi, Ronei Jesus

2011-09-01

In this work, it was used imaging spectroscopy and chemometric tools for the development and analysis of paracetamol and excipients in pharmaceutical formulations. It was also built concentration maps to study the distribution of the drug in the tablets surface. Multivariate models based on PLS regression were developed for paracetamol and excipients concentrations prediction. For the construction of the models it was used 31 samples in the tablet form containing the active principle in a concentration range of 30.0-90.0% (w/w) and errors below to 5% were obtained for validation samples. Finally, the study of the distribution in the drug was performed through the distribution maps of concentration of active principle and excipients. The analysis of maps showed the complementarity between the active principle and excipients in the tablets. The region with a high concentration of a constituent must have, necessarily, absence or low concentration of the other one. Thus, an alternative method for the paracetamol drug quality monitoring is presented.

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.

[Technological and pharmacotherapeutic properties of selected drugs with modified release of diclofenac sodium].

PubMed

Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Diclofenac and its sodium salt is one of the best-known and popular therapeutic agents from the group of NSAIDs used in medicine in many various pharmaceutical forms. Therapeutic products containing diclofenac sodium salt in doses of 100 mg and 75 mg with a qualitatively and quantitatively diversified share of excipients and a variable dosage form of the drug (solid capsules, tablets with modified release) were subjected to technological and pharmaceutical analysis. The effect of solid formulation components of polymer character making the core and the coating of the pharmaceutical form of therapeutic products on the disintegration time and pharmaceutical availability in pharmacopoeial receptor fluids was estimated. Market therapeutic products with diclofenac sodium in doses of 75 mg and 100 mg, technological analysis of the drug dosage form was conducted, disintegration time of solid oral dosage forms of the drug with diclofenac sodium salt was examined and research on pharmaceutical availability of diclofenac sodium salt from tested therapeutic products was conducted using the acid phase and the buffer phase according to the FP standards for delayed release enteral dosage forms. The experimental data was supplemented with the statistical analysis. There are three formulations in the form of solid capsules and one formulation in the form of a coated tablet. All therapeutic products bear features of a dosage form of modified release of diclofenac sodium salt, frequently of a delayed release formula in the duodenum or the small intestine with regard to the limitation of typical undesirable effects after taking NSAIDs. Considerable diversity between solid capsules and the tablet with modified release during disintegration or hydration and swelling has been observed. In the environment of a receptor fluid--purified water (pH = 7) the capsule Dicloberl retard disintegrates at the fastest rate in 5,49 minutes, and then in the order: DicloDuo 75 mg--8,13 minutes and Olfen 100 SR--11,27 minutes. The hydration degree of gelatin walls of capsules depends on the pH of the receptor fluid. The availability of diclofenac sodium salt in given receptor fluids confirms the fact of significant connection of clinical effectiveness of the tested pharmaceutical forms with the activity of hydrogen ions (pH) of the environment in which there are therapeutic products, and excipients used for making the pharmaceutical phase. Tested therapeutic products with diclofenac sodium salt are differentiated by the type of a dosage form. Dicloberl retard contains the minimally indispensable number of simple, commonly used excipients. The research on the disintegration time may only be related to the products Dicloberl retard, Olfen 100 SR and DicloDuo 75 mg treating it as the time of deformation and disintegration of a capsule. In all three types of receptor fluids, the capsule Dicloberl retard has the fastest disintegration rate. The "acid phase" demonstrated stability of the products with a slight dissolution of diclofenac sodium salt on the level 1,3-4,18% of the Q release coefficient. In the environment of artificial intestinal juice, Dicloberl retard is more effective releasing larger amounts of diclofenac sodium salt during 4 hours of exposition (differences from 10% to 14% of the Q release coefficient).

Compounding with Silicones.

PubMed

Allen, Loyd V

2015-01-01

Since the 1940s, methylchlorosilanes have been used to treat glassware to prevent blood from clotting. The use of silicones in pharmaceutical and medical applications has grown to where today they are used in many life-saving devices (pacemakers, hydrocephalic shunts) and pharmaceutical applications from tubing, to excipients in topical formulations, to adhesives to affix transdermal drug delivery systems, and are also being used in products as active pharmaceutical ingredients, such as antiflatulents. About 60% of today's skin-care products now contain some type of silicone where they are considered safe and are known to provide a pleasant "silky-touch," non-greasy, and non-staining feel. Silicones exhibit many useful characteristics, and the safety of these agents supports their numerous applications; their biocompatibility is partially due to their low-chemical reactivity displayed by silicones, low-surface energy, and their hydrophobicity. Silicones are used both as active ingredients and as excipients. In addition is their use for "siliconization," or surface treatment, of many parenteral packaging components. Dimethicone and silicone oil are used as lubricants on stoppers to aid machineability, in syringes to aid piston movement, or on syringe needles to reduce pain upon injection. Silicones are also useful in pharmaceutical compounding as is discussed in this artiele included with this article are in developing formulations with silicones.

The transit of dosage forms through the small intestine.

PubMed

Yuen, Kah-Hay

2010-08-16

The human small intestine, with its enormous absorptive surface area, is invariably the principal site of drug absorption. Hence, the residence time of a dosage form in this part of the gut can have a great influence on the absorption of the contained drug. Various methods have been employed to monitor the gastrointestinal transit of pharmaceutical dosage forms, but the use of gamma-scintigraphy has superceded all the other methods. However, careful consideration of the time interval for image acquisition and proper analysis of the scintigraphic data are important for obtaining reliable results. Most studies reported the mean small intestinal transit time of various dosage forms to be about 3-4h, being closely similar to that of food and water. The value does not appear to be influenced by their physical state nor the presence of food, but the timing of food intake following administration of the dosage forms can influence the small intestinal transit time. While the mean small intestinal transit time is quite consistent among dosage forms and studies, individual values can vary widely. There are differing opinions regarding the effect of density and size of dosage forms on their small intestinal transit properties. Some common excipients employed in pharmaceutical formulations can affect the small intestinal transit and drug absorption. There is currently a lack of studies regarding the effects of excipients, as well as the timing of food intake on the small intestinal transit of dosage forms and drug absorption. Copyright (c) 2010 Elsevier B.V. All rights reserved.

[Contact eczema in patients with leg ulcers].

PubMed

Degreef, H; Dooms-Goossens, A; Gladys, K

1986-01-01

Patients with leg ulcers or varicose eczema suffer much more often from contact eczema due to the local application of pharmaceutical preparations than patients suffering from other dermatological problems (even those of eczematous origin). This contact allergy may concern not only the active ingredient but also the excipient, the preservative, or even the perfume. In all cases of leg ulcers, of varicose eczema, but also of badly healed ulcers, epicutaneous tests should be carried out with all the components of the pharmaceutical preparations concerned. Moreover, the pharmaceutical industry really must perfect non-allergenic preparations.

On-line coupling of size exclusion chromatography with mixed-mode liquid chromatography for comprehensive profiling of biopharmaceutical drug product.

PubMed

He, Yan; Friese, Olga V; Schlittler, Michele R; Wang, Qian; Yang, Xun; Bass, Laura A; Jones, Michael T

2012-11-02

A methodology based on on-line coupling of size exclusion chromatography (SEC) with mixed-mode liquid chromatography (LC) has been developed. The method allows for simultaneous measurement of a wide range of components in biopharmaceutical drug products. These components include the active pharmaceutical ingredient (protein) and various kinds of excipients such as cations, anions, nonionic hydrophobic surfactant and hydrophilic sugars. Dual short SEC columns are used to separate small molecule excipients from large protein molecules. The separated protein is quantified using a UV detector at 280 nm. The isolated excipients are switched, online, to the Trinity P1 mixed-mode column for separation, and detected by an evaporative light scattering detector (ELSD). Using a stationary phase with 1.7 μm particles in SEC allows for the use of volatile buffers for both SEC and mix-mode separation. This facilitates the detection of different excipients by ELSD and provides potential for online characterization of the protein with mass spectrometry (MS). The method has been applied to quantitate protein and excipients in different biopharmaceutical drug products including monoclonal antibodies (mAb), antibody drug conjugates (ADC) and vaccines. Copyright © 2012 Elsevier B.V. All rights reserved.

Evaluation of taste-masking effects of pharmaceutical sweeteners with an electronic tongue system.

PubMed

Choi, Du Hyung; Kim, Nam Ah; Nam, Tack Soo; Lee, Sangkil; Jeong, Seong Hoon

2014-03-01

Electronic tongue systems have been developed for taste measurement of bitter drug substances in accurate taste comparison to development palatable oral formulations. This study was to evaluate the taste masking effect of conventional pharmaceutical sweeteners such as neohesperidin dihydrochalcone, sucrose, sucralose and aspartame. The model drugs were acetaminophen, ibuprofen, tramadol hydrochloride, and sildenafil citrate (all at 20 mM). The degree of bitterness was measured by a multichannel taste sensor system (an electronic tongue). The data was collected by seven sensors and analyzed by a statistical method of principal components analysis (PCA). The effect of taste masking excipient was dependent on the type of model drug. Changing the concentration of taste masking excipients affected the sensitivity of taste masking effect according to the type of drug. As the excipient concentration increased, the effect of taste masking increased. Moreover, most of the sensors showed a concentration-dependent pattern of the taste-masking agents as higher concentration provided higher selectivity. This might indicate that the sensors can detect small concentration changes of a chemical in solution. These results suggest that the taste masking could be evaluated based on the data of the electronic tongue system and that the formulation development process could be performed in a more efficient way.

Interference of 1:1 and 2:1 layered phyllosilicates as excipients with ranitidine.

PubMed

Li, Zhaohui; Fitzgerald, Nicole M; Albert, Zachary; Jiang, Wei-Teh

2016-04-01

As natural ingredients and excipients, kaolinite and talc were frequently studied for their interactions with drugs in pharmaceutical formulations. In this study, the uptake of ranitidine (RT) on these two minerals was studied under different physic-chemical conditions and the mechanism of RT uptake on these two minerals contrasted. Although the thermodynamic and kinetic RT uptake on these two minerals was similar and the RT uptake on both minerals were limited to the external surfaces only, drastic difference in RT uptake was found under different equilibrium solution pH and ionic strength conditions. As cation exchange process was strongly affected by solution pH and ionic strength, the RT uptake on kaolinite was dominated by cation exchange and electrostatic interactions, while the RT uptake on talc was more controlled by inter- and intra- molecular hydrogen bonding interactions. For kaolinite, the limiting factor for RT uptake was the specific surface area due to monolayer RT adsorption. In contract, multilayer RT uptake was found on talc surfaces. No matter which mechanism dominated RT uptake on these minerals, the interaction should not be neglected in pharmaceutical formulations should these minerals be used as additives and/or excipients. Copyright © 2015 Elsevier B.V. All rights reserved.

Spray drying from organic solvents to prepare nanoporous/nanoparticulate microparticles of protein: excipient composites designed for oral inhalation.

PubMed

Ní Ógáin, Orla; Tajber, Lidia; Corrigan, Owen I; Healy, Anne Marie

2012-09-01

The aim of this study was to determine if spray-drying could successfully produce microparticles containing the model protein trypsin in a form suitable for inhalation. Trypsin was spray-dried with raffinose from a methanol : n-butyl acetate solvent system (MeOH : BA). The solvent system was then adjusted to include water, and trypsin was co-spray-dried with raffinose, trehalose or hydroxpropyl-β-cyclodextrin. The spray-dried products were characterised by SEM, XRD, DSC, TGA and FTIR. Protein biological activity and in-vitro deposition of trypsin : excipient nanoporous/nanoparticulate microparticles (NPMPs) was also assessed. The inclusion of water in a MeOH : BA solvent system allowed for the successful production of NPMPs of trypsin : excipient by spray-drying. Trypsin formulated as trypsin : excipient NPMPs retained biological activity on processing and showed no deterioration in activity or morphological characteristics when stored with desiccant at either 4 or 25°C. Hydroxpropyl-β-cyclodextrin showed advantages over the sugars in terms of producing powders with appropriate density and with greater physical stability under high-humidity conditions. Fine particle fractions of between 41 and 45% were determined for trypsin : excipient NPMPs. NPMPs of trypsin : excipient systems can be produced by spray-drying by adjustment of the solvent system to allow for adequate solubility of trypsin. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator.

PubMed

Tarlier, Nicolas; Soulairol, Ian; Bataille, Bernard; Baylac, Gilles; Ravel, Patrice; Nofrerias, Isaac; Lefèvre, Philippe; Sharkawi, Tahmer

2015-11-10

Textured mannitol powder is widely used as a pharmaceutical excipient for tablet compaction. In order to choose the right tableting parameters, it is necessary to understand its mechanical behavior during deformation under industrial tableting conditions. The aim of this study was to evaluate the mechanical behavior during deformation of a textured mannitol using a rotary tablet press simulator. Mean yield pressure (Py) obtained by Heckel modeling, Walker coefficients (W) and Stress Rate Sensitivity (SRS) were compared to reference excipients, known for either their plastic (microcrystalline cellulose) or fragmentary (lactose and dibasic calcium phosphate) deformation behavior. Py, W and SRS values showed that the studied textured mannitol has a fragmentary deformation mechanism. Furthermore, this mechanical behavior was not sensitive to lubrication, which is characteristic of fragmentary excipients. Copyright © 2015 Elsevier B.V. All rights reserved.

Utilization of nanoemulsions to enhance bioactivity of pharmaceuticals, supplements, and nutraceuticals: Nanoemulsion delivery systems and nanoemulsion excipient systems.

PubMed

Aboalnaja, Khaled Omer; Yaghmoor, Soonham; Kumosani, Taha Abdullah; McClements, David Julian

2016-09-01

The efficacy of many hydrophobic bioactives (pharmaceuticals, supplements, and nutraceuticals) is limited due to their relatively low or highly variable bioavailability. Nanoemulsions consisting of small lipid droplets (r < 100 nm) dispersed in water can be designed to improve bioavailability. The major factors limiting the oral bioavailability of hydrophobic bioactive agents are highlighted: bioaccessibility, absorption and transformation. Two nanoemulsion-based approaches to control these processes and improve bioavailability are discussed: nanoemulsion delivery systems (NDS) and nanoemulsion excipient systems (NES). In NDS, hydrophobic bioactives are dissolved within the lipid phase of oil-in-water nanoemulsions. In NES, the bioactives are present within a conventional drug, supplement, or food, which is consumed with an oil-in-water nanoemulsion. Examples of NDS and NES utilization to improve bioactive bioavailability are given. Considerable progress has been made in nanoemulsion design, fabrication, and testing. This knowledge facilitates the design of new formulations to improve the bioavailability of pharmaceuticals, supplements, and nutraceuticals. NDS and NES must be carefully designed based on the major factors limiting the bioavailability of specific bioactives. Research is still required to ensure these systems are commercially viable, and to demonstrate their safety and efficacy using animal and human feeding studies.

Towards integrated drug substance and drug product design for an active pharmaceutical ingredient using particle engineering.

PubMed

Kougoulos, Eleftherios; Smales, Ian; Verrier, Hugh M

2011-03-01

A novel experimental approach describing the integration of drug substance and drug production design using particle engineering techniques such as sonocrystallization, high shear wet milling (HSWM) and dry impact (hammer) milling were used to manufacture samples of an active pharmaceutical ingredient (API) with diverse particle size and size distributions. The API instability was addressed using particle engineering and through judicious selection of excipients to reduce degradation reactions. API produced using a conventional batch cooling crystallization process resulted in content uniformity issues. Hammer milling increased fine particle formation resulting in reduced content uniformity and increased degradation compared to sonocrystallized and HSWM API in the formulation. To ensure at least a 2-year shelf life based on predictions using an Accelerated Stability Assessment Program, this API should have a D [v, 0.1] of 55 μm and a D [v, 0.5] of 140 μm. The particle size of the chief excipient in the drug product formulation needed to be close to that of the API to avoid content uniformity and stability issues but large enough to reduce lactam formation. The novel methodology described here has potential for application to other APIs. © 2011 American Association of Pharmaceutical Scientists

Polymeric drugs: Advances in the development of pharmacologically active polymers

PubMed Central

Li, Jing; Yu, Fei; Chen, Yi; Oupický, David

2015-01-01

Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. PMID:26410809

A novel multifunctional pharmaceutical excipient: modification of the permeability of starch by processing with magnesium silicate.

PubMed

Rashid, Iyad; Al-Remawi, Mayyas; Leharne, Stephen A; Chowdhry, Babur Z; Badwan, Adnan

2011-06-15

A directly compressible excipient has been developed by co-processing starch with magnesium silicate. The foregoing was achieved either by co-precipitation of magnesium silicate onto different types of starch or by dry granulation of maize starch with magnesium silicate. A variety of techniques (permeability, water retention/swelling, compression analysis, scanning electron microscopy, tensile strength and disintegration/dissolution studies) were used to characterize these systems. The permeability of the formulations produced using the two methods was evaluated experimentally using Darcy's permeability law. Magnesium silicate, as an anti-adhering agent, increases the permeability of both maize and partially pregelatinized starch, resulting in compacts of high mechanical strength, short disintegration time and low lubricant sensitivity. Such advantages are evident when the properties of the physical mixture of maize starch with magnesium silicate are compared with the co-precipitation and dry granulation techniques. Formulation with this novel excipient system, using paracetamol as a model drug, indicated its suitability as a single multifunctional excipient. Copyright © 2011 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.

Condensational Growth of Combination Drug-Excipient Submicrometer Particles for Targeted High Efficiency Pulmonary Delivery: Comparison of CFD Predictions with Experimental Results

PubMed Central

Hindle, Michael

2011-01-01

Purpose The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Methods Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. Results The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6–2.5 µm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Conclusions Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery. PMID:21948458

Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: comparison of CFD predictions with experimental results.

PubMed

Longest, P Worth; Hindle, Michael

2012-03-01

The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6-2.5 μm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery.

Combined semi-empirical screening and design of experiments (DOE) approach to identify candidate formulations of a lyophilized live attenuated tetravalent viral vaccine candidate.

PubMed

Patel, Ashaben; Erb, Steven M; Strange, Linda; Shukla, Ravi S; Kumru, Ozan S; Smith, Lee; Nelson, Paul; Joshi, Sangeeta B; Livengood, Jill A; Volkin, David B

2018-05-24

A combination experimental approach, utilizing semi-empirical excipient screening followed by statistical modeling using design of experiments (DOE), was undertaken to identify stabilizing candidate formulations for a lyophilized live attenuated Flavivirus vaccine candidate. Various potential pharmaceutical compounds used in either marketed or investigative live attenuated viral vaccine formulations were first identified. The ability of additives from different categories of excipients, either alone or in combination, were then evaluated for their ability to stabilize virus against freeze-thaw, freeze-drying, and accelerated storage (25°C) stresses by measuring infectious virus titer. An exploratory data analysis and predictive DOE modeling approach was subsequently undertaken to gain a better understanding of the interplay between the key excipients and stability of virus as well as to determine which combinations were interacting to improve virus stability. The lead excipient combinations were identified and tested for stabilizing effects using a tetravalent mixture of viruses in accelerated and real time (2-8°C) stability studies. This work demonstrates the utility of combining semi-empirical excipient screening and DOE experimental design strategies in the formulation development of lyophilized live attenuated viral vaccine candidates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Single-step preparation and deagglomeration of itraconazole microflakes by supercritical antisolvent method for dissolution enhancement.

PubMed

Sathigari, Sateesh Kumar; Ober, Courtney A; Sanganwar, Ganesh P; Gupta, Ram B; Babu, R Jayachandra

2011-07-01

Itraconazole (ITZ) microflakes were produced by supercritical antisolvent (SAS) method and simultaneously mixed with pharmaceutical excipients in a single step to prevent drug agglomeration. Simultaneous ITZ particle formation and mixing with fast-flo lactose (FFL) was performed in a high-pressure stirred vessel at 116 bar and 40 °C by the SAS-drug excipient mixing (SAS-DEM) method. The effects of stabilizers, such as sodium dodecyl sulfate and poloxamer 407 (PLX), on particle formation and drug dissolution were studied. Drug-excipient formulations were characterized for surface morphology, crystallinity, drug-excipient interactions, drug content uniformity, and drug dissolution rate. Mixture of drug microflakes and FFL formed by the SAS-DEM process shows that the process was successful in overcoming drug-drug agglomeration. PLX produced crystalline drug flakes in loose agglomerates with superior dissolution and flow properties even at higher drug loadings. Characterization studies confirmed the crystallinity of the drug and absence of chemical interactions during the SAS process. The dissolution of ITZ was substantially higher due to SAS and SAS-DEM processes; this improvement can be attributed to the microflake particle structures, effective deagglomeration, and wetting of the drug flakes with the excipients. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

[Production and assessing release of imipramine and magnesium from tablets].

PubMed

Kasperek, Regina; Zimmer, Łukasz; Szalast-Pietrzak, Agnieszka; Marzec, Zbigniew; Poleszak, Ewa

2014-01-01

In the pharmaceutical technology there is a trend to produce tablets composed of several medicinal substances to increase therapeutic effect and reduce the frequency of drug administration. In the literature there are reports concerning pharmacological studies in which a potentiation of the effects has been observed after a co-administration of antidepressant imipramine and magnesium. Currently, there is no formulation on the market comprising imipramine and magnesium, therefore, it was decided to produce uncoated tablets. In order to prepare the tablets by direct compression, it was necessary to select suitable excipients. The aim of the study was to elaborate the composition and to prepare the tablets with imipramine and magnesium, as well as to assess the quality of the tablets by physical characteristics and by the release study of the active substances. In order to prepare the tablets, compositions of different polymers and other excipients were added. The tablets were produced by direct compression method in a tablet press. Physical properties of the obtained tablets and the release of the active substances into an acidic medium in a paddle apparatus were tested. The contents of imipramine and magnesium were determined by different methods: spectrophotometrically and atomic absorption spectrometry, respectively. The composition of excipients necessary to produce tablets comprising imipramine and magnesium was established. All of prepared tablets were in compliance with the pharmacopoeial requirements. The release tests showed that above 80% of imipramine was released within 20-35 min and 80-76% of magnesium up to 45 min from the composed tablets and one-ingredient tablets, respectively. The compositions of excipients for tablets consisting of imipramine and magnesium were presented. The active substances were released within 45 min in the acidic medium, and the administration of these substances in the composed tablets did not affect pharmaceutical availability.

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.

Rapid method for protein quantitation by Bradford assay after elimination of the interference of polysorbate 80.

PubMed

Cheng, Yongfeng; Wei, Haiming; Sun, Rui; Tian, Zhigang; Zheng, Xiaodong

2016-02-01

Bradford assay is one of the most common methods for measuring protein concentrations. However, some pharmaceutical excipients, such as detergents, interfere with Bradford assay even at low concentrations. Protein precipitation can be used to overcome sample incompatibility with protein quantitation. But the rate of protein recovery caused by acetone precipitation is only about 70%. In this study, we found that sucrose not only could increase the rate of protein recovery after 1 h acetone precipitation, but also did not interfere with Bradford assay. So we developed a method for rapid protein quantitation in protein drugs even if they contained interfering substances. Copyright © 2015 Elsevier Inc. All rights reserved.

[Current situations and problem analysis of influencing factors of traditional Chinese medicine tablets on forming quality].

PubMed

Li, Yan-Nian; Wu, Zhen-Feng; Wan, Na; Li, Yuan-Hui; Li, Hui-Ting; Yang, Ming

2018-04-01

The compressibility of tablets is the essential operating unit during the preparation of traditional Chinese medicine tablets, as well as a complicated process. Therefore, it is of great significance to comprehensively study the influencing factors on the formation process. This paper aimed to review the evaluation methods for the tablet forming quality and highlight the effects of material powder properties, excipients and preparation technology on the quality of traditional Chinese medicine tablets on the basis of relevant literatures. Furthermore, the common problems in tablet forming process are also analyzed to provide useful references for the development of tablet forming quality of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

Water entrapment and structure ordering as protection mechanisms for protein structural preservation

NASA Astrophysics Data System (ADS)

Arsiccio, A.; Pisano, R.

2018-02-01

In this paper, molecular dynamics is used to further gain insight into the mechanisms by which typical pharmaceutical excipients preserve the protein structure. More specifically, the water entrapment scenario will be analyzed, which states that excipients form a cage around the protein, entrapping and slowing water molecules. Human growth hormone will be used as a model protein, but the results obtained are generally applicable. We will show that water entrapment, as well as the other mechanisms of protein stabilization in the dried state proposed so far, may be related to the formation of a dense hydrogen bonding network between excipient molecules. We will also present a simple phenomenological model capable of explaining the behavior and stabilizing effect provided by typical cryo- and lyo-protectants. This model uses, as input data, molecular properties which can be easily evaluated. We will finally show that the model predictions compare fairly well with experimental data.

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.

Quantitative (13)C Solid-State NMR Spectra by Multiple-Contact Cross-polarization for Drug Delivery: From Active Principles to Excipients and Drug Carriers.

PubMed

Saïdi, Fadila; Taulelle, Francis; Martineau, Charlotte

2016-08-01

In this contribution, we present an analysis of the main parameters influencing the efficiency of the (1)H → (13)C multiple-contact cross-polarization nuclear magnetic resonance (NMR) experiment in the context of solid pharmaceutical materials. Using the optimum experimental conditions, quantitative (13)C NMR spectra are then obtained for porous metal-organic frameworks (potential drug carriers) and for components present in drug formulations (active principle ingredient and excipients, amorphous or crystalline). Finally, we show that mixtures of components can also be quantified with this method and, hence, that it represents an ideal tool for quantification of pharmaceutical formulations by (13)C cross-polarization under magic-angle spinning NMR in the industry as it is robust and easy to set up, much faster than direct (13)C polarization and is efficient for samples at natural abundance. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Quantitation of active pharmaceutical ingredients and excipients in powder blends using designed multivariate calibration models by near-infrared spectroscopy.

PubMed

Li, Weiyong; Worosila, Gregory D

2005-05-13

This research note demonstrates the simultaneous quantitation of a pharmaceutical active ingredient and three excipients in a simulated powder blend containing acetaminophen, Prosolv and Crospovidone. An experimental design approach was used in generating a 5-level (%, w/w) calibration sample set that included 125 samples. The samples were prepared by weighing suitable amount of powders into separate 20-mL scintillation vials and were mixed manually. Partial least squares (PLS) regression was used in calibration model development. The models generated accurate results for quantitation of Crospovidone (at 5%, w/w) and magnesium stearate (at 0.5%, w/w). Further testing of the models demonstrated that the 2-level models were as effective as the 5-level ones, which reduced the calibration sample number to 50. The models had a small bias for quantitation of acetaminophen (at 30%, w/w) and Prosolv (at 64.5%, w/w) in the blend. The implication of the bias is discussed.

Pharmaceutical analysis in solids using front face fluorescence spectroscopy and multivariate calibration with matrix correction by piecewise direct standardization

NASA Astrophysics Data System (ADS)

Alves, Julio Cesar L.; Poppi, Ronei J.

2013-02-01

This paper reports the application of piecewise direct standardization (PDS) for matrix correction in front face fluorescence spectroscopy of solids when different excipients are used in a pharmaceutical preparation based on a mixture of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine. As verified in earlier studies, the use of different excipients and their ratio can cause a displacement, change in fluorescence intensity or band profile. To overcome this important drawback, a standardization strategy was adopted to convert all the excitation-emission fluorescence spectra into those used for model development. An excitation-emission matrix (EEM) for which excitation and emission wavelengths ranging from 265 to 405 nm and 300 to 480 nm, respectively, was used. Excellent results were obtained using unfolded partial least squares (U-PLS), with RMSEP values of 8.2 mg/g, 10.9 mg/g and 2.7 mg/g for ASA, paracetamol and caffeine, respectively, and with relative errors lesser than 5% for the three analytes.

Advanced qualification of pharmaceutical excipient suppliers by multiple analytics and multivariate analysis combined.

PubMed

Hertrampf, A; Müller, H; Menezes, J C; Herdling, T

2015-11-10

Pharmaceutical excipients have different functions within a drug formulation, consequently they can influence the manufacturability and/or performance of medicinal products. Therefore, critical to quality attributes should be kept constant. Sometimes it may be necessary to qualify a second supplier, but its product will not be completely equal to the first supplier product. To minimize risks of not detecting small non-similarities between suppliers and to detect lot-to-lot variability for each supplier, multivariate data analysis (MVA) can be used as a more powerful alternative to classical quality control that uses one-parameter-at-a-time monitoring. Such approach is capable of supporting the requirements of a new guideline by the European Parliament and Council (2015/C-95/02) demanding appropriate quality control strategies for excipients based on their criticality and supplier risks in ensuring quality, safety and function. This study compares calcium hydrogen phosphate from two suppliers. It can be assumed that both suppliers use different manufacturing processes. Therefore, possible chemical and physical differences were investigated by using Raman spectroscopy, laser diffraction and X-ray powder diffraction. Afterwards MVA was used to extract relevant information from each analytical technique. Both CaHPO4 could be discriminated by their supplier. The gained knowledge allowed to specify an enhanced strategy for second supplier qualification. Copyright © 2015 Elsevier B.V. All rights reserved.

Sensitive analytical method for simultaneous analysis of some vasoconstrictors with highly overlapped analytical signals

NASA Astrophysics Data System (ADS)

Nikolić, G. S.; Žerajić, S.; Cakić, M.

2011-10-01

Multivariate calibration method is a powerful mathematical tool that can be applied in analytical chemistry when the analytical signals are highly overlapped. The method with regression by partial least squares is proposed for the simultaneous spectrophotometric determination of adrenergic vasoconstrictors in decongestive solution containing two active components: phenyleprine hydrochloride and trimazoline hydrochloride. These sympathomimetic agents are that frequently associated in pharmaceutical formulations against the common cold. The proposed method, which is, simple and rapid, offers the advantages of sensitivity and wide range of determinations without the need for extraction of the vasoconstrictors. In order to minimize the optimal factors necessary to obtain the calibration matrix by multivariate calibration, different parameters were evaluated. The adequate selection of the spectral regions proved to be important on the number of factors. In order to simultaneously quantify both hydrochlorides among excipients, the spectral region between 250 and 290 nm was selected. A recovery for the vasoconstrictor was 98-101%. The developed method was applied to assay of two decongestive pharmaceutical preparations.

Zinc oxide as a new antimicrobial preservative of topical products: interactions with common formulation ingredients.

PubMed

Pasquet, Julia; Chevalier, Yves; Couval, Emmanuelle; Bouvier, Dominique; Bolzinger, Marie-Alexandrine

2015-02-01

Zinc oxide (ZnO) appears as a promising preservative for pharmaceutical or cosmetic formulations. The other ingredients of the formulations may have specific interactions with ZnO that alter its antimicrobial properties. The influence of common formulation excipients on the antimicrobial efficacy of ZnO has been investigated in simple model systems and in typical topical products containing a complex formulation. A wide variety of formulation excipients have been investigated for their interactions with ZnO: antioxidants, chelating agents, electrolytes, titanium dioxide pigment. The antimicrobial activity of ZnO against Escherichia coli was partially inhibited by NaCl and MgSO4 salts. A synergistic influence of uncoated titanium dioxide has been observed. The interference effects of antioxidants and chelating agents were quite specific. The interactions of these substances with ZnO particles and with the soluble species released by ZnO were discussed so as to reach scientific guidelines for the choice of the ingredients. The preservative efficacy of ZnO was assessed by challenge testing in three different formulations: an oil-in-water emulsion; a water-in-oil emulsion and a dry powder. The addition of ZnO in complex formulations significantly improved the microbiological quality of the products, in spite of the presence of other ingredients that modulate the antimicrobial activity. Copyright © 2014 Elsevier B.V. All rights reserved.

A direct HPLC method for the resolution and quantitation of the R-(-)- and S-(+)-enantiomers of vigabatrin (gamma-vinyl-GABA) in pharmaceutical dosage forms using teicoplanin aglycone chiral stationary phase.

PubMed

Al-Majed, Abdulrahman A

2009-08-15

A direct chiral high-performance liquid chromatography (HPLC) method was developed and validated for the resolution and quantification of antiepileptic drug enantiomers, R-(-)- and S-(+)-vigabatrin (gamma-vinyl-gamma-aminobutyric acid) in pharmaceutical products. The separation was optimized on a macrocyclic glycopeptide antibiotic chiral stationary phase (CSP) based on teicoplanin aglycone, chirobiotic (TAG), using a mobile phase system containing ethanol-water (80:20, v/v), at a flow rate of 0.4ml/min and UV detection set at 210nm. The stability of vigabatrin enantiomers under different degrees of temperature was also studied. The enantiomers of vigabatrin were separated from each other. The calibration curves were linear over a range of 100-1600microg/ml (r=0.999) for both enantiomers. The overall recoveries of R-(-)- and S-(+)-vigabatrin enantiomers from pharmaceutical products were in the range of 98.3-99.8% with %RSD ranged from 0.48 to 0.52%. The limit of quantification (LOQ) and limit of detection (LOD) for each enantiomer were 100 and 25microg/ml, respectively. No interferences were found from commonly co-formulated excipients.

Silver nanoparticles enhanced flow injection chemiluminescence determination of gatifloxacin in pharmaceutical formulation and spiked urine sample.

PubMed

Wabaidur, Saikh mohammad; Alam, Seikh Mafiz; Alothman, Zeid A; Mohsin, Kazi

2015-06-05

Silver nanoparticles have been utilized for the enhanced chemiluminogenic estimation of fluoroquinolone antibiotic gatifloxacin. It has been found that the weak chemiluminescence intensity produced from the reaction between calcein and KMnO4 can further be strengthened by the addition of silver nanoparticles in the presence of gatifloxacin. This phenomenon has been exploited to the quantitative determination of gatifloxacin. Under the optimum experimental conditions, the calibration curves are linear over the range of 8.9×10(-9)-4.0×10(-6) M, while the limits of detections were found to be 2.6×10(-9) M with correlation coefficient value (r(2)) 0.9999. The relative standard deviation calculated from six replicate measurements (1.0×10(-4) M gatifloxacin) was 1.70%. The method was applied to pharmaceutical preparations and the results obtained were in reasonable agreement with the amount labeled on the formulations. The proposed method was also used for the determination of gatifloxacin in spiked urine samples with satisfactory results. No interference effects from some common excipients used in pharmaceutical preparations have been found. Copyright © 2015 Elsevier B.V. All rights reserved.

Biochemical stabilization of glucagon at alkaline pH.

PubMed

Caputo, Nicholas; Jackson, Melanie A; Castle, Jessica R; El Youssef, Joseph; Bakhtiani, Parkash A; Bergstrom, Colin P; Carroll, Julie M; Breen, Matthew E; Leonard, Gerald L; David, Larry L; Roberts, Charles T; Ward, W Kenneth

2014-11-01

For patients with type 1 diabetes mellitus, a bihormonal artificial endocrine pancreas system utilizing glucagon and insulin has been found to stabilize glycemic control. However, commercially available formulations of glucagon cannot currently be used in such systems because of physical instability characterized by aggregation and chemical degradation. Storing glucagon at pH 10 blocks protein aggregation but results in chemical degradation. Reductions in pH minimize chemical degradation, but even small reductions increase protein aggregation. We hypothesized that common pharmaceutical excipients accompanied by a new excipient would inhibit glucagon aggregation at an alkaline pH. As measured by tryptophan intrinsic fluorescence shift and optical density at 630 nm, protein aggregation was indeed minimized when glucagon was formulated with curcumin and albumin. This formulation also reduced chemical degradation, measured by liquid chromatography with mass spectrometry. Biological activity was retained after aging for 7 days in an in vitro cell-based bioassay and also in Yorkshire swine. Based on these findings, a formulation of glucagon stabilized with curcumin, polysorbate-80, l-methionine, and albumin at alkaline pH in glycine buffer may be suitable for extended use in a portable pump in the setting of a bihormonal artificial endocrine pancreas.

Biochemical Stabilization of Glucagon at Alkaline pH

PubMed Central

Jackson, Melanie A.; Castle, Jessica R.; El Youssef, Joseph; Bakhtiani, Parkash A.; Bergstrom, Colin P.; Carroll, Julie M.; Breen, Matthew E.; Leonard, Gerald L.; David, Larry L.; Roberts, Charles T.; Ward, W. Kenneth

2014-01-01

Abstract Background: For patients with type 1 diabetes mellitus, a bihormonal artificial endocrine pancreas system utilizing glucagon and insulin has been found to stabilize glycemic control. However, commercially available formulations of glucagon cannot currently be used in such systems because of physical instability characterized by aggregation and chemical degradation. Storing glucagon at pH 10 blocks protein aggregation but results in chemical degradation. Reductions in pH minimize chemical degradation, but even small reductions increase protein aggregation. We hypothesized that common pharmaceutical excipients accompanied by a new excipient would inhibit glucagon aggregation at an alkaline pH. Methods and Results: As measured by tryptophan intrinsic fluorescence shift and optical density at 630 nm, protein aggregation was indeed minimized when glucagon was formulated with curcumin and albumin. This formulation also reduced chemical degradation, measured by liquid chromatography with mass spectrometry. Biological activity was retained after aging for 7 days in an in vitro cell-based bioassay and also in Yorkshire swine. Conclusions: Based on these findings, a formulation of glucagon stabilized with curcumin, polysorbate-80, l-methionine, and albumin at alkaline pH in glycine buffer may be suitable for extended use in a portable pump in the setting of a bihormonal artificial endocrine pancreas. PMID:24968220

Noninvasive authentication of pharmaceutical products through packaging using spatially offset Raman spectroscopy.

PubMed

Eliasson, Charlotte; Matousek, Pavel

2007-02-15

We demonstrate the use of spatially offset Raman spectroscopy (SORS) in the identification of counterfeit pharmaceutical tablets and capsules through different types of packaging. The technique offers a substantially higher sensitivity than that available from conventional backscattering Raman spectroscopy. The approach is particularly beneficial in situations where the conventional Raman backscattering method is hampered or fails because of excessive surface Raman or fluorescence signals emanating from the packaging, capsule shell, or tablet coating contaminating the much weaker subsurface Raman signals of the active pharmaceutical ingredients and excipients held in the product. It is demonstrated that such interfering signals can be effectively suppressed by SORS.

Study of formulation of mild pharmaceutical forms of paracetamol in medical practice.

PubMed

Abdullahu, Bedri; Morina, Naim; Islami, Hilmi

2012-01-01

Paracetamol is one of the most used antipyretic- analgesic preparation, which can be found in different pharmaceutical forms and in different doses. Due to its wide utilization in the clinical practice, determination of paracetamol in pharmaceutical formulation is of a great importance since that over dosage with paracetamol may cause the hepatic fulminant necroses and other toxic effects. Study has included two formulations of paracetamol suppositories with doses of 125 mg widely used in the paediatric practice. Suppositories prepared according to these two formulations by the melting method and spilling into forms was subject to the quality control by implementing a series of trials and analyses for that aim, such are: reactions of identification, average mass, disintegration time, and homogeneity whilst quantitative determination was performed by applying two methods of instrumental analyze: spectrophotometry in UV zone and cromatography in liquid phase with high pressure. Results of these analyses, performed immediately following the preparation and 3 months after the preparation, showed that content of paracetamol in both of two formulations is within the norms of Pharmacopoeia. Suppositories of paracetamol in doses of 125 mg prepared as per formulation 1 are to be considered as more appropriate because it contains semi synthetic glycerides as excipient which has better features than other suppository excipients.

Pharmaceutical acrylic beads obtained by suspension polymerization containing cellulose nanowhiskers as excipient for drug delivery.

PubMed

Villanova, J C O; Ayres, E; Carvalho, S M; Patrício, P S; Pereira, F V; Oréfice, R L

2011-03-18

Direct compression is one of the most popular techniques to prepare tablets but only a few commercial excipients are well adapted for this process into controlled release formulations. In the last years, the introduction of new materials for drug delivery matrix tablets has become more important. This paper evaluated the physicochemical and flow properties of new polymeric excipient of ethyl acrylate, methyl methacrylate and butyl metacrylate, synthesized by suspension polymerization using cellulose nanowhiskers as co-stabilizer, to be used as direct compression for modified release tablets. Infrared spectroscopy (FTIR) confirmed the success of the copolymerization reaction. Scanning electron microscopy (SEM) showed that excipient was obtained how spherical beads. Thermal properties of the beads were characterized by thermogravimetric (TG) analysis. Particle size analysis of the beads with cellulose nanowhiskers (CNWB) indicated that the presence of the nanowhiskers led to a reduction of particle size and to a narrower size distribution. In vitro test showed that the nanowhiskers and beads produced are nontoxic. Parameters such as Hausner ratio, Carr's index and cotangent of angle α were employed to characterize the flow properties of CNWB beads. Furthermore, the beads are used to produce tablets by direct compression contained propranolol hydrochloride as model drug. Dissolution tests performed suggested that beads could be used as excipient in matrix tablets with a potential use in drug controlled release. Copyright © 2011 Elsevier B.V. All rights reserved.

Determination of excipient based solubility increases using the CheqSol method.

PubMed

Etherson, Kelly; Halbert, Gavin; Elliott, Moira

2014-04-25

Aqueous solubility is an essential characteristic assessed during drug development to determine a compound's drug-likeness since solubility plays an important pharmaceutical role. However, nearly half of the drug candidates discovered today display poor water solubility; therefore methods have to be applied to increase solubility. Solubility determination using the CheqSol method is a novel rapid solubility screening technique for ionisable compounds. The aim of this study is to determine if the CheqSol method can be employed to determine solubility increases of four test drugs (ibuprofen, gliclazide, atenolol and propranolol) induced by non-ionising excipients such as hydroxypropyl-β-cyclodextrin and poloxamers 407 and 188. CheqSol assays were performed for the drugs alone or in combination with varying solubiliser concentrations. The measured intrinsic solubility of all four drugs increased with all the excipients tested in an excipient concentration dependent manner providing results consistent with previous literature. The results demonstrate that it may be possible to use this method to determine the solubility increases induced by non-ionic solubilising excipients with results that are comparable to standard equilibrium based solubility techniques. Since the technique is automated and requires only small drug quantities it may serve as a useful solubility or formulation screening tool providing more detailed physicochemical information than multiwell plate or similar visual systems. Copyright © 2014. Published by Elsevier B.V.

Designing excipient emulsions to increase nutraceutical bioavailability: emulsifier type influences curcumin stability and bioaccessibility by altering gastrointestinal fate.

PubMed

Zou, Liqiang; Liu, Wei; Liu, Chengmei; Xiao, Hang; McClements, David Julian

2015-08-01

The influence of emulsifier type on the ability of excipient emulsions to improve the solubility, stability, and bioaccessibility of powdered curcumin was examined. Oil-in-water emulsions prepared using three different emulsifiers (whey protein isolate, caseinate, or Tween 80) were mixed with curcumin powder and then incubated at either 30 °C (to simulate applications of salad dressings) or 100 °C (to simulate applications of cooking sauces). The transfer of curcumin into the excipient emulsions was appreciably higher for excipient emulsions held at 100 °C than those held at 30 °C, and was appreciably higher for surfactant-stabilized emulsions than protein-stabilized emulsions. For example, the amounts of curcumin transferred into emulsions held at 30 and 100 °C were 66 and 280 μg mL(-1) for Tween 80, but only 17 and 208 μg mL(-1) for caseinate. The total curcumin concentration in the digesta and mixed micelle phases collected after excipient emulsions were exposed to a simulated gastrointestinal tract (mouth, stomach, and small intestine) depended on emulsifier type. The total amount of curcumin within the digesta was higher for protein-stabilized emulsions than surfactant-stabilized ones, which was attributed to the ability of the proteins to protect curcumin from chemical degradation. For example, the digesta contained 204 μg mL(-1) curcumin for caseinate emulsions, but only 111 μg mL(-1) for Tween 80 emulsions. This study shows the potential of designing excipient emulsions to increase the oral bioavailability of curcumin for food and pharmaceutical applications.

A validated spectrofluorimetric method for the determination of citalopram in bulk and pharmaceutical preparations based on the measurement of the silver nanoparticles-enhanced fluorescence of citalopram/terbium complexes.

PubMed

Khan, Muhammad Naeem; Shah, Jasmin; Jan, Muhammad Rasul; Lee, Sang Hak

2013-01-01

A simple, sensitive, and accurate spectrofluorimetric method was developed for the determination of citalopram in bulk and pharmaceutical preparations. The method is based on the enhancement of the weak fluorescence signal (FL) of the Tb (III)-citalopram system in the presence of silver nanoparticles. Fluorescence intensities were measured at 555 nm after excitation at 281 nm. Prepared silver nanoparticles (AgNPs) were characterized by UV-Visible spectra and transmission electron microscopy (TEM). Various factors affecting the formation of citalopram-Tb (III)-AgNPs complexes were studied and optimized. The fluorescence intensity versus concentration plot was linear over the range 0.02-14 μg mL(-1), with an excellent correlation coefficient of 0.9978. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 7.15 × 10(-6) μg mL(-1) and 2.38 × 10(-5) μg mL(-1) respectively. The proposed method was found to have good reproducibility with a relative standard deviation of 3.66% (n = 6). The interference effects of common excipients found in pharmaceutical preparations were studied. The developed method was validated statistically by performing recoveries studies and successfully applied for the assay of citalopram in bulk powder and pharmaceutical preparations. Percent recoveries were found to range from 98.98% to 100.97% for bulk powder and from 96.57% to 101.77% for pharmaceutical preparations.

Extraction and Characterization of Boswellia Serrata Gum as Pharmaceutical Excipient.

PubMed

Panta, Sumedha; Malviya, Rishabha; Sharma, Pramod

2015-01-01

This manuscript deals with the purification and characterization of Boswellia serrata gum as a suspending agent. The Boswellia serrata gum was purchased as crude material, purified and further characterized in terms of organoleptic properties and further micromeritic studies were carried out to characterize the polymer as a pharmaceutical excipient. The suspending properties of the polymer were also evaluated. The results showed that the extracted gum possesses optimum organoleptic as well as micromeritic and suspending properties. To characterize Boswellia serrata gum as a natural excipient. Boswellia serrata gum, paracetamol, distilled water. The results showed that the extracted gum possesses optimum organoleptic as well as micromeritic and suspending properties. It is concluded from the research work that the gum extracted from Boswellia serrata shows the presence of carbohydrates after chemical tests. All the organoleptic properties evaluated were found to be acceptable. The pH was found to be slightly acidic. Swelling Index reveals that the gum swells well in water. Total ash value was within the limits. The values of angle of repose and Carr's Index of powdered gum powder showed that the flow property was good. IR spectra confirmed the presence of alcohol, amines, ketones, anhydrides and aromatic rings. The suspending properties of Boswellia serrata gum were found to be higher as compared to gum acacia while the flow rate of Boswellia serrata gum (1% suspension) was less than gum acacia (1% suspension). The viscosity measurement of both Boswellia serrata gum suspension and gum acacia suspension showed approximately similar results.

Indinavir-loaded pH-sensitive microparticles for taste masking: toward extemporaneous pediatric anti-HIV/AIDS liquid formulations with improved patient compliance.

PubMed

Chiappetta, Diego A; Carcaboso, Angel M; Bregni, Carlos; Rubio, Modesto; Bramuglia, Guillermo; Sosnik, Alejandro

2009-01-01

The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads approximately 15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7-1.5 g).

Bolaamphiphiles: A Pharmaceutical Review

PubMed Central

Fariya, Mayur; Jain, Ankitkumar; Dhawan, Vivek; Shah, Sanket; Nagarsenker, Mangal S.

2014-01-01

The field of drug discovery is ever growing and excipients play a major role in it. A novel class of amphiphiles has been discussed in the review. The review focuses on natural as well as synthetic bolaamphiphiles, their chemical structures and importantly, their ability to self assemble rendering them of great use to pharmaceutical industry. Recent reports on their ability to be used in fabrication of suitable nanosized carriers for drug as well as genes to target site, has been discussed substantially to understand the potential of bolaamphiphiles in field of drug delivery. PMID:25671179

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.

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.

Identification of Protein–Excipient Interaction Hotspots Using Computational Approaches

PubMed Central

Barata, Teresa S.; Zhang, Cheng; Dalby, Paul A.; Brocchini, Steve; Zloh, Mire

2016-01-01

Protein formulation development relies on the selection of excipients that inhibit protein–protein interactions preventing aggregation. Empirical strategies involve screening many excipient and buffer combinations using force degradation studies. Such methods do not readily provide information on intermolecular interactions responsible for the protective effects of excipients. This study describes a molecular docking approach to screen and rank interactions allowing for the identification of protein–excipient hotspots to aid in the selection of excipients to be experimentally screened. Previously published work with Drosophila Su(dx) was used to develop and validate the computational methodology, which was then used to determine the formulation hotspots for Fab A33. Commonly used excipients were examined and compared to the regions in Fab A33 prone to protein–protein interactions that could lead to aggregation. This approach could provide information on a molecular level about the protective interactions of excipients in protein formulations to aid the more rational development of future formulations. PMID:27258262

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.

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.

Determination of the pseudoephedrine content in pharmaceutical formulations and in biological fluids using a microbore HPLC system interfaced to a microfluidic chemiluminescence detector.

PubMed

Kadavilpparampu, Afsal Mohammed; Al-Lawati, Haider A J; Suliman, FakhrEldin O; Al Kindy, Salma M Z

2015-12-01

A novel automated precolumn derivatization followed by separation using liquid chromatography for the determination of pseudoephedrine (PSE) by a microfluidic chemiluminescence detector has been developed. An on-line derivatization procedure was utilized by converting PSE into a highly light emitting species in a Ru(bipy)3(2+)-peroxydisulphate chemiluminescence (CL) system by derivatizing it with a 1.0 M formaldehyde solution. The derivatized analyte was directly injected into a microbore high-performance liquid chromatography (HPLC) system coupled to an on-chip chemiluminescence detector. The newly developed highly selective, sensitive and fast HPLC-CL method was validated and successfully applied for the analysis of PSE in pharmaceutical formulations and a human urine sample. The selectivity of the method is not only due to the HPLC separation but is also due to the highly selective detection principle of the Ru(bipy)3(2+)-peroxydisulphate CL system used. There was no interference observed from the common preservatives and excipients used in pharmaceutical preparations, which did not show any significant CL signal. The retention time of PSE was less than 3 min, and the detection limits and quantification limits were found to be 5.7 and 26.0 µg L(-1), respectively. Copyright © 2015 John Wiley & Sons, Ltd.

Studying the association complex formation of atomoxetine and fluvoxamine with eosin Y and its application in their fluorimetric determination

NASA Astrophysics Data System (ADS)

Derayea, Sayed M.; Omar, Mahmoud A.; Abu-hassan, Ahmed A.

2018-03-01

A simple, sensitive and non-extractive spectrofluorimetric method has been developed and validated for the determination of two psychoanaleptic drugs, atomoxetine and fluvoxamine, in pure forms and pharmaceutical dosage forms. The proposed method is based on the formation of binary complexes between eosin Y and the studied drugs in the presence of a Teorell-Stenhagen buffer. The quenching of the native fluorescence of eosin Y due to complex formation with the studied drugs was measured spectrofluorimetrically at 545 nm after excitation at 302 nm. At the optimum reaction conditions, the fluorescence quenching values (ΔF) and concentrations were rectilinear over the concentration ranges of 0.2-2.2 and 0.3-2.2 µg ml-1 for atomoxetine and fluvoxamine, respectively. The developed method was successfully applied for the determination of the studied drugs in their pharmaceutical formulations with average percentage recoveries of 100.13 ± 0.66 and 99.69 ± 0.44 for atomoxetine and fluvoxamine, respectively (n = 5), without interference from common excipients.

Studying the association complex formation of atomoxetine and fluvoxamine with eosin Y and its application in their fluorimetric determination

PubMed Central

Omar, Mahmoud A.; Abu-hassan, Ahmed A.

2018-01-01

A simple, sensitive and non-extractive spectrofluorimetric method has been developed and validated for the determination of two psychoanaleptic drugs, atomoxetine and fluvoxamine, in pure forms and pharmaceutical dosage forms. The proposed method is based on the formation of binary complexes between eosin Y and the studied drugs in the presence of a Teorell–Stenhagen buffer. The quenching of the native fluorescence of eosin Y due to complex formation with the studied drugs was measured spectrofluorimetrically at 545 nm after excitation at 302 nm. At the optimum reaction conditions, the fluorescence quenching values (ΔF) and concentrations were rectilinear over the concentration ranges of 0.2–2.2 and 0.3–2.2 µg ml−1 for atomoxetine and fluvoxamine, respectively. The developed method was successfully applied for the determination of the studied drugs in their pharmaceutical formulations with average percentage recoveries of 100.13 ± 0.66 and 99.69 ± 0.44 for atomoxetine and fluvoxamine, respectively (n = 5), without interference from common excipients. PMID:29657744

A structural investigation into the compaction behavior of pharmaceutical composites using powder X-ray diffraction and total scattering analysis.

PubMed

Moore, Michael D; Steinbach, Alison M; Buckner, Ira S; Wildfong, Peter L D

2009-11-01

To use advanced powder X-ray diffraction (PXRD) to characterize the structure of anhydrous theophylline following compaction, alone, and as part of a binary mixture with either alpha-lactose monohydrate or microcrystalline cellulose. Compacts formed from (1) pure theophylline and (2) each type of binary mixture were analyzed intact using PXRD. A novel mathematical technique was used to accurately separate multi-component diffraction patterns. The pair distribution function (PDF) of isolated theophylline diffraction data was employed to assess structural differences induced by consolidation and evaluated by principal components analysis (PCA). Changes induced in PXRD patterns by increasing compaction pressure were amplified by the PDF. Simulated data suggest PDF dampening is attributable to molecular deviations from average crystalline position. Samples compacted at different pressures were identified and differentiated using PCA. Samples compacted at common pressures exhibited similar inter-atomic correlations, where excipient concentration factored in the analyses involving lactose. Practical real-space structural analysis of PXRD data by PDF was accomplished for intact, compacted crystalline drug with and without excipient. PCA was used to compare multiple PDFs and successfully differentiated pattern changes consistent with compaction-induced disordering of theophylline as a single component and in the presence of another material.

Induction of oxidative stress by Taxol® vehicle Cremophor-EL triggers production of interleukin-8 by peripheral blood mononuclear cells through the mechanism not requiring de novo synthesis of mRNA.

PubMed

Ilinskaya, Anna N; Clogston, Jeffrey D; McNeil, Scott E; Dobrovolskaia, Marina A

2015-11-01

Understanding the ability of cytotoxic oncology drugs, and their carriers and formulation excipients, to induce pro-inflammatory responses is important for establishing safe and efficacious formulations. Literature data about cytokine response induction by the traditional formulation of paclitaxel, Taxol®, are controversial, and no data are available about the pro-inflammatory profile of the nano-albumin formulation of this drug, Abraxane®. Herein, we demonstrate and explain the difference in the cytokine induction profile between Taxol® and Abraxane®, and describe a novel mechanism of cytokine induction by a nanosized excipient, Cremophor EL, which is not unique to Taxol® and is commonly used in the pharmaceutical industry for delivery of a wide variety of small molecular drugs. Advances in nanotechnology have enabled the production of many nano-formulation drugs. The cellular response to drugs has been reported to be different between traditional and nano-formulations. In this article, the authors investigated and compared cytokine response induction profiles between Taxol® and Abraxane®. The findings here provided further understanding to create drugs with better safety profiles. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of drug particle size in ultrasound compacted tablets. Continuum percolation model approach.

PubMed

Millán, Mónica; Caraballo, Isidoro

2006-03-09

The main objective of this work is to study the influence of the drug particle size on the pharmaceutical availability of ultrasound compacted tablets. Inert matrix systems containing different drug particle sizes were prepared using both, an ultrasound-assisted press and a traditional eccentric machine. Potassium chloride was used as drug model and Eudragit RS-PM as matrix forming excipient. The excipient particle size was kept constant. The cross-sectional microphotographs of ultrasound tablets show the existence of a quasi-continuum medium. Keeping constant the drug load, US-tablets showed very similar release rates, whereas for traditional tablets, an increase in the particle size resulted in a clear decrease in the release rate. In these tablets, the excipient forms an almost continuum medium. In an infinite theoretical system of these characteristics, the size of the drug particles will not modify the percolation threshold. The percolation of the excipient in this system can be assimilated to a continuum percolation model. In accordance with the proposed model, a lower influence of the drug particle size on the drug release rate was obtained for the US-tablets in comparison with traditional tablets. This fact can be indicative of the similarity of the drug percolation thresholds in these systems.

Harmful excipients in medicines for neonates in Spain.

PubMed

Garcia-Palop, Beatriz; Movilla Polanco, Emma; Cañete Ramirez, Carmen; Cabañas Poy, Maria Jose

2016-04-01

Neonates may respond differently from adults to drug components. Hence, ingredients that seem safe in adults may not be safe in this age group. To describe the content of harmful excipients in drugs used in our neonatal wards and compare the daily dose a neonate may receive with the accepted daily intake (ADI) in adults. All drugs included in the hospital's neonatal treatment guide were reviewed, using information from the package inserts or the summary of product characteristics. Those containing at least one harmful excipient (e.g., metabisulfite, sorbitol) were analyzed. Minimum and maximum usual daily drug doses were determined, and excipient exposure was estimated by extrapolation of the minimum and maximum of excipient referred to the active ingredient. These amounts were compared with ADIs for each excipient in adults. In total, 32 % of intravenous and 62 % of oral formulations used in neonates contained at least one harmful excipient. On quantitative analysis, 25 % of intravenous and 19 % of oral drugs contained harmful excipients exceeding the ADI in adults. Several drugs commonly used to treat neonates contain harmful excipients in amounts that may exceed the ADI in adults. Clinicians should be aware of this to prescribe appropriate treatment in this population.

Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.

PubMed

Wirth, D D; Baertschi, S W; Johnson, R A; Maple, S R; Miller, M S; Hallenbeck, D K; Gregg, S M

1998-01-01

Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearrangement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characterization of this reduced adduct. The lactose-fluoxetine HCl reaction was examined in aqueous ethanol and in the solid state, in which factors such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug-excipient interaction since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4 H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found; however, at least one product decomposed at a rate nearly 10 times that predicted from the simple models. Maillard products have also been identified in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amines or their salts, just as it currently is for primary amines.

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.

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.

[Comprehensive analysis on "toxicity and effect" of Chinese pharmaceutical preparations].

PubMed

Hu, Hui-Ling; Fu, Chao-Mei; Zhao, Xuan; Zhang, Jin-Ming; Gao, Fei; He, Yao; Fu, Shu; Li, Ling

2016-09-01

The manufacturing process of Chinese medicines is the significant link to achieve "effect-enhancing and toxicity-reducing", including an interaction between "toxicity and effect". This paper would elucidate the effects of Chinese herbal compound decoction, preparation, dosage forms, route of administration and quality of pharmaceutical excipients on "toxicity-effect" theory from the formulation approaches. The article pointed out that the comprehensive analysis on "toxicity-effect" theory should be strengthened from the aspects of overall manufacturing, fundamental research and modern Chinese preparation, to explore the mechanism of "effect-enhancing and toxicity-reducing" in the manufacturing process, clarify the core status of Chinese preparation in "toxicity-effect" theory, and ensure the security and effectiveness in traditional Chinese medicine clinical application. Copyright© by the Chinese Pharmaceutical Association.

Development of a gas chromatography method for the determination of isotretinoin and its degradation products in pharmaceuticals.

PubMed

Lima, Eliana Martins; Diniz, Danielle G Almeida; Antoniosi-Filho, Nelson R

2005-07-15

This paper describes the development of a gas chromatography (GC) method used for the assay of isotretinoin in its isolated form and in pharmaceutical formulations. Isotretinoin soft and hard gelatin capsules were prepared with various excipients. The performance of the proposed gas chromatography method was compared to that of traditional high performance liquid chromatography (HPLC) systems for this substance, and the GC parameters were established based on several preliminary tests, including thermal analysis of isotretinoin. Results showed that gas chromatography-flame ionization detector (GC-FID) exhibited a separation efficiency superior to that of HPLC, particularly for separating isotretinoin degradation products. This method was proven to be effectively applicable to stability evaluation assays of isotretinoin and isotretinoin based pharmaceuticals.

[Oral disintegrating tablets. A new, modern, solid dosage form].

PubMed

Popa, Graţiela; Gafiţanu, Eliza

2003-01-01

The pharmaceutical market shows lately an increasing interest in orally disintegrating tablets, due to their good acceptability among certain age categories (ex. elderly, children), and other patients with difficulties in swallowing classic solid dosage forms. Some of the methods of preparing such tablets have gained industrial applicability: molding, lyophilization, direct compression with highly soluble excipients, super disintegrants and/or effervescent systems. Some of the patients have had a good impact on the pharmaceutical market and more improvements are expected in the next few years, with new drugs to be formulated as fast dissolving dosage formulations.

Safe excipient exposure in neonates and small children - protocol for the SEEN project.

PubMed

Valeur, Kristine Svinning; Hertel, Steen Axel; Lundstrøm, Kaare Engell; Holst, Helle

2017-02-01

The pharmacokinetics of excipients in neonates differs from that of older children. In a recent pan--European survey, two thirds of neonates received at least one potentially harmful excipient, such as ethanol and benzoates. The content of sweeteners varied by route of administration (more common by enteral than parenteral route), and regional differences were revealed. The survey did not identify if the content of excipients was more pronounced in medications prescribed for specific medical diseases, e.g. more common in cardiovascular conditions than lung diseases. Furthermore, the quantitative amount of e.g. ethanol in the multi-medicated neonate has not been investigated. The aim of the present study was to quantify the total amount of excipients administered to poly-medicated neonatal and paediatric patients during hospitalisation; and to investigate if any particular medical diseases are treated with potentially harmful excipients. This is a retrospective cohort study based on chart-audit on multi-medicated patients ≤ 5 years of age treated at the Rigshospitalet, Denmark. Preparations with ethanol, propylene glycol, benzyl alcohol, parabens, acesulfame p, aspartame, glycerol, sorbitol and polysorbate-80 will be recorded and cumulative amounts will be calculated. By quantifying the amount of harmful excipients to which paediatric patients are exposed, the study will contribute to a risk/benefit assessment of the medication standards of neonatal and paediatric patients. The Danish Council for Independent Research, grant-id: DFF - 6110-00266. This study was registered at clinicaltrials.gov (reg. no. NCT02545712).

The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers.

PubMed

Parr, Alan; Hidalgo, Ismael J; Bode, Chris; Brown, William; Yazdanian, Mehran; Gonzalez, Mario A; Sagawa, Kazuko; Miller, Kevin; Jiang, Wenlei; Stippler, Erika S

2016-01-01

Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

Spectrofluorimetric determination of fluoroquinolones in pharmaceutical preparations.

PubMed

Ulu, Sevgi Tatar

2009-02-01

Simple, rapid and highly sensitive spectrofluorimetric method is presented for the determination of four fluoroquinolone (FQ) drugs, ciprofloxacin, enoxacin, norfloxacin and moxifloxacin in pharmaceutical preparations. Proposed method is based on the derivatization of FQ with 4-chloro-7-nitrobenzofurazan (NBD-Cl) in borate buffer of pH 9.0 to yield a yellow product. The optimum experimental conditions have been studied carefully. Beer's law is obeyed over the concentration range of 23.5-500 ng mL(-1) for ciprofloxacin, 28.5-700 ng mL(-1) for enoxacin, 29.5-800 ng mL(-1) for norfloxacin and 33.5-1000 ng mL(-1) for moxifloxacin using NBD-Cl reagent, respectively. The detection limits were found to be 7.0 ng mL(-1) for ciprofloxacin, 8.5 ng mL(-1) for enoxacin, 9.2 ng mL(-1) for norfloxacin and 9.98 ng mL(-1) for moxifloxacin, respectively. Intra-day and inter-day relative standard deviation and relative mean error values at three different concentrations were determined. The low relative standard deviation values indicate good precision and high recovery values indicate accuracy of the proposed methods. The method is highly sensitive and specific. The results obtained are in good agreement with those obtained by the official and reference method. The results presented in this report show that the applied spectrofluorimetric method is acceptable for the determination of the four FQ in the pharmaceutical preparations. Common excipients used as additives in pharmaceutical preparations do not interfere with the proposed method.

Formation of oligonucleotide adducts in pharmaceutical formulations.

PubMed

Krotz, Achim H; Gaus, Hans; Hardee, Gregory E

2005-01-01

During preformulation studies, we observed that oligonucleotide extracted from topical formulations contained considerable amounts of covalently modified oligonucleotide adducts. In this report, we describe the identification and characterization of reaction products that form when PS-oligodeoxyribonucleotide ISIS 2302 (1) is brought into contact with aqueous solutions of glycerol-derived excipients. Compatibility tests showed that the presence of certain glycerides in the formulation lead to adduct formation (1+58x amu, 1+72x amu, 1+58x+72y amu, x, and y are the number of modifications on one oligonucleotide strand). No adduct formation was observed in the presence of triglycerides or propylene glycol-derived excipients used in the study. Using nucleosides as model compounds, two modifications of deoxyguanosine were isolated by preparative reversed phase (RP)-high pressure liquid chromatography (HPLC) and characterized by nuclear magnetic resonance (NMR) and HPLC-mass spectrometry (MS). Modifications were identified as N2-(1-carboxymethyl)- and N2-(1-carboxyethyl) derivatives of 2'-deoxyguanosine. The mechanism of formation of these adducts may involve advanced glycation reactions possibly caused by excipient impurities or degradation products such as glyceraldehyde or glyceraldehyde derivatives.

EXCI-CEST: Exploiting pharmaceutical excipients as MRI-CEST contrast agents for tumor imaging.

PubMed

Longo, Dario Livio; Moustaghfir, Fatima Zzahra; Zerbo, Alexandre; Consolino, Lorena; Anemone, Annasofia; Bracesco, Martina; Aime, Silvio

2017-06-15

Chemical Exchange Saturation Transfer (CEST) approach is a novel tool within magnetic resonance imaging (MRI) that allows visualization of molecules possessing exchangeable protons with water. Many molecules, employed as excipients for the formulation of finished drug products, are endowed with hydroxyl, amine or amide protons, thus can be exploitable as MRI-CEST contrast agents. Their high safety profiles allow them to be injected at very high doses. Here we investigated the MRI-CEST properties of several excipients (ascorbic acid, sucrose, N-acetyl-d-glucosamine, meglumine and 2-pyrrolidone) and tested them as tumor-detecting agents in two different murine tumor models (breast and melanoma cancers). All the investigated molecules showed remarkable CEST contrast upon i.v. administration in the range 1-3ppm according to the type of mobile proton groups. A marked increase of CEST contrast was observed in tumor regions up to 30min post injection. The combination of marked tumor contrast enhancement and lack of toxicity make these molecules potential candidates for the diagnosis of tumors within the MRI-CEST approach. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems.

PubMed

Gurram, A K; Deshpande, P B; Kar, S S; Nayak, Usha Y; Udupa, N; Reddy, M S

2015-01-01

Pharmaceutical research is focused in designing novel drug delivery systems to improve the bioavailability of poorly water soluble drugs. Self-microemulsifying drug delivery systems, one among the lipid-based dosage forms were proven to be promising in improving the oral bioavailability of such drugs by enhancing solubility, permeability and avoiding first-pass metabolism via enhanced lymphatic transport. Further, they have been successful in avoiding both inter and intra individual variations as well as the dose disproportionality. Aqueous insoluble drugs, in general, show greater solubility in lipid based excipients, and hence they are formulated as lipid based drug delivery systems. The extent of solubility of a hydrophobic drug in lipid excipients i.e. oil, surfactant and co-surfactant (components of self-microemulsifying drug delivery systems) greatly affects the drug loading and in producing stable self-microemulsifying drug delivery systems. The present review highlighted the influence of physicochemical factors and structural features of the hydrophobic drug on its solubility in lipid excipients and an attempt was made to explore the role of each component of self-microemulsifying drug delivery systems in the formation of stable microemulsion upon dilution.

Oromucosal film preparations: points to consider for patient centricity and manufacturing processes.

PubMed

Krampe, Raphael; Visser, J Carolina; Frijlink, Henderik W; Breitkreutz, Jörg; Woerdenbag, Herman J; Preis, Maren

2016-01-01

According to the European Pharmacopoeia, oromucosal films comprise mucoadhesive buccal films and orodispersible films. Both oral dosage forms receive considerable interest in the recent years as commercially available pharmaceutical products and as small scale personalized extemporaneous preparations. In this review, technological issues such as viscosity of the casting liquid, mechanical properties of the film, upscaling and the stability of the casting solution and produced films will be discussed. Furthermore, patient-related problems like appearance, mucosal irritation, taste, drug load, safety and biopharmaceutics are described. Current knowledge and directions for solutions are summarized. The viscosity of the casting solution is a key factor for producing suitable films. This parameter is amongst others dependent on the polymer and active pharmaceutical ingredient, and the further excipients that are used. For optimal patient compliance, an acceptable taste and palatability are desirable. Safe and inert excipients should be used and appropriate packaging should be provided to produced films. Absorption through the oral mucosa will vary for each active compound, formulation and patient, which gives rise to pharmacokinetic questions. Finally, the European Pharmacopoeia needs to specify methods, requirement and definitions for oromucosal film preparations based on bio-relevant data.

New approaches with two cyano columns to the separation of acetaminophen, phenylephrine, chlorpheniramine and related compounds.

PubMed

Olmo, B; García, A; Marín, A; Barbas, C

2005-03-25

The development of new pharmaceutical forms with classical active compounds generates new analytical problems. That is the case of sugar-free sachets of cough-cold products containing acetaminophen, phenylephrine hydrochloride and chlorpheniramine maleate. Two cyanopropyl stationary phases have been employed to tackle the problem. The Discovery cyanopropyl (SUPELCO) column permitted the separation of the three actives, maleate and excipients (mainly saccharine and orange flavour) with a constant proportion of aqueous/ organic solvent (95:5, v/v) and a pH gradient from 7.5 to 2. The run lasted 14 min. This technique avoids many problems related to baseline shifts with classical organic solvent gradients and opens great possibilities to modify selectivity not generally used in reversed phase HPLC. On the other hand, the Agilent Zorbax SB-CN column with a different retention profile permitted us to separate not only the three actives and the excipients but also the three known related compounds: 4-aminophenol, 4-chloracetanilide and 4-nitrophenol in an isocratic method with a run time under 30 min. This method was validated following ICH guidelines and validation parameters showed that it could be employed as stability-indicating method for this pharmaceutical form.

Suberin Fatty Acids from Outer Birch Bark: Isolation and Physical Material Characterization.

PubMed

Heinämäki, Jyrki; Pirttimaa, Minni M; Alakurtti, Sami; Pitkänen, H Pauliina; Kanerva, Heimo; Hulkko, Janne; Paaver, Urve; Aruväli, Jaan; Yliruusi, Jouko; Kogermann, Karin

2017-04-28

The isolation and physical material properties of suberin fatty acids (SFAs) were investigated with special reference to their potential applications as novel pharmaceutical excipients. SFAs were isolated from outer birch bark (OBB) with a new extractive hydrolysis method. The present simplified isolation process resulted in a moderate batch yield and chemical purity of SFAs, but further development is needed for establishing batch-to-batch variation. Cryogenic milling was the method of choice for the particle size reduction of SFAs powder. The cryogenically milled SFAs powder exhibited a semicrystalline structure with apparent microcrystalline domains within an amorphous fatty acids matrix. The thermogravimetric analysis (TGA) of SFAs samples showed a good thermal stability up to 200 °C, followed by a progressive weight loss, reaching a plateau at about 95% volatilization at about 470 °C. The binary blends of SFAs and microcrystalline cellulose (MCC; Avicel PH 101) in a ratio of 25:75 (w/w) displayed good powder flow and tablet compression properties. The corresponding theophylline-containing tablets showed sustained or prolonged-release characteristics. The physicochemical and bulk powder properties of SFAs isolated from OBB are auspicious in terms of potential pharmaceutical excipient applications.

[Efficient Pharmaceutical Formulation Designs and Their Development Using Mathematical and Statistical Analysis].

PubMed

Iwao, Yasunori

2015-01-01

With the aim of directly predicting the functionality and mechanism of pharmaceutical excipients, we investigated an analysis method based on available surface area (S(t)), which is the surface area of a drug in direct contact with the external solvent during dissolution. First, to study the effect of lubricant concentration on the dissolution rate of acetaminophen (APAP), the dissolution behaviors as well as the change over time in S(t) of APAP tablets were examined. In the dissolution tests, a retarded dissolution of APAP was not observed with new lubricant triglycerin full behenate (TR-FB), whereas magnesium stearate (Mg-St) retarded the dissolution. The S(t) profiles for APAP with Mg-St at>0.5% showed downward curvature indicating a gradual decrease in surface area over time. Conversely, with TR-FB, even when its concentration was increased, the S(t) profile for APAP had a maximum value. The differences between Mg-St and TR-FB could be explained by the differences in extensibility deriving from their morphology. Next, we evaluated the effect of disintegtant concentration using five disintegrants. When disintegrant was added to ethenzamide tablet formulation, an increase in the dissolution rate and S(t) dependent on disintegrant concentration was observed, according to the type of disintegrant. It was found that the water absorption ability of disintegrants had strong correlations with the parameters of S(t). Taken together, this study demonstrates that analysis of S(t) can directly provide useful information, especially about the functionality of pharmaceutical excipients.

A Proposed In Vitro Method to Assess Effects of Inhaled Particles on Lung Surfactant Function.

PubMed

Sørli, Jorid B; Da Silva, Emilie; Bäckman, Per; Levin, Marcus; Thomsen, Birthe L; Koponen, Ismo K; Larsen, Søren T

2016-03-01

The lung surfactant (LS) lining is a thin liquid film covering the air-liquid interface of the respiratory tract. LS reduces surface tension, enabling lung surface expansion and contraction with minimal work during respiration. Disruption of surface tension is believed to play a key role in severe lung conditions. Inhalation of aerosols that interfere with the LS may induce a toxic response and, as a part of the safety assessment of chemicals and inhaled medicines, it may be relevant to study their impact on LS function. Here, we present a novel in vitro method, based on the constrained drop surfactometer, to study LS functionality after aerosol exposure. The applicability of the method was investigated using three inhaled asthma medicines, micronized lactose, a pharmaceutical excipient used in inhaled medication, and micronized albumin, a known inhibitor of surfactant function. The surfactometer was modified to allow particles mixed in air to flow through the chamber holding the surfactant drop. The deposited dose was measured with a custom-built quartz crystal microbalance. The alterations allowed the study of continuously increasing quantified doses of particles, allowing determination of the dose of particles that affects the LS function. The tested pharmaceuticals did not inhibit the function of a model LS even at extreme doses--neither did lactose. Micronized albumin, however, impaired surfactant function. The method can discriminate between safe inhaled aerosols--as exemplified by the approved inhaled medicines and the pharmaceutical excipient lactose--and albumin known to impair lung functionality by inhibiting LS function.

A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures.

PubMed

Reynolds, Gavin K; Campbell, Jacqueline I; Roberts, Ron J

2017-10-05

A new model to predict the compressibility and compactability of mixtures of pharmaceutical powders has been developed. The key aspect of the model is consideration of the volumetric occupancy of each powder under an applied compaction pressure and the respective contribution it then makes to the mixture properties. The compressibility and compactability of three pharmaceutical powders: microcrystalline cellulose, mannitol and anhydrous dicalcium phosphate have been characterised. Binary and ternary mixtures of these excipients have been tested and used to demonstrate the predictive capability of the model. Furthermore, the model is shown to be uniquely able to capture a broad range of mixture behaviours, including neutral, negative and positive deviations, illustrating its utility for formulation design. Copyright © 2017 Elsevier B.V. All rights reserved.

Supercritical fluid technologies: an innovative approach for manipulating the solid-state of pharmaceuticals.

PubMed

Pasquali, Irene; Bettini, Ruggero; Giordano, Ferdinando

2008-02-14

Solid-state, crystallographic purity and careful monitoring of the polymorphism of drugs and excipients are currently an integral part of the development of modern drug delivery systems. The reproducible preparation of organic crystals in a specific form and size is a major issue that must be addressed. A recent approach for obtaining pharmaceutical materials in pure physical form is represented by the technologies based on supercritical fluids. The present work aims to provide a critical review of the recent advances in the use of supercritical fluids for the preparation and control of the specific physical form of pharmaceutical substances with particular attention to those fluids used for drug delivery systems. These innovative technologies are highly promising for future application in particle design and engineering.

Fast and non-destructive pore structure analysis using terahertz time-domain spectroscopy.

PubMed

Markl, Daniel; Bawuah, Prince; Ridgway, Cathy; van den Ban, Sander; Goodwin, Daniel J; Ketolainen, Jarkko; Gane, Patrick; Peiponen, Kai-Erik; Zeitler, J Axel

2018-02-15

Pharmaceutical tablets are typically manufactured by the uni-axial compaction of powder that is confined radially by a rigid die. The directional nature of the compaction process yields not only anisotropic mechanical properties (e.g. tensile strength) but also directional properties of the pore structure in the porous compact. This study derives a new quantitative parameter, S a , to describe the anisotropy in pore structure of pharmaceutical tablets based on terahertz time-domain spectroscopy measurements. The S a parameter analysis was applied to three different data sets including tablets with only one excipient (functionalised calcium carbonate), samples with one excipient (microcrystalline cellulose) and one drug (indomethacin), and a complex formulation (granulated product comprising several excipients and one drug). The overall porosity, tablet thickness, initial particle size distribution as well as the granule density were all found to affect the significant structural anisotropies that were observed in all investigated tablets. The S a parameter provides new insights into the microstructure of a tablet and its potential was particularly demonstrated for the analysis of formulations comprising several components. The results clearly indicate that material attributes, such as particle size and granule density, cause a change of the pore structure, which, therefore, directly impacts the liquid imbibition that is part of the disintegration process. We show, for the first time, how the granule density impacts the pore structure, which will also affect the performance of the tablet. It is thus of great importance to gain a better understanding of the relationship of the physical properties of material attributes (e.g. intragranular porosity, particle shape), the compaction process and the microstructure of the finished product. Copyright © 2017 Elsevier B.V. All rights reserved.

Differential scanning calorimetry: An invaluable tool for a detailed thermodynamic characterization of macromolecules and their interactions

PubMed Central

Chiu, Michael H.; Prenner, Elmar J.

2011-01-01

Differential Scanning Calorimetry (DSC) is a highly sensitive technique to study the thermotropic properties of many different biological macromolecules and extracts. Since its early development, DSC has been applied to the pharmaceutical field with excipient studies and DNA drugs. In recent times, more attention has been applied to lipid-based drug delivery systems and drug interactions with biomimetic membranes. Highly reproducible phase transitions have been used to determine values, such as, the type of binding interaction, purity, stability, and release from a drug delivery mechanism. This review focuses on the use of DSC for biochemical and pharmaceutical applications. PMID:21430954

Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide.

PubMed

Woolfson, A David; Malcolm, R Karl; Morrow, Ryan J; Toner, Clare F; McCullagh, Stephen D

2006-11-15

TMC 120 (Dapivirine) is a potent non-nucleoside reverse transcriptase inhibitor that is presently being developed as a vaginal HIV microbicide. To date, most vaginal microbicides under clinical investigation have been formulated as single-dose semi-solid gels, designed for application to the vagina before each act of intercourse. However, a clear rationale exists for providing long-term, controlled release of vaginal microbicides in order to afford continuous protection against heterosexually transmitted HIV infection and to improve user compliance. In this study we report on the incorporation of various pharmaceutical excipients into TMC 120 silicone, reservoir-type intravaginal rings (IVRs) in order to modify the controlled release characteristics of the microbicide. The results demonstrate that TMC 120 is released in zero-order fashion from the rings over a 28-day period and that release parameters could be modified by the inclusion of release-modifying excipients in the IVR. The hydrophobic liquid excipient isopropyl myristate had little effect on steady-state daily release rates, but did increase the magnitude and duration of burst release in proportion to excipient loading in the IVR. By comparison, the hydrophobic liquid poly(dimethylsiloxane) had little effect on TMC 120 release parameters. A hydrophilic excipient, lactose, had the surprising effect of decreasing TMC 120 burst release while increasing the apparent steady-state daily release in a concentration-dependent manner. Based on previous cell culture data and vaginal physiology, TMC120 is released from the various ring formulations in amounts potentially capable of maintaining a protective vaginal concentration. It is further predicted that the observed release rates may be maintained for at least a period of 1 year from a single ring device. TMC 120 release profiles and the mechanical properties of rings could be modified by the physicochemical nature of hydrophobic and hydrophilic excipients incorporated into the IVRs.

On the exfoliating polymeric cellular dosage forms for immediate drug release.

PubMed

Blaesi, Aron H; Saka, Nannaji

2016-06-01

The most prevalent pharmaceutical dosage forms at present-the oral immediate-release tablets and capsules-are granular solids. Though effective in releasing drug rapidly, development and manufacture of such dosage forms are fraught with difficulties inherent to particulate processing. Predictable dosage form manufacture could be achieved by liquid-based processing, but cast solid dosage forms are not suitable for immediate drug release due to their resistance to fluid percolation. To overcome this limitation, we have recently introduced cellular dosage forms that can be readily prepared from polymeric melts. It has been shown that open-cell structures comprising polyethylene glycol 8000 (PEG 8k) excipient and a drug exfoliate upon immersion in a dissolution medium. The drug is then released rapidly due to the large specific surface area of the exfoliations. In this work, we vary the molecular weight of the PEG excipient and investigate its effect on the drug release kinetics of structures with predominantly open-cell topology. We demonstrate that the exfoliation rate decreases substantially if the excipient molecular weight is increased from 12 to 100kg/mol, which causes the drug dissolution time to increase by more than a factor of ten. A model is then developed to elucidate the exfoliation behavior of cellular structures. Diverse transport processes are considered: percolation due to capillarity, diffusion of dissolution medium through the cell walls, and viscous flow of the saturated excipient. It is found that the lower exfoliation rate and the longer dissolution time of the dosage forms with higher excipient molecular weight are primarily due to the greater viscosity of the cell walls after fluid penetration. Copyright © 2016 Elsevier B.V. All rights reserved.

Transforming lipid-based oral drug delivery systems into solid dosage forms: an overview of solid carriers, physicochemical properties, and biopharmaceutical performance.

PubMed

Tan, Angel; Rao, Shasha; Prestidge, Clive A

2013-12-01

The diversity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications.

Cyclodextrins, blood-brain barrier, and treatment of neurological diseases.

PubMed

Vecsernyés, Miklós; Fenyvesi, Ferenc; Bácskay, Ildikó; Deli, Mária A; Szente, Lajos; Fenyvesi, Éva

2014-11-01

Biological barriers are the main defense systems of the homeostasis of the organism and protected organs. The blood-brain barrier (BBB), formed by the endothelial cells of brain capillaries, not only provides nutrients and protection to the central nervous system but also restricts the entry of drugs, emphasizing its importance in the treatment of neurological diseases. Cyclodextrins are increasingly used in human pharmacotherapy. Due to their favorable profile to form hydrophilic inclusion complexes with poorly soluble active pharmaceutical ingredients, they are present as excipients in many marketed drugs. Application of cyclodextrins is widespread in formulations for oral, parenteral, nasal, pulmonary, and skin delivery of drugs. Experimental and clinical data suggest that cyclodextrins can be used not only as excipients for centrally acting marketed drugs like antiepileptics, but also as active pharmaceutical ingredients to treat neurological diseases. Hydroxypropyl-β-cyclodextrin received orphan drug designation for the treatment of Niemann-Pick type C disease. In addition to this rare lysosomal storage disease with neurological symptoms, experimental research revealed the potential therapeutic use of cyclodextrins and cyclodextrin nanoparticles in neurodegenerative diseases, stroke, neuroinfections and brain tumors. In this context, the biological effects of cyclodextrins, their interaction with plasma membranes and extraction of different lipids are highly relevant at the level of the BBB. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Screening of anionic-modified polymers in terms of stability, disintegration, and swelling behavior.

PubMed

Laffleur, Flavia; Ijaz, Muhammad; Menzel, Claudia

2017-11-01

This study aimed to screen the stability, disintegration, and swelling behavior of chemically modified anionic polymers. Investigated polymers were well-known and widely used staples of the pharmaceutical and medical field, namely, alginate (AL), carboxymethyl cellulose (CMC), polycarbophil (PC), and hyaluronic acid (HA). On the basis of amide bond formation between the carboxylic acid moieties of anionic polymers and the primary amino group of the modification ligand cysteine (CYS), the modified polymers were obtained. Unmodified polymers served as controls throughout all studies. With the Ellman's assay, modification degrees were determined of synthesized polymeric excipients. Stability assay in terms of erosion study at physiological conditions were performed. Moreover, water uptake of compressed polymeric discs were evaluated and further disintegration studies according to the USP were carried out to define the potential ranking. Results ranking figured out PCCYS > CMCCYS > HACYS > ALCYS in terms of water uptake capacity compared to respective controls. Cell viability assays on Caco-2 cell line as well as on RPMI 2650 (ATTC CCL30) proved modification not being harmful to those. Due to the results of this study, an intense screening of prominent anionic polymer derivate was performed in order to help the pharmaceutical research for the best choice of polymeric excipients for developments of controlled drug release systems.

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.

Determination of ambroxol hydrochloride, guaifenesin, and theophylline in ternary mixtures and in the presence of excipients in different pharmaceutical dosage forms.

PubMed

Abdelwahab, Nada S

2012-01-01

Determination of ternary mixtures of ambroxol hydrochloride, guaifenesin, and theophylline with minimum sample pretreatment and without analyte separation has been successfully achieved by using chemometric and RP-HPLC methods. The developed chemometric models are partial least squares (PLS) and genetic algorithm coupled with PLS. Data of the analyses were obtained from UV-Vis spectra of the studied drugs in different concentration ranges. These models have been successfully updated to be applied for determination of the proposed drugs in Farcosolvin syrup and in the presence of a syrup excipient (methyl paraben). In the developed RP-HPLC method, chromatographic runs were performed on an RP-C18 analytical column with the isocratic mobile phase 0.05 M phosphate buffer-methanol-acetonitrile-triethylamine (63.5 + 27.5 + 9 + 0.25, v/v/v/v, pH 5.5 adjusted with orthophosphoric acid) at a flow rate of 1.2 mL/min. The analytes were detected and quantified at 220 nm. The method was optimized in order to obtain good resolution between the studied components and to prevent interference from methyl paraben. Method validation was performed with respect to International Conference on Harmonization guidelines and the validation acceptance criteria were met in all cases. The proposed methods can be considered acceptable for QC of the studied drugs in pharmaceutical capsules and syrup. The results obtained by the suggested chemometric methods for determination of the studied mixture in different pharmaceutical preparations were statistically compared to those obtained by applying the developed RP-HPLC method, and no significant difference was found.

Oral bioavailability and intestinal absorption of candesartan cilexetil: role of naringin as P-glycoprotein inhibitor.

PubMed

Gurunath, Surampalli; Nanjwade, Basavaraj K; Patil, P A

2015-01-01

The aim of the study is to explore the pharmacokinetic behavior of candesartan solid dispersions prepared by different pharmaceutical interventions using P-gp inhibitor in rabbits to validate the effectiveness of naringin as a pharmaceutical excipient in enhancing the oral delivery of lipophilic candesartan cilexetil. Male albino rabbits (1-1.5 kg) were orally administered pure CAN suspensions and various candesartan solid dispersions (10 mg/kg) with and without naringin (15 mg/kg) and blood samples were collected at specified time points. CAN plasma samples were measured using HPLC. After oral dosing of pure CAN suspension, the mean AUC0-8 h was found to be 0.14 ± 0.09 μgh/ml which was increased significantly, i.e. 0.52 ± 0.13 μgh/ml with freeze-dried solid dispersions in the presence of naringin (p < 0.01). Similarly, the mean Cmax of pure CAN suspension increased from 35.81 ± 0.13 μg/ml (without naringin) to 112.23 ± 0.13 μg/ml (freeze-dried solid dispersions with naringin) (p < 0.01). A 3.7-folds increase in apparent bioavailability was noticed with freeze-dried solid dispersions with naringin as compared to free CAN suspension administered alone. These results are quite stimulating for further development of a clinically useful oral formulation of candesartan cilexetil based on P-gp inhibition using naringin, a natural flavonoid as a pharmaceutical excipient.

Cationic surfactants-modified natural zeolites: improvement of the excipients functionality.

PubMed

Krajisnik, Danina; Milojević, Maja; Malenović, Anđelija; Daković, Aleksandra; Ibrić, Svetlana; Savić, Snezana; Dondur, Vera; Matijasević, Srđan; Radulović, Aleksandra; Daniels, Rolf; Milić, Jela

2010-10-01

In this study an investigation of cationic surfactants-modified natural zeolites as drug formulation excipient was performed. The aim of this work was to carry out a study of the purified natural zeolitic tuff with high amount of clinoptilolite as a potential carrier for molecules of pharmaceutical interest. Two cationic surfactants (benzalkonium chloride and hexadecyltrimethylammonium bromide) were used for modification of the zeolitic surface in two levels (equal to and twice as external cation-exchange capacity of the zeolitic tuff). Prepared samples were characterized by Fourier transform infrared spectroscopy, thermogravimetric, high-performance liquid chromatography analysis, and powder flow determination. Different surfactant/zeolite composites were used for additional investigation of three model drugs: diclofenac diethylamine, diclofenac sodium, and ibuprofen by means of adsorption isotherm measurements in aqueous solutions. The modified zeolites with two levels of surfactant coverage within the short activation time were prepared. Determination of flow properties showed that modification of zeolitic surface reflected on powder flow characteristics. Investigation of the model drugs adsorption on the obtained composites revealed that a variation between adsorption levels was influenced by the surfactant type and the amount present at the surface of the composites. In vitro release profiles of the drugs from the zeolite-surfactant-drug composites revealed that sustained drug release could be attained over a period of 8 hours. The presented results for drug uptake by surfactant-zeolite composites and the afterward drug release demonstrated the potential use of investigated modified natural zeolite as excipients for advanced excipients in drug formulations.

Preparation and evaluation of self-microemulsions for improved bioavailability of ginsenoside-Rh1 and Rh2.

PubMed

Yang, Feifei; Zhou, Jing; Hu, Xiao; Yu, Stephanie Kyoungchun; Liu, Chunyu; Pan, Ruile; Chang, Qi; Liu, Xinmin; Liao, Yonghong

2017-10-01

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Indirect potentiometric titration of ascorbic acid in pharmaceutical preparations using copper based mercury film electrode.

PubMed

Abdul Kamal Nazer, Meeran Mohideen; Hameed, Abdul Rahman Shahul; Riyazuddin, Patel

2004-01-01

A simple and rapid potentiometric method for the estimation of ascorbic acid in pharmaceutical dosage forms has been developed. The method is based on treating ascorbic acid with iodine and titration of the iodide produced equivalent to ascorbic acid with silver nitrate using Copper Based Mercury Film Electrode (CBMFE) as an indicator electrode. Interference study was carried to check possible interference of usual excipients and other vitamins. The precision and accuracy of the method was assessed by the application of lack-of-fit test and other statistical methods. The results of the proposed method and British Pharmacopoeia method were compared using F and t-statistical tests of significance.

Anodic Oxidation of Etodolac and its Linear Sweep, Square Wave and Differential Pulse Voltammetric Determination in Pharmaceuticals

PubMed Central

Yilmaz, B.; Kaban, S.; Akcay, B. K.

2015-01-01

In this study, simple, fast and reliable cyclic voltammetry, linear sweep voltammetry, square wave voltammetry and differential pulse voltammetry methods were developed and validated for determination of etodolac in pharmaceutical preparations. The proposed methods were based on electrochemical oxidation of etodolac at platinum electrode in acetonitrile solution containing 0.1 M lithium perchlorate. The well-defined oxidation peak was observed at 1.03 V. The calibration curves were linear for etodolac at the concentration range of 2.5-50 μg/ml for linear sweep, square wave and differential pulse voltammetry methods, respectively. Intra- and inter-day precision values for etodolac were less than 4.69, and accuracy (relative error) was better than 2.00%. The mean recovery of etodolac was 100.6% for pharmaceutical preparations. No interference was found from three tablet excipients at the selected assay conditions. Developed methods in this study are accurate, precise and can be easily applied to Etol, Tadolak and Etodin tablets as pharmaceutical preparation. PMID:26664057

Hot-melt extrusion--basic principles and pharmaceutical applications.

PubMed

Lang, Bo; McGinity, James W; Williams, Robert O

2014-09-01

Originally adapted from the plastics industry, the use of hot-melt extrusion has gained favor in drug delivery applications both in academia and the pharmaceutical industry. Several commercial products made by hot-melt extrusion have been approved by the FDA, demonstrating its commercial feasibility for pharmaceutical processing. A significant number of research articles have reported on advances made regarding the pharmaceutical applications of the hot-melt extrusion processing; however, only limited articles have been focused on general principles regarding formulation and process development. This review provides an in-depth analysis and discussion of the formulation and processing aspects of hot-melt extrusion. The impact of physicochemical properties of drug substances and excipients on formulation development using a hot-melt extrusion process is discussed from a material science point of view. Hot-melt extrusion process development, scale-up, and the interplay of formulation and process attributes are also discussed. Finally, recent applications of hot-melt extrusion to a variety of dosage forms and drug substances have also been addressed.

Mapping the pharmaceutical design space by amorphous ionic liquid strategies.

PubMed

Wiest, Johannes; Saedtler, Marco; Balk, Anja; Merget, Benjamin; Widmer, Toni; Bruhn, Heike; Raccuglia, Marc; Walid, Elbast; Picard, Franck; Stopper, Helga; Dekant, Wolfgang; Lühmann, Tessa; Sotriffer, Christoph; Galli, Bruno; Holzgrabe, Ulrike; Meinel, Lorenz

2017-12-28

Poor water solubility of drugs fuels complex formulations and jeopardizes patient access to medication. Simplifying these complexities we systematically synthesized a library of 36 sterically demanding counterions and mapped the pharmaceutical design space for amorphous ionic liquid strategies for Selurampanel, a poorly water soluble drug used against migraine. Patients would benefit from a rapid uptake after oral administration to alleviate migraine symptoms. Therefore, we probed the ionic liquids for the flux, supersaturation period and hygroscopicity leading to algorithms linking molecular counterion descriptors to predicted pharmaceutical outcome. By that, 30- or 800-fold improvements of the supersaturation period and fluxes were achieved as were immediate to sustained release profiles through structural counterions' optimization compared to the crystalline free acid of Selurampanel. Guided by ionic liquid structure, in vivo profiles ranged from rapid bioavailability and high maximal plasma concentrations to sustained patterns. In conclusion, the study outlined and predicted the accessible pharmaceutical design space of amorphous ionic liquid based and excipient-free formulations pointing to the enormous pharmaceutical potential of ionic liquid designs. Copyright © 2017 Elsevier B.V. All rights reserved.

Cyclodextrins as new formulation entities and therapeutic agents.

PubMed

Sikharam, Sreevalli; Egan, Talmage D; Kern, Steven E

2005-08-01

This review is focused on recent advances in the application of cyclodextrins to new drug formulations, with emphasis on the field of anesthesia. Cyclodextrins are well-known excipients in the pharmaceutical industry. Their recent application to the anesthetic induction agent propofol as a means of creating a non-lipid formulation may lead to their introduction into anesthesia pharmacology. The development of a novel cyclodextrin as specific reversal agent for the neuromuscular blocker rocuronium (that acts as an in-vivo scavenging system to bind free rocuronium in the circulation) will also increase the likelihood that cyclodextrins will have a greater clinical presence in anesthesiology in the future. Cyclodextrin-containing polymers are also finding a role in the delivery of nucleic acids and protein therapeutic agents. Recent developments in cyclodextrins as excipients for anesthetics may soon culminate in their introduction into anesthesiology, although more research is necessary to better define their potential.

Sustained Release Oral Nanoformulated Green Tea for Prostate Cancer Prevention

DTIC Science & Technology

2013-05-01

epigallocatechin-3-gallate. Cancer Res. 2009;69:1712-6. 2. Adhami VM, Siddiqui IA, Syed DN, Lall RK, Mukhtar H. Oral infusion of pomegranate fruit ...and fungi , and is also known for its non-toxic, non-immunogenic properties (23). It has already been used as a pharmaceutical excipient, a weight loss...component EGCG and perceived toxicity associated with its long-term use affect its clinical outcome (36,37). This study suggests a different

Spectrofluorimetric method for the determination of sulpiride in pharmaceutical preparations and human plasma through derivatization with 2-cyanoacetamide.

PubMed

Shah, Jasmin; Jan, M Rasul; Khan, M Naeem; Shah, Sultan

2013-01-01

A sensitive and accurate spectrofluorimetric method has been developed for the determination of sulpiride in pharmaceutical preparations and human plasma. The developed method is based on the derivatization reaction of 2-cyanoacetamide with sulpiride in 30% ammonical solution. The fluorescent derivatized reaction product exhibited maximum fluorescence intensity at 379 nm after excitation at 330 nm. The optimum conditions for derivatization reactions were studied and the fluorescence intensity versus concentration plot was found to be linear over the concentration range 0.2-20.0 µg/mL with a correlation coefficient of 0.9985. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.82 and 2.73 ng/mL, respectively. The proposed method was validated according to ICH guidelines. The effects of common excipients and co-administered drugs were also studied. The accuracy of the method was checked using the standard addition method and percent recoveries were found to be in the range of 99.00-101.25% for pharmaceutical preparations and 97.00-97.80% for spiked human plasma. The method was successfully applied to commercial formulations and the results obtained for the proposed method were compared with a high-performance liquid chromatography reference method and statistically evaluated using the Student's t-test for accuracy and the variance ratio F-test for precision. A reaction pathway was also proposed. Copyright © 2012 John Wiley & Sons, Ltd.

Basics of Compounding with Dilutions and Concentrates.

PubMed

Allen, Loyd V

2017-01-01

Pharmacists use various sources for obtaining the active pharmaceutical ingredient for compounding medications. In many cases, it is the pure drug (United States Pharmacopeia, National Formulary, or similar grade); in some cases, it can be a commercial dosage form; and, in some cases, it may be a dilution or concentrate. If the drug is not present at full strength, then adjustments may be necessary to obtain the required quantity of drug. Also, in many cases, it is necessary to use a dilution or a concentrate of a drug due to safety and quality reasons. Presented within this article are new sources of active pharmaceutical ingredients that are now available to aid pharmacists in meeting future United States Pharmacopeia <800> standards. It is critical that the pharmacist be aware of the strength of the drug and any other excipients that may be available. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Determination of sulpiride in pharmaceutical preparations and biological fluids using a Cr (III) enhanced chemiluminescence method.

PubMed

Khan, Muhammad Naeem; Jan, Muhammad Rasul; Shah, Jasmin; Lee, Sang Hak; Kim, Young Ho

2013-01-01

A highly sensitive and simple method for identifying sulpiride in pharmaceutical formulations and biological fluids is presented. The method is based on increased chemiluminescence (CL) intensity of a luminol-H2O2 system in response to the addition of Cr (III) under alkaline conditions. The CL intensity of the luminol-H2O2-Cr (III) system was greatly enhanced by the addition of sulpiride and the CL intensity was proportional to the concentration of sulpiride in a sample solution. Various parameters affecting the CL intensity were systematically investigated and optimized for determination of the sulpiride in a sample. Under the optimum conditions, the CL intensity was proportional to the concentration of sulpiride in the range of 0.068-4.0 µg/mL, with a good correlation coefficient of 0.997. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 8.50 × 10(-6) µg/mL and 2.83 × 10(-5) µg/mL, respectively. The method presented here produced good reproducibility with a relative standard deviation (RSD) of 2.70% (n = 7). The effects of common excipients and metal ions were studied for their interference effect. The method was validated statistically through recovery studies and successfully applied for the determination of sulpiride in pure form, pharmaceutical preparations and spiked human plasma samples. The percentage recoveries were found to range from 99.10 to 100.05% for pure form, 98.12 to 100.18% for pharmaceutical preparations and 97.9 to 101.4% for spiked human plasma. Copyright © 2012 John Wiley & Sons, Ltd.

A validated silver-nanoparticle-enhanced chemiluminescence method for the determination of citalopram in pharmaceutical preparations and human plasma.

PubMed

Khan, Muhammad Naeem; Jan, Muhammad Rasul; Shah, Jasmin; Lee, Sang Hak

2014-05-01

A simple and sensitive chemiluminescence (CL) method was developed for the determination of citalopram in pharmaceutical preparations and human plasma. The method is based on the enhancement of the weak CL signal of the luminol-H2 O2 system. It was found that the CL signal arising from the reaction between alkaline luminol and H2 O2 was greatly increased by the addition of silver nanoparticles in the presence of citalopram. Prepared silver nanoparticles (AgNPs) were characterized by UV-visible spectroscopy and transmission electron microscopy (TEM). Various experimental parameters affecting CL intensity were studied and optimized for the determination of citalopram. Under optimized experimental conditions, CL intensity was found to be proportional to the concentration of citalopram in the range 40-2500 ng/mL, with a correlation coefficient of 0.9997. The limit of detection (LOD) and limit of quantification (LOQ) of the devised method were 3.78 and 12.62 ng/mL, respectively. Furthermore, the developed method was found to have excellent reproducibility with a relative standard deviation (RSD) of 3.65% (n = 7). Potential interference by common excipients was also studied. The method was validated statistically using recovery studies and was successfully applied to the determination of citalopram in the pure form, in pharmaceutical preparations and in spiked human plasma samples. Percentage recoveries were found to range from 97.71 to 101.99% for the pure form, from 97.84 to 102.78% for pharmaceutical preparations and from 95.65 to 100.35% for spiked human plasma. Copyright © 2013 John Wiley & Sons, Ltd.

A method to evaluate the effect of contact with excipients on the surface crystallization of amorphous drugs.

PubMed

Zhang, Si-Wei; Yu, Lian; Huang, Jun; Hussain, Munir A; Derdour, Lotfi; Qian, Feng; de Villiers, Melgardt M

2014-12-01

Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the β polymorph from two to five times when samples were stored in a desiccator, while D-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.

Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

PubMed Central

Zgair, Atheer; Wong, Jonathan CM; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

2016-01-01

There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines. PMID:27648135

Fractal aspects of the flow and shear behaviour of free-flowable particle size fractions of pharmaceutical directly compressible excipient sorbitol.

PubMed

Hurychová, Hana; Lebedová, Václava; Šklubalová, Zdenka; Dzámová, Pavlína; Svěrák, Tomáš; Stoniš, Jan

Flowability of powder excipients is directly influenced by their size and shape although the granulometric influence of the flow and shear behaviour of particulate matter is not studied frequently. In this work, the influence of particle size on the mass flow rate through the orifice of a conical hopper, and the cohesion and flow function was studied for four free-flowable size fractions of sorbitol for direct compression in the range of 0.080-0.400 mm. The particles were granulometricaly characterized using an optical microscopy; a boundary fractal dimension of 1.066 was estimated for regular sorbitol particles. In the particle size range studied, a non-linear relationship between the mean particle size and the mass flow rate Q10 (g/s) was detected having amaximum at the 0.245mm fraction. The best flow properties of this fraction were verified with aJenike shear tester due to the highest value of flow function and the lowest value of the cohesion. The results of this work show the importance of the right choice of the excipient particle size to achieve the best flow behaviour of particulate material.Key words: flowability size fraction sorbitol for direct compaction Jenike shear tester fractal dimension.

[Generics: essentially similar, bioequivalent but not identical].

PubMed

Even-Adin, D; De Muylder, J A; Sternon, J

2001-12-01

The using of generic forms (GF) is presented as a potential source of budgetary "saving of money" in the field of pharmaceutical expenses. Not frequently prescribed in Belgium, they win a new interest thanks to the recent making use of the "reference repayment". Sale's authorization of GF is controlled by european rules, but some questions about their identity to original medications remain. Do similarities based only upon qualitative and quantitative composition in active molecules, pharmaceutical forms and biodisponibility give us all requested guarantees? Several cases of discordances can appear: the major elements of non conformity are the nature of excipients, notice's contents and the value of biodisponibility studies. However, in term of economy, in the drug market, development of GF appears to constitute an unavoidable phenomenon.

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.

Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs.

PubMed

Zhang, Zhi-hong; Dong, Hong-ye; Peng, Bo; Liu, Hong-fei; Li, Chun-lei; Liang, Min; Pan, Wei-san

2011-05-30

The purpose of this article was to build an expert system for the development and formulation of push-pull osmotic pump tablets (PPOP). Hundreds of PPOP formulations were studied according to different poorly water-soluble drugs and pharmaceutical acceptable excipients. The knowledge base including database and rule base was built based on the reported results of hundreds of PPOP formulations containing different poorly water-soluble drugs and pharmaceutical excipients and the experiences available from other researchers. The prediction model of release behavior was built using back propagation (BP) neural network, which is good at nonlinear mapping and learning function. Formulation design model was established based on the prediction model of release behavior, which was the nucleus of the inference engine. Finally, the expert system program was constructed by VB.NET associating with SQL Server. Expert system is one of the most popular aspects in artificial intelligence. To date there is no expert system available for the formulation of controlled release dosage forms yet. Moreover, osmotic pump technology (OPT) is gradually getting consummate all over the world. It is meaningful to apply expert system on OPT. Famotidine, a water insoluble drug was chosen as the model drug to validate the applicability of the developed expert system. Copyright © 2011 Elsevier B.V. All rights reserved.

Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence.

PubMed

García-Arieta, Alfredo

2014-12-18

The aim of the present paper is to illustrate the impact that excipients may have on the bioavailability of drugs and to review existing US-FDA, WHO and EMA regulatory guidelines on this topic. The first examples illustrate that small amounts of sorbitol (7, 50 or 60mg) affect the bioavailability of risperidone, a class I drug, oral solution, in contrast to what is stated in the US-FDA guidance. Another example suggests, in contrast to what is stated in the US-FDA BCS biowaivers guideline, that a small amount of sodium lauryl sulphate (SLS) (3.64mg) affects the bioavailability of risperidone tablets, although the reference product also includes SLS in an amount within the normal range for that type of dosage form. These factors are considered sufficient to ensure that excipients do not affect bioavailability according to the WHO guideline. The alternative criterion, defined in the WHO guideline and used in the FIP BCS biowaivers monographs, that asserts that excipients present in generic products of the ICH countries do not affect bioavailability if used in normal amounts, is shown to be incorrect with an example of alendronate (a class III drug) tablets, where 4mg of SLS increases bioavailability more than 5-fold, although a generic product in the USA contains SLS. Finally, another example illustrates that a 2mg difference in SLS may affect bioavailability of a generic product of a class II drug, even if SLS is contained in the comparator product, and in all cases its amount was within the normal range. Therefore, waivers of in vivo bioequivalence studies (e.g., BCS biowaivers, waivers of certain dosage forms in solution at the time of administration and variations in the excipient composition) should be assessed more cautiously. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Determination of Bosentan in Pharmaceutical Preparations by Linear Sweep, Square Wave and Differential Pulse Voltammetry Methods

PubMed Central

Atila, Alptug; Yilmaz, Bilal

2015-01-01

In this study, simple, fast and reliable cyclic voltammetry (CV), linear sweep voltammetry (LSV), square wave voltammetry (SWV) and differential pulse voltammetry (DPV) methods were developed and validated for determination of bosentan in pharmaceutical preparations. The proposed methods were based on electrochemical oxidation of bosentan at platinum electrode in acetonitrile solution containing 0.1 M TBACIO4. The well-defined oxidation peak was observed at 1.21 V. The calibration curves were linear for bosentan at the concentration range of 5-40 µg/mL for LSV and 5-35 µg/mL for SWV and DPV methods, respectively. Intra- and inter-day precision values for bosentan were less than 4.92, and accuracy (relative error) was better than 6.29%. The mean recovery of bosentan was 100.7% for pharmaceutical preparations. No interference was found from two tablet excipients at the selected assay conditions. Developed methods in this study are accurate, precise and can be easily applied to Tracleer and Diamond tablets as pharmaceutical preparation. PMID:25901151

Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol.

PubMed

Kaialy, Waseem; Khan, Usman; Mawlud, Shadan

2016-08-20

Mannitol is a pharmaceutical excipient that is receiving increased popularity in solid dosage forms. The aim of this study was to provide comparative evaluation on the effect of mannitol concentration on the physicochemical, mechanical, and pharmaceutical properties of lyophilised mannitol. The results showed that the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol powders are strong functions of mannitol concentration. By decreasing mannitol concentration, the true density, bulk density, cohesivity, flowability, netcharge-to-mass ratio, and relative degree of crystallinity of LM were decreased, whereas the breakability, size distribution, and size homogeneity of lyophilised mannitol particles were increased. The mechanical properties of lyophilised mannitol tablets improved with decreasing mannitol concentration. The use of lyophilised mannitol has profoundly improved the dissolution rate of indomethacin from tablets in comparison to commercial mannitol. This improvement exhibited an increasing trend with decreasing mannitol concentration. In conclusion, mannitols lyophilised from lower concentrations are more desirable in tableting than mannitols from higher concentrations due to their better mechanical and dissolution properties. Copyright © 2016 Elsevier B.V. All rights reserved.

Determination of bosentan in pharmaceutical preparations by linear sweep, square wave and differential pulse voltammetry methods.

PubMed

Atila, Alptug; Yilmaz, Bilal

2015-01-01

In this study, simple, fast and reliable cyclic voltammetry (CV), linear sweep voltammetry (LSV), square wave voltammetry (SWV) and differential pulse voltammetry (DPV) methods were developed and validated for determination of bosentan in pharmaceutical preparations. The proposed methods were based on electrochemical oxidation of bosentan at platinum electrode in acetonitrile solution containing 0.1 M TBACIO4. The well-defined oxidation peak was observed at 1.21 V. The calibration curves were linear for bosentan at the concentration range of 5-40 µg/mL for LSV and 5-35 µg/mL for SWV and DPV methods, respectively. Intra- and inter-day precision values for bosentan were less than 4.92, and accuracy (relative error) was better than 6.29%. The mean recovery of bosentan was 100.7% for pharmaceutical preparations. No interference was found from two tablet excipients at the selected assay conditions. Developed methods in this study are accurate, precise and can be easily applied to Tracleer and Diamond tablets as pharmaceutical preparation.

Medicinal plants used as excipients in the history in Ghanaian herbal medicine.

PubMed

Freiesleben, Sara Holm; Soelberg, Jens; Jäger, Anna K

2015-11-04

The present study was carried out to investigate the traditional use, pharmacology and active compounds of four plants commonly used as excipients in herbal medicine in Ghana. A comprehensive literature search was conducted to gain knowledge about the traditional use, pharmacology and active compounds of the four plant excipients. The broth dilution antibacterial assay and the DPPH radical scavenging antioxidant assay were used to evaluate the antibacterial and antioxidant activity of the plants, respectively. Ethanol, warm water and cold water extracts were prepared from the dried seeds/fruits of Aframomum melegueta, Piper guineense, Xylopia aethiopica and Monodora myristica, and tested in the assays. A. melegueta and P. guineense seemed to act as pharmacoenhancers, since they have been shown to inhibit specific CYP-enzymes. A. melegueta could act as an antioxidant to preserve herbal preparations. None of the plant excipients had antibacterial activity against the bacteria tested in this study. Compounds with an aromatic or pungent smell had been identified in all the plant excipients. An explanation for the use of the plants as excipients could rely on their taste properties. The present study suggests that there may be more than one simple explanation for the use of these four plants as excipients. Plausible explanations have been proven to be: (1) a way to increase the effect of the medicine, (2) a way to make the medicine more palatable or (3) a way to preserve the activity of the medicinal preparation over time. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Toxicity of Aluminum Silicates Used in Hemostatic Dressings Toward Human Umbilical Veins Endothelial Cells, HeLa Cells, and RAW267.4 Mouse Macrophages

DTIC Science & Technology

2011-09-01

ORIGINAL ARTICLE Toxicity of Aluminum Silicates Used in Hemostatic Dressings Toward Human Umbilical Veins Endothelial Cells, HeLa Cells, and RAW267.4...not known. Clay minerals are generally considered nontoxic to humans and have been widely used in cosmetics and as excipient in drugs and foods...Bentonite, which has a long history in pharmaceutical formulations,7 along with kaolin are listed in the US Pharmacopeia.8 The sensitivity of some human

Influence of Polymer Type on the Physical Properties and Release Profile of Papaverine Hydrochloride From Hard Gelatin Capsules.

PubMed

Polski, Andrzej; Iwaniak, Karol; Kasperek, Regina; Modrzewska, Joanna; Sobótka-Polska, Karolina; Sławińska, Karolina; Poleszak, Ewa

2015-01-01

The capsule is one of the most important solid dosage forms in the pharmaceutical industry. It is easier and faster to produce than a tablet, because it requires fewer excipients. Generally, capsules are easy to swallow and mask any unpleasant taste of the substances used while their release profiles can be easily modified. Papaverine hydrochloride was used as a model substance to show different release profiles using different excipients. The main aim of the study was to analyze the impact of using different polymers on the release profile of papaverine hydrochloride from hard gelatin capsules. Six series of hard gelatin capsules containing papaverine hydrochloride as a model drug and different excipients were made. Then, the angle of repose, flow rate, mass flow rate and volume flow rate of the powders used for capsule production were analyzed. The uniform weight and disintegration time of the capsules were studied. The dissolution study was performed in a basket apparatus, while the amount of papaverine hydrochloride released was determined spectrophotometrically at 251 nm. Only one formula of powder had satisfactory flow properties, while all formulas had good Hausner ratios. The best properties were from powder containing polyvinylpyrrolidone 10k. The disintegration time of capsules varied from 1:30 min to 2:00 min. As required by Polish Pharmacopoeia X, 80% of the active substance in all cases was released within 15 minutes. The capsules with polyvinylpyrrolidone 10k were characterized by the longest release. On the other hand, capsules containing microcrystalline cellulose had the fastest release profile. Using 10% of different polymers, without changing the other excipients, had a significant impact on the physical properties of the powders and papaverine hydrochloride release profile. The two most preferred capsule formulations contained either polyvinylpyrrolidone 10k or microcrystalline cellulose.

3D-micro-patterned fibrous dosage forms for immediate drug release.

PubMed

Blaesi, Aron H; Saka, Nannaji

2018-03-01

At present, the most prevalent pharmaceutical dosage forms, the orally-delivered immediate-release tablets and capsules, are porous, granular solids. They disintegrate into their constituent particulates upon ingestion to release drug rapidly. The design, development, and manufacture of such granular solids, however, is inefficient due to difficulties associated with the unpredictable inter-particle interactions. Therefore, to achieve more predictable dosage form properties and processing, we have recently introduced melt-processed polymeric cellular dosage forms. The cellular forms disintegrated and released drug rapidly if the cells were predominantly interconnected. Preparation of interconnected cells, however, relies on the coalescence of gas bubbles in the melt, which is unpredictable. In the present work, therefore, new melt-processed fibrous dosage forms with contiguous void space are presented. The dosage forms are prepared by melt extrusion of the drug-excipient mixture followed by patterning the fibrous extrudate on a moving surface. It is demonstrated that the resulting fibrous structures are fully predictable by the extruder nozzle diameter and the motion of the surface. Furthermore, drug release experiments show that the disintegration time of the fibrous forms prepared in this work is of the order of that of the corresponding single fibers. The thin fibers of polyethylene glycol (excipient) and acetaminophen (drug) in turn disintegrate in a time proportional to the fiber radius and well within immediate-release specification. Finally, models of dosage form disintegration and drug release by single fibers and fibrous dosage forms are developed. It is found that drug release from fibrous forms is predictable by the physico-chemical properties of the excipient and such microstructural parameters as the fiber radius, the inter-fiber spacing, and the volume fraction of water-soluble excipient in the fibers. Copyright © 2017 Elsevier B.V. All rights reserved.

EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension.

PubMed

Sitbon, Olivier; Delcroix, Marion; Bergot, Emmanuel; Boonstra, Anco B; Granton, John; Langleben, David; Subías, Pilar Escribano; Galiè, Nazzareno; Pfister, Thomas; Lemarié, Jean-Christophe; Simonneau, Gérald

2014-02-01

Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience. The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication. Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience. Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience. © 2014.

Design and monitoring of photostability systems for amlodipine dosage forms.

PubMed

Ragno, G; Cione, E; Garofalo, A; Genchi, G; Ioele, G; Risoli, A; Spagnoletta, A

2003-10-20

Photostability of amlodipine (AML) has been monitored in several pharmaceutical inclusion systems characterized by plurimolecular aggregation of the drug and excipients with high molecular weight. Several formulations including cyclodextrins, liposomes and microspheres have been prepared and characterized. The photodegradation process has been monitored according to the conditions suggested by the ICH Guideline for photostability testing, by using a light cabinet equipped with a Xenon lamp and monitored by spectrophotometry. The formulations herein tested have been found to be able to considerably increase drug stability, when compared with usual pharmaceutical forms. The residual concentration detected in the inclusion complexes with cyclodextrins and liposomes was 90 and 77%, respectively, while a very good value of 97% was found for microspheres, after a radiant exposure of 11,340 kJm(-2).

Chemometrics resolution and quantification power evaluation: Application on pharmaceutical quaternary mixture of Paracetamol, Guaifenesin, Phenylephrine and p-aminophenol

NASA Astrophysics Data System (ADS)

Yehia, Ali M.; Mohamed, Heba M.

2016-01-01

Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference.

Formulation and Characterization of a Plasma Sterilized, Pharmaceutical Grade Chitosan Powder

PubMed Central

Crofton, Andrew R; Hudson, Samuel M; Howard, Kristy; Pender, Tyler; Abdelgawad, Abdelrahman; Wolski, Daniel; Kirsch, Wolff M

2016-01-01

Chitosan has great potential as a pharmaceutical excipient. In this study, chitosan flake was micronized using cryo-ball and cryo-jet milling and subsequently sterilized with nitrogen plasma. Micronized chitosan was characterized by laser diffraction, scanning electron microscopy (SEM), conductometric titration, viscometry, loss on drying, FTIR, and limulus amebocyte lysate (LAL) assays. Cryo-jet milling produced mean particle size of 16.05 μm, 44% smaller than cryo-ball milling. Cryomilled chitosan demonstrated increased hygroscopicity, but reduced molecular weight and degree of deacetylation (DD). SEM imaging showed highly irregular shapes. FTIR showed changes consistent with reduced DD and an unexplained shift at 1100 cm−1. Plasma treated chitosan was sterile with <2.5 EU/g after low-pressure plasma and <1.3 EU/g after atmospheric pressure plasma treatment. Plasma treatment decreased the reduced viscosity of chitosan flake and powder, with a greater effect on powder. In conclusion, pharmaceutical grade, sterile chitosan powder was produced with cryo-jet milling and plasma sterilization. PMID:27112892

A rapid Fourier-transform infrared (FTIR) spectroscopic method for direct quantification of paracetamol content in solid pharmaceutical formulations

NASA Astrophysics Data System (ADS)

Mallah, Muhammad Ali; Sherazi, Syed Tufail Hussain; Bhanger, Muhammad Iqbal; Mahesar, Sarfaraz Ahmed; Bajeer, Muhammad Ashraf

2015-04-01

A transmission FTIR spectroscopic method was developed for direct, inexpensive and fast quantification of paracetamol content in solid pharmaceutical formulations. In this method paracetamol content is directly analyzed without solvent extraction. KBr pellets were formulated for the acquisition of FTIR spectra in transmission mode. Two chemometric models: simple Beer's law and partial least squares employed over the spectral region of 1800-1000 cm-1 for quantification of paracetamol content had a regression coefficient of (R2) of 0.999. The limits of detection and quantification using FTIR spectroscopy were 0.005 mg g-1 and 0.018 mg g-1, respectively. Study for interference was also done to check effect of the excipients. There was no significant interference from the sample matrix. The results obviously showed the sensitivity of transmission FTIR spectroscopic method for pharmaceutical analysis. This method is green in the sense that it does not require large volumes of hazardous solvents or long run times and avoids prior sample preparation.

Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control.

PubMed

Sluggett, Gregory W; Zelesky, Todd; Hetrick, Evan M; Babayan, Yelizaveta; Baertschi, Steven W

2018-02-05

Accelerated stability studies of pharmaceutical products are commonly conducted at various combinations of temperature and relative humidity (RH). The RH of the sample environment can be controlled to set points using humidity-controlled stability chambers or via storage of the sample in a closed container in the presence of a saturated aqueous salt solution. Herein we report an unexpected N-nitrosation reaction that occurs upon storage of carvedilol- or propranolol-excipient blends in a stability chamber in the presence of saturated sodium nitrite (NaNO 2 ) solution to control relative humidity (∼60% RH). In both cases, the major products were identified as the corresponding N-nitroso derivatives of the secondary amine drugs based on mass spectrometry, UV-vis and retention time. These degradation products were not observed upon storage of the samples at the same temperature and humidity but in the presence of saturated potassium iodide (KI) solution (∼60% RH) for humidity control. The levels of the N-nitrosamine derivatives varied with the pH of various NaNO 2 batches. The presence of volatile NOx species in the headspace of a container containing saturated NaNO 2 solution was confirmed via the Griess assay. The process for formation of the N-nitrosamine derivatives is proposed to involve volatilization of nitric oxide (NO) from aqueous nitrite solution into the headspace of the container followed by diffusion into the solid drug-excipient blend and subsequent reaction of NOx with the secondary amine. Copyright © 2017 Elsevier B.V. All rights reserved.

Clarification of terminology in drug safety.

PubMed

Aronson, Jeffrey K; Ferner, Robin E

2005-01-01

Nomenclature surrounding drug safety needs to be clear and unambiguous, so that patients, prescribers, manufacturers, and regulators can all understand each other. In particular, it needs to make it clear how adverse events and drug therapy are related to one another, how they are best classified, and their frequency, intensity and seriousness. In this article, we therefore discuss and define terms used in the field of drug safety, particularly terms that are sometimes misunderstood or misused, including medicinal product, pharmaceutical formulation, excipient, adverse event (or experience) and adverse drug reaction (or effect). We also discuss terms used to define the seriousness, intensity, and risk of adverse reactions, and their classification. Instead of creating definitions from scratch, as is commonly done, we have taken the novel approach of critically examining definitions that have been proposed or widely used and have formulated new or modified definitions based on a logical appraisal of their merits and demerits. We hope that these definitions will lead to discussion that will allow a corpus of satisfactory definitions to be widely agreed.

Development of a Rapid Derivative Spectrophotometric Method for Simultaneous Determination of Acetaminophen, Diphenhydramine and Pseudoephedrine in Tablets

PubMed Central

Souri, Effat; Rahimi, Aghil; Shabani Ravari, Nazanin; Barazandeh Tehrani, Maliheh

2015-01-01

A mixture of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride is used for the symptomatic treatment of common cold. In this study, a derivative spectrophotometric method based on zero-crossing technique was proposed for simultaneous determination of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride. Determination of these drugs was performed using the 1D value of acetaminophen at 281.5 nm, 2D value of diphenhydramine hydrochloride at 226.0 nm and 4D value of pseudoephedrine hydrochloride at 218.0 nm. The analysis method was linear over the range of 5-50, 0.25-4, and 0.5-5 µg/mL for acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride, respectively. The within-day and between-day CV and error values for all three compounds were within an acceptable range (CV<2.2% and error<3%). The developed method was used for simultaneous determination of these drugs in pharmaceutical dosage forms and no interference from excipients was observed. PMID:25901150

EPR study on non- and gamma-irradiated herbal pills

NASA Astrophysics Data System (ADS)

Aleksieva, K.; Lagunov, O.; Dimov, K.; Yordanov, N. D.

2011-06-01

The results of EPR studies on herbal pills of marigold, hawthorn, yarrow, common balm, tutsan, nettle and thyme before and after gamma-irradiation are reported. Before irradiation all samples exhibit one weak singlet EPR line with a g-factor of 2.0048±0.0005. After irradiation herbal pills could be separated in two groups according to their EPR spectra. Radiation-induced free radicals in pills of marigold, yarrow, nettle, tutsan and thyme could be attributed mainly to saccharide excipients. Tablets of hawthorn and common balm show "cellulose-like" EPR spectrum, superimposed on partly resolved carbohydrate spectrum, due to the active part (herb) and inulin, which is present in the pills as an excipient. Fading study of the radiation-induced EPR signals confirms that sugar radicals are more stable than cellulose species. The reported results show that the presence of characteristic EPR spectra of herbal pills due to excipients or active part can be used as unambiguous proof of radiation processing within 35 or more days after irradiation.

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.

In-vitro evaluation of enteric coated insulin tablets containing absorption enhancer and enzyme inhibitor.

PubMed

Wong, Chun Y; Martinez, Jorge; Carnagarin, Revathy; Dass, Crispin R

2017-03-01

The aim of this study was to develop an enteric coated insulin tablet formulation using polymers, absorption enhancer and enzyme inhibitor, which protect the tablets in acidic pH and enhance systemic bioavailability. In this study, the influence of coating by cellulose acetate hydrogen phthalate solution and chosen excipients on Glut-4 transporter translocation in C2C12 skeletal muscle cells was examined. Following the determination of optimum number of coating layers, two dissolution buffers such as 0.01 m hydrochloric acid, pH 2, and 50 mm phosphate, pH 7.4, were employed to determine the in-vitro release of insulin. Insulin was protected by the coating during the dissolution process. Five (5-CL) coating layers and eight (8-CL) coating layers had minimal insulin release in hydrochloric acid, but not three (3-CL) coating layers. Glut-4 translocation in C2C12 cells was promoted by the chosen excipients. No detrimental metabolic effects were observed in these cells. To date, limited studies combine the overall effectiveness of multiple excipients. Our study showed that the coated tablets have an immediate release effect in phosphate buffer. In Glut-4 translocation assay, insulin was still functional after releasing from the tablet. Such tablet formulation can be potentially beneficial to type 1 diabetes patients. © 2017 Royal Pharmaceutical Society.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate.

PubMed

Thambavita, Dhanusha; Galappatthy, Priyadarshani; Mannapperuma, Uthpali; Jayakody, Lal; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Groot, Dirk W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E; Shah, Vinod P; Dressman, Jennifer

2017-10-01

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study. Copyright © 2017 American Pharmacists Association®. All rights reserved.

EFFECT OF SIMULTANEOUSLY SILICIFIED MICROCRYSTALLINE CELLULOSE AND PREGELATINIZED STARCH ON THE THEOPHYLLINE TABLETS STABILITY.

PubMed

Mazurek-Wadołkowska, Edyta; Winnicka, Katarzyna; Czyzewska, Urszula; Miltyk, Wojciech

2016-07-01

High profitability and simplicity of direct compression, encourages pharmaceutical industry to create universal excipients to improve technology process. Prosolv® SMCC - silicified microcrystalline cellulose and Starch 1500® - pregelatinized starch, are the example of multifunctional excipients. The aim of the present study was to evaluate the stability of theophylline (API) in the mixtures with excipients with various physico-chemical properties (Prosolv® SMCC 90, Prosolv® SMCC HD 90, Prosolv* SMCC 50®, Starch 1500® and magnesium stearate). The study presents results of thermal analysis of the mixtures with theophylline before and after 6 months storage of the tablets at various temperatures and relative humidity conditions (25 ± 2°C/40 ± 5% RH, 40 ± 2°C/75 ± 5% RH). It was shown that high concentration of Starch 1500® (49%) affects the stability of the theophylline tablets with Prosolv® SMCC. Prosolv® SMCC had no effect on API stability as confirmed by the differential scanning calorimetry (DSC). Changes in peak placements were observed just after tabletting process, which might indicate that compression accelerated the incompatibilities between theophylline and Starch 1500. TGA analysis showed loss in tablets mass equal to water content in starch. GC-MS study established no chemical decomposition of theophylline. We demonstrated that high content of Starch 1500® (49%) in the tablet mass, affects stability on tablets containing theophylline and Prosolv® SMCC.

Molecular Factors Governing the Liquid and Glassy States Recrystallization of Celecoxib in Binary Mixtures with Excipients of Different Molecular Weights.

PubMed

Grzybowska, K; Chmiel, K; Knapik-Kowalczuk, J; Grzybowski, A; Jurkiewicz, K; Paluch, M

2017-04-03

Transformation of poorly water-soluble crystalline pharmaceuticals to the amorphous form is one of the most promising strategies to improve their oral bioavailability. Unfortunately, the amorphous drugs are usually thermodynamically unstable and may quickly return to their crystalline form. A very promising way to enhance the physical stability of amorphous drugs is to prepare amorphous compositions of APIs with certain excipients which can be characterized by significantly different molecular weights, such as polymers, acetate saccharides, and other APIs. By using different experimental techniques (broadband dielectric spectroscopy, differential scanning calorimetry, X-ray diffraction) we compare the effect of adding the large molecular weight polymer-polyvinylpyrrolidone (PVP K30)-and the small molecular weight excipient-octaacetylmaltose (acMAL)-on molecular dynamics as well as the tendency to recrystallization of the amorphous celecoxib (CEL) in the amorphous solid dispersions: CEL-PVP and CEL-acMAL. The physical stability investigations of the binary systems were performed in both the supercooled liquid and glassy states. We found that acMAL is a better inhibitor of recrystallization of amorphous CEL than PVP K30 deep in the glassy state (T < T g ). In contrast, PVP K30 is a better crystallization inhibitor of CEL than acMAL in the supercooled liquid state (at T > T g ). We discuss molecular factors governing the recrystallization of amorphous CEL in examined solid dispersions.

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.

[Physical fingerprint for quality control of traditional Chinese medicine extract powders].

PubMed

Zhang, Yi; Xu, Bing; Sun, Fei; Wang, Xin; Zhang, Na; Shi, Xin-Yuan; Qiao, Yan-Jiang

2016-06-01

The physical properties of both raw materials and excipients are closely correlated with the quality of traditional Chinese medicine preparations in oral solid dosage forms. In this paper, based on the concept of the chemical fingerprint for quality control of traditional Chinese medicine products, the method of physical fingerprint for quality evaluation of traditional Chinese medicine extract powders was proposed. This novel physical fingerprint was built by the radar map, and consisted of five primary indexes (i.e. stackablity, homogeneity, flowability, compressibility and stability) and 12 secondary indexes (i.e. bulk density, tap density, particle size<50 μm percentage, relative homogeneity index, hausner ratio, angle of repose, powder flow time, inter-particle porosity, Carr index, cohesion index, loss on drying, hygroscopicity). Panax notoginseng saponins (PNS) extract was taken for an example. This paper introduced the application of physical fingerprint in the evaluation of source-to-source and batch-to-batch quality consistence of PNS extract powders. Moreover, the physical fingerprint of PNS was built by calculating the index of parameters, the index of parametric profile and the index of good compressibility, in order to successfully predict the compressibility of the PNS extract powder and relevant formulations containing PNS extract powder and conventional pharmaceutical excipients. The results demonstrated that the proposed method could not only provide new insights into the development and process control of traditional Chinese medicine solid dosage forms. Copyright© by the Chinese Pharmaceutical Association.

[The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

PubMed

Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration-dissolving of a tablet, is conducive to the reduction of gastrointestinal side effects and better tolerance of the therapeutic product by a patient. The study on pharmaceutical availability indicated relevant kinetic differences between tested therapeutic products. They are particularly visible between standard formulations and the one with prolonged release (Glucophage XR500). Its release profile bears features of kinetics similar to zero-order reactions. Tested therapeutic products contain a large amount of the biologically active substance in relation to the content of excipients. A higher content of excipients in a single tablet mass distinguishes Siofor in comparison with Glucophage i Metformax. The excipients used in the formulations of tested preparations are comparable. A higher percentage of binding agents (HPMC, PVP) is observed, but there is a lack of typical disintegrants which results in a longer disintegration time up to 15 minutes. Siofor disintegrates at the same time as Formetic, but longer than Glucophage i Metformax. Considering the large content of the active substance and pharmacological properties of metformin hydrochloride, such a disintegration might have beneficial consequences, because the amount of the free active substance in the gastrointestinal tract will increase over the longer time period what will reduce the level of gastrointestinal side effects. The release profiles of metformin hydrochloride from tested therapeutic products are comparable. The Glucophage XR 500 formulation with the release kinetics of metformin hydrochloride similar to the zero-order kinetics is completely different from the others. The above is confirmed by the mathematical analysis of release profiles of metformin hydrochloride from tested preparations where equations of lines describing the release profile are characterized by similar values of correlation coefficients.

A critical review on tablet disintegration.

PubMed

Quodbach, Julian; Kleinebudde, Peter

2016-09-01

Tablet disintegration is an important factor for drug release and can be modified with excipients called tablet disintegrants. Tablet disintegrants act via different mechanisms and the efficacy of these excipients is influenced by various factors. In this review, the existing literature on tablet disintegration is critically reviewed. Potential disintegration mechanisms, as well as impact factors on the disintegration process will be discussed based on experimental evidence. Search terms for Scopus and Web of Science included "tablet disintegration", "mechanism tablet disintegration", "superdisintegrants", "disintegrants", "swelling force", "disintegration force", "disintegration mechanisms", as well as brand names of commonly applied superdisintegrants. References of identified papers were screened as well. Experimental data supports swelling and shape recovery as main mechanisms of action of disintegrants. Other tablet excipients and different manufacturing techniques greatly influence the disintegration process. The use of different excipients, experimental setups and manufacturing techniques, as well as the demand for original research led to a distinct patchwork of knowledge. Broader, more systematic approaches are necessary not only to structure the past but also future findings.

Biopharmaceutical evaluation of surface active ophthalmic excipients using in vitro and ex vivo corneal models.

PubMed

Juretić, Marina; Cetina-Čižmek, Biserka; Filipović-Grčić, Jelena; Hafner, Anita; Lovrić, Jasmina; Pepić, Ivan

2018-07-30

The objective of this study was to systematically investigate the effects of surface active ophthalmic excipients on the corneal permeation of ophthalmic drugs using in vitro (HCE-T cell-based model) and ex vivo (freshly excised porcine cornea) models. The permeation of four ophthalmic drugs (i.e., timolol maleate, chloramphenicol, diclofenac sodium and dexamethasone) across in vitro and ex vivo corneal models was evaluated in the absence and presence of four commonly used surface active ophthalmic excipients (i.e., Polysorbate 80, Tyloxapol, Cremophor® EL and Pluronic® F68). The concentration and self-aggregation-dependent effects of surface active ophthalmic excipients on ophthalmic drug permeability were studied from the concentration region where only dissolved monomer molecules of surface active ophthalmic excipients exist, as well as the concentration region in which aggregates of variable size and dispersion are spontaneously formed. Neither the surface active ophthalmic excipients nor the ophthalmic drugs at all concentrations that were tested significantly affected the barrier properties of both corneal models, as assessed by transepithelial electrical resistance (TEER) monitoring during the permeability experiments. The lowest concentration of all investigated surface active ophthalmic excipients did not significantly affect the ophthalmic drug permeability across both of the corneal models that were used. For three ophthalmic drugs (i.e., chloramphenicol, diclofenac sodium and dexamethasone), depressed in vitro and ex vivo permeability were observed in the concentration range of either Polysorbate 80, Tyloxapol, Cremophor® EL or Pluronic® F68, at which self-aggregation is detected. The effect was the most pronounced for Cremophor® EL (1 and 2%, w/V) and was the least pronounced for Pluronic® F68 (1%, w/V). However, all surface active ophthalmic excipients over the entire concentration range that was tested did not significantly affect the in vitro and ex vivo permeability of timolol maleate, which is the most hydrophilic ophthalmic drug that was investigated. The results of the dynamic light scattering measurements point to the association of ophthalmic drugs with self-aggregates of surface active ophthalmic excipients as the potential mechanism of the observed permeability-depressing effect of surface active ophthalmic excipients. A strong and statistically significant correlation was observed between in vitro and ex vivo permeability of ophthalmic drugs in the presence of surface active ophthalmic excipients, which indicates that the observed permeability-altering effects of surface active ophthalmic excipients were comparable and were mediated by the same mechanism in both corneal models. Copyright © 2018 Elsevier B.V. All rights reserved.

Quantification of Tribocharging of Pharmaceutical Powders in V-Blenders: Experiments, Multiscale Modeling, and Simulations.

PubMed

Naik, Shivangi; Hancock, Bruno; Abramov, Yuriy; Yu, Weili; Rowland, Martin; Huang, Zhonghui; Chaudhuri, Bodhisattwa

2016-04-01

Pharmaceutical powders are very prone to electrostatic charging by colliding and sliding contacts. In pharmaceutical formulation processes, particle charging is often a nuisance and can cause problems in the manufacture of products, such as affecting powder flow, fill, and dose uniformity. For a fundamental understanding of the powder triboelectrification, it is essential to study charge transfer under well-defined conditions. Hence, all experiments in the present study were conducted in a V-blender located inside a glove box with a controlled humidity of 20%. To understand tribocharging, different contact surfaces, namely aluminum, Teflon, poly methyl methacrylate, and nylon were used along with 2 pharmaceutical excipients and 2 drug substances. For the pharmaceutical materials, the work function values were estimated using MOPAC, a semiempirical molecular orbital package which has been previously used for the solid-state studies and molecular structure predictions. For a mechanistic understanding of tribocharging, a discrete element model incorporating charge transfer and electrostatic forces was developed. An effort was made to correlate tribocharging of pharmaceutical powders to properties such as cohesive energy density and surface energy. The multiscale model used is restricted as it considers only spherical particles with smooth surfaces. It should be used judiciously for other experimental assemblies because it does not represent a full validation of a tightly integrated model. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Detection of Botulinum Neurotoxin Serotype A, B, and F Proteolytic Activity in Complex Matrices with Picomolar to Femtomolar Sensitivity

PubMed Central

Dunning, F. Mark; Ruge, Daniel R.; Piazza, Timothy M.; Stanker, Larry H.; Zeytin, Füsûn N.

2012-01-01

Rapid, high-throughput assays that detect and quantify botulinum neurotoxin (BoNT) activity in diverse matrices are required for environmental, clinical, pharmaceutical, and food testing. The current standard, the mouse bioassay, is sensitive but is low in throughput and precision. In this study, we present three biochemical assays for the detection and quantification of BoNT serotype A, B, and F proteolytic activities in complex matrices that offer picomolar to femtomolar sensitivity with small assay volumes and total assay times of less than 24 h. These assays consist of magnetic beads conjugated with BoNT serotype-specific antibodies that are used to purify BoNT from complex matrices before the quantification of bound BoNT proteolytic activity using the previously described BoTest reporter substrates. The matrices tested include human serum, whole milk, carrot juice, and baby food, as well as buffers containing common pharmaceutical excipients. The limits of detection were below 1 pM for BoNT/A and BoNT/F and below 10 pM for BoNT/B in most tested matrices using 200-μl samples and as low as 10 fM for BoNT/A with an increased sample volume. Together, these data describe rapid, robust, and high-throughput assays for BoNT detection that are compatible with a wide range of matrices. PMID:22923410

Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid-Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms.

PubMed

Colgan, Stephen T; Zelesky, Todd C; Chen, Raymond; Likar, Michael D; MacDonald, Bruce C; Hawkins, Joel M; Carroll, Sophia C; Johnson, Gail M; Space, J Sean; Jensen, James F; DeMatteo, Vincent A

2016-07-01

Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug product's shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Indirect spectrophotometric determination of propranolol hydrochloride and piroxicam in pure and pharmaceutical formulations.

PubMed

Gowda, Babu G; Seetharamappa, Jaldappa; Melwanki, Mahaveer B

2002-06-01

Two simple and sensitive indirect spectrophotometric methods for the assay of propranolol hydrochloride (PPH) and piroxicam (PX) in pure and pharmaceutical formulations have been proposed. The methods are based on the oxidation of PPH by a known excess of standard N-bromosuccinimide (NBS) and PX by ceric ammonium sulfate (CAS) in an acidic medium followed by the reaction of excess oxidant with promethazine hydrochloride (PMH) and methdilazine hydrochloride (MDH) to yield red-colored products. The absorbance values decreased linearly with increasing concentration of the drugs. The systems obeyed Beer's law over the concentration ranges of 0.5 - 12.5 and 0.3 - 16.0 microg/ml for PPH, and 0.4 - 7.5 and 0.2 - 10 microg/ml for PX with PMH and MDH, respectively. Molar absorptivity values, as calculated from Beer's law data, were found to be 1.36 x 10(4) and 2.55 x 10(4) l mol(-1) cm(-1) for PPH, and 2.08 x 10(4) and 2.05 x 10(4) l mol(-1) cm(-1) for PX with PMH and MDH, respectively. The common excipients and additives did not interfere with their determinations. The proposed methods have been successfully applied to the determinations of PPH and PX in various dosage forms. The results obtained by the proposed methods compare favorably with those of official methods.

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.

FEM simulation of the die compaction of pharmaceutical products: influence of visco-elastic phenomena and comparison with experiments.

PubMed

Diarra, Harona; Mazel, Vincent; Busignies, Virginie; Tchoreloff, Pierre

2013-09-10

This work studies the influence of visco-elastic behavior in the finite element method (FEM) modeling of die compaction of pharmaceutical products and how such a visco-elastic behavior may improve the agreement between experimental and simulated compression curves. The modeling of the process was conducted on a pharmaceutical excipient, microcrystalline cellulose (MCC), by using Drucker-Prager cap model coupled with creep behavior in Abaqus(®) software. The experimental data were obtained on a compaction simulator (STYLCAM 200R). The elastic deformation of the press was determined by performing experimental tests on a calibration disk and was introduced in the simulation. Numerical optimization was performed to characterize creep parameters. The use of creep behavior in the simulations clearly improved the agreement between the numerical and experimental compression curves (stresses, thickness), mainly during the unloading part of the compaction cycle. For the first time, it was possible to reproduce numerically the fact that the minimum tablet thickness is not obtained at the maximum compression stress. This study proves that creep behavior must be taken into account when modeling the compaction of pharmaceutical products using FEM methods. Copyright © 2013 Elsevier B.V. All rights reserved.

Chemometrics resolution and quantification power evaluation: Application on pharmaceutical quaternary mixture of Paracetamol, Guaifenesin, Phenylephrine and p-aminophenol.

PubMed

Yehia, Ali M; Mohamed, Heba M

2016-01-05

Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Failure of Cleaning Verification in Pharmaceutical Industry Due to Uncleanliness of Stainless Steel Surface.

PubMed

Haidar Ahmad, Imad A; Blasko, Andrei

2017-08-11

The aim of this work is to identify the parameters that affect the recovery of pharmaceutical residues from the surface of stainless steel coupons. A series of factors were assessed, including drug product spike levels, spiking procedure, drug-excipient ratios, analyst-to-analyst variability, intraday variability, and cleaning procedure of the coupons. The lack of a well-defined procedure that consistently cleaned the coupon surface was identified as the major contributor to low and variable recoveries. Assessment of cleaning the surface of the coupons with clean-in-place solutions (CIP) gave high recovery (>90%) and reproducible results (Srel≤4%) regardless of the conditions that were assessed previously. The approach was successfully applied for cleaning verification of small molecules (MW <1,000 Da) as well as large biomolecules (MW up to 50,000 Da).

Validated Colorimetric Assay of Clonidine Hydrochloride from Pharmaceutical Preparations

PubMed Central

Corciova, Andreia

2016-01-01

Clonidine hydrochloride is an antihypertensive agent used for migraine prophylaxis, attention deficit hyperactivity disorder, menopausal flushing and Tourette syndrome. The quantity of the active substance in pharmaceutical preparations must be within specific limits, in agreement with the respective label claim. Therefore, the aim of this study was to establish the conditions for two spectrophotometric methods for clonidine determination, based on the formation of the ion pair complex between clonidine hydrochloride and thymol blue/bromophenol blue. A Jasco UV-Vis 530 spectrophotometer was used for the analysis and the maxim absorbance was measured at 418 nm/448 nm against blank solution. After validation, the methods were used for quantification of clonidine hydrochloride in two commercial samples (tablets). The recovery of active substance varies between 98.06 and 100.13 % without interferences from the excipients. PMID:27610155

Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps

PubMed Central

2007-01-01

Inhibition of efflux pumps is an emerging approach in cancer therapy and drug delivery. Since it has been discovered that polymeric pharmaceutical excipients such as Tweens® or Pluronics® can inhibit efflux pumps, various other polymers have been investigated regarding their potential efflux pump inhibitory activity. Among them are polysaccharides, polyethylene glycols and derivatives, amphiphilic block copolymers, dendrimers and thiolated polymers. In the current review article, natural and synthetic polymers that are capable of inhibiting efflux pumps as well as their application in cancer therapy and drug delivery are discussed. PMID:17896100

Oral Medicines for Children in the European Paediatric Investigation Plans

PubMed Central

van Riet – Nales, Diana A.; Römkens, Erwin G. A. W.; Saint-Raymond, Agnes; Kozarewicz, Piotr; Schobben, Alfred F. A. M.; Egberts, Toine C. G.; Rademaker, Carin M. A.

2014-01-01

Introduction Pharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review. Methods All PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports. Results A hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified. Conclusion The EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound. PMID:24897509

Oral medicines for children in the European paediatric investigation plans.

PubMed

van Riet-Nales, Diana A; Römkens, Erwin G A W; Saint-Raymond, Agnes; Kozarewicz, Piotr; Schobben, Alfred F A M; Egberts, Toine C G; Rademaker, Carin M A

2014-01-01

Pharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review. All PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports. A hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified. The EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound.

New approach for determination of sulfadiazine in pharmaceutical preparations using 4(4-sulphophenylazo)pyrogallol: Kinetic spectrophotometric method.

PubMed

Naser, Naser A; Alasedi, Kasim M; Khan, Zainab A

2018-05-04

A new trend describes the development and validation of a simple, sensitive and selective kinetic spectrophotometric methods for the determination of sulfadiazine in pharmaceutical formulations has been conducted. In this paper, sulfadiazine was derivatized as a new organic compound 4(4-sulphophenylazo) pyrogallol, 4-SPAP, by coupling pyrogallol with diazotized sulfadiazine in medium of controlled pH. 4-SPAP was characterized by techniques of FT-IR, H-NMR, GC-Mass, TG and DSC thermal analysis methods. Solvatochromic behavior in solvents of various polarities was also investigated. The determination of sulfadiazine was accomplished by initial rate and fixed time methods. These methods were based on the reaction of the compound containing sulfadiazine, 4-SPAP, with Ca(II) to form colored product with a maximum absorbance at 520 nm. The two methods were adopted for constructing the calibration curves and examined for their suitability for the quantitation of sulfadiazine in pharmaceuticals. The limit of detection (LOD) and limit of quantification (LOQ) were found to be, by initial rate method, 0.35 and 1.05 μg·mL -1 and that by fixed time method were found to be 0.69 and 2.07 μg·mL -1 , respectively. The percent relative standard deviations (%RSD) for the results ranged from 1.04% to 1.76% and 0.85% to 1.42% for the initial rate and fixed time methods of the proposed kinetic spectrophotometric method, respectively. The existence of common excipients in the pharmaceutical formulation did not produce any significant interference. Statistical comparison was reported as indicated from the F- and t-test data of the proposed methods with that of reference method showing excellent agreement and indicating no significant difference in their accuracy and precision. Copyright © 2018 Elsevier B.V. All rights reserved.

Combining Two-Dimensional Diffusion-Ordered Nuclear Magnetic Resonance Spectroscopy, Imaging Desorption Electrospray Ionization Mass Spectrometry, and Direct Analysis in Real-Time Mass Spectrometry for the Integral Investigation of Counterfeit Pharmaceuticals

PubMed Central

Nyadong, Leonard; Harris, Glenn A.; Balayssac, Stéphane; Galhena, Asiri S.; Malet-Martino, Myriam; Martino, Robert; Parry, R. Mitchell; Wang, May Dongmei; Fernández, Facundo M.; Gilard, Véronique

2016-01-01

During the past decade, there has been a marked increase in the number of reported cases involving counterfeit medicines in developing and developed countries. Particularly, artesunate-based antimalarial drugs have been targeted, because of their high demand and cost. Counterfeit antimalarials can cause death and can contribute to the growing problem of drug resistance, particularly in southeast Asia. In this study, the complementarity of two-dimensional diffusion-ordered 1H nuclear magnetic resonance spectroscopy (2D DOSY 1H NMR) with direct analysis in real-time mass spectrometry (DART MS) and desorption electrospray ionization mass spectrometry (DESI MS) was assessed for pharmaceutical forensic purposes. Fourteen different artesunate tablets, representative of what can be purchased from informal sources in southeast Asia, were investigated with these techniques. The expected active pharmaceutical ingredient was detected in only five formulations via both nuclear magnetic resonance (NMR) and mass spectrometry (MS) methods. Common organic excipients such as sucrose, lactose, stearate, dextrin, and starch were also detected. The graphical representation of DOSY 1H NMR results proved very useful for establishing similarities among groups of samples, enabling counterfeit drug “chemotyping”. In addition to bulk- and surface-average analyses, spatially resolved information on the surface composition of counterfeit and genuine antimalarial formulations was obtained using DESI MS that was performed in the imaging mode, which enabled one to visualize the homogeneity of both genuine and counterfeit drug samples. Overall, this study suggests that 2D DOSY 1H NMR, combined with ambient MS, comprises a powerful suite of instrumental analysis methodologies for the integral characterization of counterfeit antimalarials. PMID:19453162

Combining two-dimensional diffusion-ordered nuclear magnetic resonance spectroscopy, imaging desorption electrospray ionization mass spectrometry, and direct analysis in real-time mass spectrometry for the integral investigation of counterfeit pharmaceuticals.

PubMed

Nyadong, Leonard; Harris, Glenn A; Balayssac, Stéphane; Galhena, Asiri S; Malet-Martino, Myriam; Martino, Robert; Parry, R Mitchell; Wang, May Dongmei; Fernández, Facundo M; Gilard, Véronique

2009-06-15

During the past decade, there has been a marked increase in the number of reported cases involving counterfeit medicines in developing and developed countries. Particularly, artesunate-based antimalarial drugs have been targeted, because of their high demand and cost. Counterfeit antimalarials can cause death and can contribute to the growing problem of drug resistance, particularly in southeast Asia. In this study, the complementarity of two-dimensional diffusion-ordered (1)H nuclear magnetic resonance spectroscopy (2D DOSY (1)H NMR) with direct analysis in real-time mass spectrometry (DART MS) and desorption electrospray ionization mass spectrometry (DESI MS) was assessed for pharmaceutical forensic purposes. Fourteen different artesunate tablets, representative of what can be purchased from informal sources in southeast Asia, were investigated with these techniques. The expected active pharmaceutical ingredient was detected in only five formulations via both nuclear magnetic resonance (NMR) and mass spectrometry (MS) methods. Common organic excipients such as sucrose, lactose, stearate, dextrin, and starch were also detected. The graphical representation of DOSY (1)H NMR results proved very useful for establishing similarities among groups of samples, enabling counterfeit drug "chemotyping". In addition to bulk- and surface-average analyses, spatially resolved information on the surface composition of counterfeit and genuine antimalarial formulations was obtained using DESI MS that was performed in the imaging mode, which enabled one to visualize the homogeneity of both genuine and counterfeit drug samples. Overall, this study suggests that 2D DOSY (1)H NMR, combined with ambient MS, comprises a powerful suite of instrumental analysis methodologies for the integral characterization of counterfeit antimalarials.

Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions.

PubMed

Brewster, M E; Vandecruys, R; Verreck, G; Peeters, J

2008-03-01

Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates.

New multifunctional pharmaceutical excipient in tablet formulation based on citric acid-cyclodextrin polymer.

PubMed

Garcia-Fernandez, Maria José; Tabary, Nicolas; Chai, Feng; Cazaux, Frédéric; Blanchemain, Nicolas; Flament, Marie-Pierre; Martel, Bernard

2016-09-25

A β-cyclodextrin (β-CD) polymer obtained by crosslinking β-CD with citric acid in its water-insoluble (PCD-I) and soluble (PCD-S) forms was used as a multifunctional direct compression excipient for tablet designing. PCD-I powder was obtained after grinding the solid fraction through a 200μm grid. PCD-S powder was recovered after lyophilization or spray drying of the PCD-S aqueous solutions, eventually followed by a wet granulation step. Both PCD-I and PCD-S powders were characterized, separately and mixed in variable ratios, based on dynamic water vapor sorption, SEM, particle size distribution, tapped density, compressibility, and flowability. PCD-I and spray dried and lyophilized/wet granulated PCD-S, as well as the mixture PCD-I/PCD-S=90/10, presented optimal free flowing characteristics. Then, PCD-I or PCD-S powders - separately or mixed in variable ratios - were used for tablets preparation by direct compression without adding any other excipient (e.g. binder, lubricant, disintegrant etc). As PCD-I decreased, tablets resistance to crushing and disintegration time increased from 15s to 15min (against 30min for β-CD), showing the improved disintegrant functionality of PCD-I, that rapidly swelled once in contact with water. Finally, PCD was force-fed to Sprague-Dawley rats (2g/kg) which were then observed during 14days for any clinical signs of toxicity. Copyright © 2016. Published by Elsevier B.V.

Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy.

PubMed

Kakio, Tomoko; Nagase, Hitomi; Takaoka, Takashi; Yoshida, Naoko; Hirakawa, Junichi; Macha, Susan; Hiroshima, Takashi; Ikeda, Yukihiro; Tsuboi, Hirohito; Kimura, Kazuko

2018-06-01

The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market.

Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing.

PubMed

Goyanes, Alvaro; Fina, Fabrizio; Martorana, Annalisa; Sedough, Daniel; Gaisford, Simon; Basit, Abdul W

2017-07-15

The aim of this study was to manufacture 3D printed tablets (printlets) from enteric polymers by single filament fused deposition modeling (FDM) 3D printing (3DP). Hot melt extrusion was used to generate paracetamol-loaded filaments from three different grades of the pharmaceutical excipient hypromellose acetate succinate (HPMCAS), grades LG, MG and HG. One-step 3DP was used to process these filaments into enteric printlets incorporating up to 50% drug loading with two different infill percentages (20 and 100%). X-ray Micro Computed Tomography (Micro-CT) analysis revealed that printlets with 20% infill had cavities in the core compared to 100% infill, and that the density of the 50% drug loading printlets was higher than the equivalent formulations loaded with 5% drug. In biorelevant bicarbonate dissolution media, drug release from the printlets was dependent on the polymer composition, drug loading and the internal structure of the formulations. All HPMCAS-based printlets showed delayed drug release properties, and in the intestinal conditions, drug release was faster from the printlets prepared with polymers with a lower pH-threshold: HPMCAS LG > HPMCAS MG > HPMCAS HG. These results confirm that FDM 3D printing makes it possible not only to manufacture delayed release printlets without the need for an outer enteric coating, but it is also feasible to adapt the release profile in response to the personal characteristics of the patient, realizing the full potential of additive manufacturing in the development of personalised dose medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmaceutical applications of cyclodextrins: basic science and product development.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2010-11-01

Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing. © 2010 The Authors. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

Grewia gum as a potential aqueous film coating agent. I: Some physicochemical characteristics of fractions of grewia gum

PubMed Central

Ogaji, Ikoni J.; Okafor, Ignatius S.; Hoag, Stephen W.

2013-01-01

Background: Grewia gum has received attention as a polymeric pharmaceutical excipient in the recent times, being employed as a suspending, film coating, mucoadhesive, and binding agent. The low aqueous solubility, however, has limited its characterization and application. Objective: The purpose of this study was to fractionate and evaluate some physicochemical properties of the gum. Materials and Methods: Aqueous dispersion of the gum was treated at 80°C for 30 min in the presence of sodium chloride and was subsequently fractionated by successively centrifuging it at 3445 rpm for 30 min. Skeletal density, solubility, particle size, and rheological as well as thermal characteristics of the fractions were evaluated. The 1H nuclear magnetic resonance (NMR) and near infrared (NIR) profiles of the fractions were also investigated. The solubility of the gum increased up to fourfold while the viscosity decreased from 244 to as low as70 cP at 40 rpm with some fractions. Results: Grewia gum and the fractions showed good thermal stability exhibiting no thermal events, but charred irreversibly at 297°C irrespective of the fraction. The molecular weight averages by weight and by number of the fractions were between 233,100 and 235,000. The 1H nuclear magnetic resonance (NMR) spectra showed broad peaks. The NMR and NIR spectra suggested the presence of –OH and –OCH3 functional groups in this gum. Conclusion: The fractionation improved solubility and facilitated further investigations on its characteristics that may have implication on its processing, application, and optimization as a potential pharmaceutical excipient. PMID:23559825

Qualitative and quantitative control of pediatric syrups using Nuclear Magnetic Resonance and chemometrics.

PubMed

Alves Filho, Elenilson G; Silva, Lorena Mara A; Araújo, Nathália V P; Alves, Elenilson G; Lião, Luciano M; Alcantara, Glaucia B

2018-05-10

Several flavoring and sweetening agents added to excipient of pediatric syrups are not declared in the package leaflet. Therefore, the aim of this study was to develop a non-target, simple, and precise method for qualitative and quantitative evaluation of pediatric syrups using NMR spectroscopy combined with chemometrics. This approach allowed the identification of several added compounds as citric acid, cyclamate, ethanol, glycerol, propylene glycol, saccharin, sorbitol, fructose, glucose, and sucrose. Among the sugared syrups, sucrose was the main carbohydrate with approximately 59.1%, and for sweetened syrups, glycerol with 25.5%. The ethanol was found with highest concentration of 4.0%, approximately. In addition, some syrups presented both sugar and sweetener, which is inconsistent according to the purpose of the addition. Consequently, institutional structures of countries as Brazil that are in charge of public health should put additional compliance pressure on pharmaceutical companies to clearly declare in package leaflet the presence and exact amount of the main compounds (at least) existent in the pediatric excipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Optimization of orodispersible and conventional tablets using simplex lattice design: Relationship among excipients and banana extract.

PubMed

Duangjit, Sureewan; Kraisit, Pakorn

2018-08-01

The objective of this study was focused on the optimization of the pharmaceutical excipients and banana extract in the preparation of orally disintegrating banana extract tablets (OD-BET) and conventional banana extract tablets (CO-BET) using a simplex lattice design. Various ratios of banana extract (BE), dibasic calcium phosphate (DCP) and microcrystalline cellulose (MCC) were used to prepare banana extract tablets (BET). The results indicated that the optimal OD-BET and CO-BET consisted of BE: DCP: MCC at 10.0, 88.8, 1.2, 10.0, 83.8: and 6.2, respectively. AFM demonstrated that the surface of BET with BE + MCC was smooth and compacted when compared to BET with BE + DCP + MCC and BE + DCP. FTIR and XRD showed a correlation in the results and indicated that no interaction of each ingredient occurred in the process of BET formulation. Therefore, the experimental design is potentially useful in formulated OD-BET and CO-BET by using only one design simultaneously. Copyright © 2018 Elsevier Ltd. All rights reserved.

Co-processing as a tool to improve aqueous dispersibility of cellulose ethers.

PubMed

Sharma, Payal; Modi, Sameer R; Bansal, Arvind K

2015-01-01

Cellulose ethers are important materials with numerous applications in pharmaceutical industry. They are widely employed as stabilizers and viscosity enhancers for dispersed systems, binders in granulation process and as film formers for tablets. These polymers, however, exhibit challenge during preparation of their aqueous dispersions. Rapid hydration of their surfaces causes formation of a gel that prevents water from reaching the inner core of the particle. Moreover, the surfaces of these particles become sticky, thus leading to agglomeration, eventually reducing their dispersion kinetics. Numerous procedures have been tested to improve dispersibility of cellulose ethers. These include the use of cross-linking agents, alteration in the synthesis process, adjustment of water content of cellulose ether, modification by attaching hydrophobic substituents and co-processing using various excipients. Among these, co-processing has provided the most encouraging results. This review focuses on the molecular mechanisms responsible for the poor dispersibility of cellulose ethers and the role of co-processing technologies in overcoming the challenge. An attempt has been made to highlight various co-processing techniques and specific role of excipients used for co-processing.

Halogen bonding and pharmaceutical cocrystals: the case of a widely used preservative.

PubMed

Baldrighi, Michele; Cavallo, Gabriella; Chierotti, Michele R; Gobetto, Roberto; Metrangolo, Pierangelo; Pilati, Tullio; Resnati, Giuseppe; Terraneo, Giancarlo

2013-05-06

3-Iodo-2-propynyl-N-butylcarbamate (IPBC) is an iodinated antimicrobial product used globally as a preservative, fungicide, and algaecide. IPBC is difficult to obtain in pure form as well as to handle in industrial products because it tends to be sticky and clumpy. Here, we describe the preparation of four pharmaceutical cocrystals involving IPBC. The obtained cocrystals have been characterized by X-ray diffraction, solution and solid-state NMR, IR, and DSC analyses. In all the described cases the halogen bond (XB) is the key interaction responsible for the self-assembly of the pharmaceutical cocrystals thanks to the involvement of the 1-iodoalkyne moiety of IPBC, which functions as a very reliable XB-donor, with both neutral and anionic XB-acceptors. Most of the obtained cocrystals have improved properties with respect to the source API, in terms, e.g., of thermal stability. The cocrystal involving the GRAS excipient CaCl2 has superior powder flow characteristics compared to the pure IPBC, representing a promising solution to the handling issues related to the manufacturing of products containing IPBC.

Derivative spectrophotometry for the determination of faropenem in the presence of degradation products: an application for kinetic studies.

PubMed

Cielecka-Piontek, Judyta

2013-07-01

A simple and selective derivative spectrophotometric method was developed for the quantitative determination of faropenem in pure form and in pharmaceutical dosage. The method is based on the zero-crossing effect of first-derivative spectrophotometry (λ = 324 nm), which eliminates the overlapping effect caused by the excipients present in the pharmaceutical preparation, as well as degradation products, formed during hydrolysis, oxidation, photolysis, and thermolysis. The method was linear in the concentration range 2.5-300 μg/mL (r = 0.9989) at λ = 341 nm; the limits of detection and quantitation were 0.16 and 0.46 μg/mL, respectively. The method had good precision (relative standard deviation from 0.68 to 2.13%). Recovery of faropenem ranged from 97.9 to 101.3%. The first-order rate constants of the degradation of faropenem in pure form and in pharmaceutical dosage were determined by using first-derivative spectrophotometry. A statistical comparison of the validation results and the observed rate constants for faropenem degradation with these obtained with the high-performance liquid chromatography method demonstrated that both were compatible.

Pharmaceutical Particle Engineering via Spray Drying

PubMed Central

2007-01-01

This review covers recent developments in the area of particle engineering via spray drying. The last decade has seen a shift from empirical formulation efforts to an engineering approach based on a better understanding of particle formation in the spray drying process. Microparticles with nanoscale substructures can now be designed and their functionality has contributed significantly to stability and efficacy of the particulate dosage form. The review provides concepts and a theoretical framework for particle design calculations. It reviews experimental research into parameters that influence particle formation. A classification based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination with process parameters influence the morphology of the engineered particles. A wide range of pharmaceutical application examples—low density particles, composite particles, microencapsulation, and glass stabilization—is discussed, with specific emphasis on the underlying particle formation mechanisms and design concepts. PMID:18040761

Development of NIRS method for quality control of drug combination artesunate–azithromycin for the treatment of severe malaria

PubMed Central

Boyer, Chantal; Gaudin, Karen; Kauss, Tina; Gaubert, Alexandra; Boudis, Abdelhakim; Verschelden, Justine; Franc, Mickaël; Roussille, Julie; Boucher, Jacques; Olliaro, Piero; White, Nicholas J.; Millet, Pascal; Dubost, Jean-Pierre

2012-01-01

Near infrared spectroscopy (NIRS) methods were developed for the determination of analytical content of an antimalarial-antibiotic (artesunate and azithromycin) co-formulation in hard gelatin capsule (HGC). The NIRS consists of pre-processing treatment of spectra (raw spectra and first-derivation of two spectral zones), a unique principal component analysis model to ensure the specificity and then two partial least-squares regression models for the determination content of each active pharmaceutical ingredient. The NIRS methods were developed and validated with no reference method, since the manufacturing process of HGC is basically mixed excipients with active pharmaceutical ingredients. The accuracy profiles showed β-expectation tolerance limits within the acceptance limits (±5%). The analytical control approach performed by reversed phase (HPLC) required two different methods involving two different preparation and chromatographic methods. NIRS offers advantages in terms of lower costs of equipment and procedures, time saving, environmentally friendly. PMID:22579599

Preferential interactions of trehalose, L-arginine.HCl and sodium chloride with therapeutically relevant IgG1 monoclonal antibodies.

PubMed

Sudrik, Chaitanya; Cloutier, Theresa; Pham, Phuong; Samra, Hardeep S; Trout, Bernhardt L

2017-10-01

Preferential interactions of weakly interacting formulation excipients govern their effect on the equilibrium and kinetics of several reactions of protein molecules in solution. Using vapor pressure osmometry, we characterized the preferential interactions of commonly used excipients trehalose, L-arginine.HCl and NaCl with three therapeutically-relevant, IgG1 monoclonal antibodies that have similar size and shape, but differ in their surface hydrophobicity and net charge. We further characterized the effect of these excipients on the reversible self-association, aggregation and viscosity behavior of these antibody molecules. We report that trehalose, L-arginine.HCl and NaCl are all excluded from the surface of the three IgG1 monoclonal antibodies, and that the exclusion behavior is linearly related to the excipient molality in the case of trehalose and NaCl, whereas a non-linear behavior is observed for L-arginine.HCl. Interestingly, we find that the magnitude of trehalose exclusion depends upon the nature of the protein surface. Such behavior is not observed in case of NaCl and L-arginine.HCl as they are excluded to the same extent from the surface of all three antibody molecules tested in this study. Analysis of data presented in this study provides further insight into the mechanisms governing excipient-mediated stabilization of mAb formulations.

Evaluation of stir-bar sorptive extraction coupled with thermal desorption GC-MS for the detection of leachables from polymer single use systems to drugs.

PubMed

Scherer, Nicole; Marcseková, Klaudia; Posset, Tobias; Winter, Gerhard

2018-04-15

Stir-bar Sorptive Extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC-MS) is widely accepted as the gold-standard analysis method for trace amounts of organic substances, including leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method's recovery. The scope of the present work was to fill in the unexplored territory in a threefold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG)-PDMS), and 3) by proposing a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of leachables with a log K o/w  ≥ 3.6 is negligible (-3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of -42.9%. For leachables with a log K o/w  < 3.6, the relative recovery in the presence of various proteins ranged from -72.8% to 15.6%, depending on the excipients of the drug product and not on the protein itself. The highest loss in sensitivity was observed when the excipient benzyl alcohol was present in the drug. Nonetheless, the limit of detection for the tested leachables in the inhibitory matrices was still below 3 μg/L (ppb). Additionally, SBSE was observed to be quantitatively reliable in all tested drug matrices for concentrations from 0.005 to 0.1 mg/mL (r 2  > 0.992). On average, the conventional PDMS coating resulted in a 28-fold higher signal-to-noise ratio compared to EG-PDMS. Furthermore, a broader range of leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection. Copyright © 2018 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.

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.

Derivatization of labetalol hydrochloride for its spectrofluorimetric and spectrophotometric determination inhuman plasma: Application to stability study

NASA Astrophysics Data System (ADS)

Omar, Mahmoud A.; Derayea, Sayed M.; Abdel-Lateef, Mohamed A.; El Hamd, Mohamed A.

2018-02-01

Two simple, selective and accurate methods were developed for the determination of Labetalol hydrochloride in pure form and pharmaceutical tablets. Both methods are based on derivatization of the studied drug with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBDsbnd Cl) in alkaline medium (pH 7.5).The reaction product was measured spectrofluorimetrically at 540 nm after excitation at 476 nm (method I) or spectrophotometrically at 480 nm (method II). The calibration graphs were rectilinear over the concentration ranges of 0.10-2.0 and 1.0-11.0 μg mL- 1 for methods I and II, respectively. The proposed methods were successfully applied to the analysis of commercial tablets without interference from common excipients. Furthermore, the spectrofluorimetric method was utilized for the in vitro determination of labetalol in spiked human plasma, with a percent mean recovery (n = 3) of 97.80 ± 1.29%. Moreover, the spectrofluorimetric method was extended to examine the stability study of LBT under different stress conditions such as alkaline, acidic, oxidative, photolytic and a thermal degradation.

Simultaneous determination of lovastatin and niacin in tablet by first and third derivative spectrophotometry and H-point standard addition methods

PubMed Central

Kazemipour, M.; Ansari, M.; Ramezani, H.; Moradalizadeh, M.

2012-01-01

Most cardiovascular diseases need to be treated by more than a simple drug and the use of combination products diminishes noncompliance. Advicor® as a combination product of a vitamin and a fat lowering agent has no monograph in official pharmacopeias for its quality control purposes. In this study, first and third derivative signals for NA and LV quantitation at the two pairs of wavelengths, 261 and 273 nm; 245 and 249 nm were monitored with the addition of standard solutions of NA or LV, respectively. The limits of detection were 0.03 and 0.32 mg/L for LV and NA, respectively. The limits of quantitation were 0.09 and 0.78 mg/L for LV and NA, respectively. RSD% for both interday and intraday precision was lower than 2.6 and 2.7% for LV and NA, respectively. Selectivity of the method was assessed for both degradation products produced in stress conditions and common excipients that may present in the pharmaceutical dosage forms. The recommended procedure was successfully applied to real samples. PMID:23181086

Derivatization of labetalol hydrochloride for its spectrofluorimetric and spectrophotometric determination inhuman plasma: Application to stability study.

PubMed

Omar, Mahmoud A; Derayea, Sayed M; Abdel-Lateef, Mohamed A; El Hamd, Mohamed A

2018-02-05

Two simple, selective and accurate methods were developed for the determination of Labetalol hydrochloride in pure form and pharmaceutical tablets. Both methods are based on derivatization of the studied drug with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBDCl) in alkaline medium (pH7.5).The reaction product was measured spectrofluorimetrically at 540nm after excitation at 476nm (method I) or spectrophotometrically at 480nm (method II). The calibration graphs were rectilinear over the concentration ranges of 0.10-2.0 and 1.0-11.0μgmL -1 for methods I and II, respectively. The proposed methods were successfully applied to the analysis of commercial tablets without interference from common excipients. Furthermore, the spectrofluorimetric method was utilized for the in vitro determination of labetalol in spiked human plasma, with a percent mean recovery (n=3) of 97.80±1.29%. Moreover, the spectrofluorimetric method was extended to examine the stability study of LBT under different stress conditions such as alkaline, acidic, oxidative, photolytic and a thermal degradation. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Determination of Verapamil HCl in Pharmaceutical Preparations by a Fluorescent Nano Probe Based on CdTe/CdS/ZnS Quantum Dots

PubMed Central

Muhammad, Sohail; Xu, Guanhong; Wei, Fangdi; Ma, Yujie; Ma, Yunsu; Song, Yueyue; Shi, Menglan; Xu, Xiaoman; Cen, Yao; Hu, Qin

2017-01-01

An analytical technique based on fluorescence quenching of CdTe/CdS/ZnS quantum dots (QDs) was developed to quantify verapamil in commercially available preparations. Various reaction parameters were optimized and the method developed was validated. One way analysis of variance (ANOVA) and post hoc tests at a 5% significance level were performed to justify the significance of the variation in observations. The linear range of the verapamil concentration was 0.25–5 µg/mL while the limit of detection was 20 µg/mL. Recovery and relative standard deviations were not more than ±10% of the actual amount and <5.9%, respectively. Foreign materials, common metal ions and pharmaceutical excipients of dosage forms caused little interference. To verify the application of the analytical method, the quantity of verapamil in commercially available dosage forms was measured. Verapamil content in the tablets and injections was not more than ±10% of the stated amount and it conformed to the specifications of both the British and the United States pharmacopoeias. In the case of statistical analysis, p-value was <0.05 in almost all levels of all parameters except for the optimized level of system. It can be concluded from the results that the designed method is simple, reliable, cost effective, selective, rapid and sensitive enough to be used for quantitative measurement of the verapamil HCl in dosage forms for quality control purposes. PMID:29084166

A novel approach for analyzing glass-transition temperature vs. composition patterns: application to pharmaceutical compound+polymer systems.

PubMed

Kalogeras, Ioannis M

2011-04-18

In medicine, polymer-based materials are commonly used as excipients of poorly water-soluble drugs. The success of the encapsulation, as well as the physicochemical stability of the products, is often reflected on their glass transition temperature (T(g)) vs. composition (w) dependencies. The shape of the T(g)(w) patterns is critically influenced by polymer's molecular mass, drug molecule's shape and molecular volume, the type and degree of shielding of hydrogen-bonding capable functional groups, as well as aspects of the preparation process. By altering mixture's T(g) the amorphous solid form of the active ingredient may be retained at ambient or body temperatures, with concomitant improvements in handling, solubility, dissolution rate and oral bioavailability. Given the importance of the problem, the glass transitions observed in pharmaceutical mixtures have been extensively analyzed, aiming to appraise the state of mixing and intermolecular interactions. Here, accumulated experimental information on related systems is re-evaluated and comparably discussed under the light of a more effective and system-inclusive T(g)(w) equation. The present analysis indicates that free volume modifications and conformational changes of the macromolecular chains dominate, over enthalpic effects of mixing, in determining thermal characteristics and crystallization inhibition/retardation. Moreover, hydrogen-bonding and ion-dipole heterocontacts--although favorable of a higher degree of mixing--appear less significant compared to the steric hindrances and the antiplasticization proffered by the higher viscosity component. Copyright © 2011 Elsevier B.V. All rights reserved.

Sensitive Indirect Spectrophotometric Method for Determination of H2-Receptor Antagonists in Pharmaceutical Formulations

PubMed Central

Darwish, Ibrahim A.; Hussein, Samiha A.; Mahmoud, Ashraf M.; Hassan, Ahmed I.

2007-01-01

A simple, accurate and sensitive spectrophotometric method has been developed and validated for determination of H2-receptor antagonists: cimetidine, famotidine, nizatidine, and ranitidine hydrochloride. The method was based on the oxidation of these drugs with cerium (IV) in presence of perchloric acid and subsequent measurement of the excess Ce (IV) by its reaction with p-dimethylaminocinnamaldehyde to give a red colored product (λmax at 464 nm). The decrease in the absorption intensity (ΔA) of the colored product, due to the presence of the drug was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9985-0.9994) were found between ΔA values and the concentrations of the drugs in a concentration range of 1-16 µg ml-1. The assay limits of detection and quantitation were 0.12-0.44 and 0.37-1.33 µg ml-1, respectively. The method was validated, in terms of accuracy, precision, ruggedness, and robustness; the results were satisfactory. The proposed method was successfully applied to the analysis of the investigated drugs in their pure and pharmaceutical dosage forms (recovery was 98.8-102.5 ± 0.79-1.72%) without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods. PMID:23675034

Insensitivity of compaction properties of brittle granules to size enlargement by roller compaction.

PubMed

Wu, Sy-Juen; Sun, Changquan 'Calvin'

2007-05-01

Pharmaceutical granules prepared by roller compaction often exhibit significant loss of tabletability, that is, reduction in tensile strength, when compared to virgin powder. This may be attributed to granule size enlargement for highly plastic materials, for example, microcrystalline cellulose. The sensitivity of powder compaction properties on granule size variations impacts the robustness of the dry granulation process. We hypothesize that such sensitivity of compaction properties on granule size is minimum for brittle materials because extensive fracture of brittle granules during compaction minimizes differences in initial granule size. We tested the hypothesis using three common brittle excipients. Results show that the fine (44-106 microm), medium (106-250 microm), and coarse (250-500 microm) granules exhibit essentially identical tabletability below a certain critical compaction pressure, 100, 140, and 100 MPa for spray-dried lactose monohydrate, anhydrous dibasic calcium phosphate, and mannitol, respectively. Above respective critical pressure, tabletability lines diverge with smaller granules exhibiting slightly higher tablet tensile strength at identical compaction conditions. Overall, tabletability of brittle granules is insensitive to granule size enlargement. The results provide a scientific basis to the common practice of incorporating brittle filler to a typical tablet formulation processed by roller compaction granulation. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.

Compatibility of chewing gum excipients with the amino acid L-cysteine and stability of the active substance in directly compressed chewing gum formulation.

PubMed

Kartal, Alma; Björkqvist, Mikko; Lehto, Vesa-Pekka; Juppo, Anne Mari; Marvola, Martti; Sivén, Mia

2008-09-01

Using L-cysteine chewing gum to eliminate carcinogenic acetaldehyde in the mouth during smoking has recently been introduced. Besides its efficacy, optimal properties of the gum include stability of the formulation. However, only a limited number of studies exist on the compatibility of chewing gum excipients and stability of gum formulations. In this study we used the solid-state stability method, Fourier transform infrared spectroscopy and isothermal microcalorimetry to investigate the interactions between L-cysteine (as a free base or as a salt) and excipients commonly used in gum. These excipients include xylitol, sorbitol, magnesium stearate, Pharmagum S, Every T Toco and Smily 2 Toco. The influence of temperature and relative humidity during a three-month storage period on gum formulation was also studied. Cysteine alone was stable at 25 degrees C/60% RH and 45 degrees C/75% RH whether stored in open or closed glass ambers. As a component of binary mixtures, cysteine base remained stable at lower temperature and humidity but the salt form was incompatible with all the studied excipients. The results obtained with the different methods corresponded with each other. At high temperature and humidity, excipient incompatibility with both forms of cysteine was obvious. Such sensitivity to heat and humidity during storage was also seen in studies on gum formulations. It was also found that cysteine is sensitive to high pressure and increase in temperature induced by compression. The results suggest that the final product should be well protected from temperature and humidity and, for example, cooling process before compression should be considered.

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

PubMed

Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

2014-12-01

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Effect of Quaternary Ammonium Carboxymethylchitosan on Release Rate In-vitro of Aspirin Sustained-release Matrix Tablets

PubMed Central

Meng, Lingbin; Teng, Zhongqiu; Zheng, Nannan; Meng, Weiwei; Dai, Rongji; Deng, Yulin

2013-01-01

The aim of this study was to develop a derivative of chitosan as pharmaceutical excipient used in sustained-release matrix tablets of poorly soluble drugs. A water-soluble quaternary ammonium carboxymethylchitosan was synthesized by a two-step reaction with carboxymethylchitosan (CMCTS), decylalkyl dimethyl ammonium and epichlorohydrin. The elemental analysis showed that the target product with 10.27% of the maximum grafting degree was obtained. To assess the preliminary safety of this biopolymer, cell toxicity assay was employed. In order to further investigate quaternary ammonium carboxymethylchitosan application as pharmaceutical excipient, aspirin was chosen as model drug. The effect of quaternary ammonium CMCTS on aspirin release rate from sustained-release matrix tablets was examined by in-vitro dissolution experiments. The results showed that this biopolymer had a great potential in increasing the dissolution of poorly soluble drug. With the addition of CMCTS-CEDA, the final cumulative release rate of drug rose up to 90%. After 12 h, at the grade of 10, 20 and 50 cps, the drug release rate increased from 58.1 to 90.7%, from 64.1 to 93.9%, from 69.3 to 96.1%, respectively. At the same time, aspirin release rate from sustainedrelease model was found to be related to the amount of quaternary ammonium CMCTS employed. With the increase of CMCTS-CEDA content, the accumulated release rate increased from 69.1% to 86.7%. The mechanism of aspirin release from sustained-release matrix tablets was also preliminary studied to be Fick diffusion. These data demonstrated that the chitosan derivative has positive effect on drug release from sustained-release matrix tablets. PMID:24250627

Excipients and their role in approved injectable products: current usage and future directions.

PubMed

Nema, Sandeep; Brendel, Ronald J

2011-01-01

This review article is a current survey of excipients used in approved injectable products. Information provided includes concentration ranges, function, frequency of use, and role in dosage form. This article is an update of a paper published more than a decade ago (reference 11). Since then many new products have been approved. Safety concerning excipients has evolved as the scientific community continues to learn about their usage. New excipients are being used in early phases of clinical trials to support novel therapeutic entities like RNAi, aptamers, anti-sense, fusion proteins, monoclonal antibodies, and variant scaffolds. Because these excipients are not inert, various pharmacopoeias are responding with monographs or informational chapters addressing excipient functionality. The final sections of this article discuss new excipients, serving specific needs that traditional excipients are unable to provide and for which safety studies are necessary to support a novel excipient for marketing applications. Excipients are added to parenteral dosage forms to serve a variety of functions including stabilization and as vehicles. This review article is a survey of excipients used in approved injectable products. Information provided includes excipient concentrations, functional roles, and frequency of use. This article is an update of an article originally published over a decade ago. Since then new products have been approved and safety concerns have evolved as the scientific community has learned about the usage of excipients. In addition, new excipients are being used in early phases of clinical trials to support novel therapeutic entities such as RNAi, aptamers, anti-sense, fusion proteins, monoclonal antibodies, and variant scaffolds. Because these excipients are not inert, various pharmacopoeias are responding with monographs or informational chapters addressing excipient functionality. The final sections of this article discuss new excipients, serving specific needs that traditional excipients are unable to provide and for which safety studies are necessary to support a novel excipient for marketing applications.

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.

Preparation, physicochemical and pharmaceutical characterization of chitosan from Catharsius molossus residue.

PubMed

Ma, Jiahua; Xin, Chao; Tan, Chengjia

2015-09-01

Polypeptide from Catharsius molossus L. is an active ingredient in the treatment of benign prostatic hyperplasia. The residue after extraction is harmful to the environment and is also a waste of resources. Chitosan was extracted from C. molossus L. residue with chemical methods and with an improved intermittent heating method. Physicochemical and pharmaceutical characteristics of chitosan from C. molossus L. and shrimp were mainly measured by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM). The results showed chitosan from C. molossus L. was superior to commercial medical-grade chitosan from shrimp in the aspects of degree of deacetylation, crystallinity, heavy metal content, viscosity, protein residue, ash content, and in vitro adhesion. In addition, properties of chitosan membrane were studied, including water vapor permeability, light transmittance, enzymatic hydrolysis, swelling behavior, mechanical properties, and SEM images. It was found that the membrane of chitosan from C. molossus L. had better performance. This preliminary result shows chitosan from C. molossus L. is more suitable than shrimp's as a pharmaceutical excipient in colonic adhesive drug delivery system. Copyright © 2015 Elsevier B.V. All rights reserved.

Microstructure of Tablet-Pharmaceutical Significance, Assessment, and Engineering.

PubMed

Sun, Changquan Calvin

2017-05-01

To summarize the microstructure - property relationship of pharmaceutical tablets and approaches to improve tablet properties through tablet microstructure engineering. The main topics reviewed here include: 1) influence of material properties and manufacturing process parameters on the evolution of tablet microstructure; 2) impact of tablet structure on tablet properties; 3) assessment of tablet microstructure; 4) development and engineering of tablet microstructure. Microstructure plays a decisive role on important pharmaceutical properties of a tablet, such as disintegration, drug release, and mechanical strength. Useful information on mechanical properties of a powder can be obtained from analyzing tablet porosity-pressure data. When helium pycnometry fails to accurately measure true density of a water-containing powder, non-linear regression of tablet density-pressure data is a useful alternative method. A component that is more uniformly distributed in a tablet generally exerts more influence on the overall tablet properties. During formulation development, it is highly recommended to examine the relationship between any property of interest and tablet porosity when possible. Tablet microstructure can be engineered by judicious selection of formulation composition, including the use of the optimum solid form of the drug and appropriate type and amount of excipients, and controlling manufacturing process.

NanoCrySP technology for generation of drug nanocrystals: translational aspects and business potential.

PubMed

Shete, Ganesh; Bansal, Arvind Kumar

2016-08-01

Drug nanocrystals have rapidly evolved into a mature drug delivery strategy in the last decade, with almost 16 products currently on the market. Several "top-down" technologies are available in the market for generation of nanocrystals. Despite several advantages, very few bottom-up technologies have been explored for commercial purpose. This short communication highlights a novel, bottom-up, spray drying based technology-NanoCrySP-to generate drug nanocrystals. Nanocrystals are generated in the presence of non-polymeric excipients that act as crystallization inducer for the drug. Excipients encourage crystallization of drug by plasticization, primary heterogeneous nucleation, and imparting physical barrier to crystal growth. Nanocrystals have shown significant improvement in dissolution and thereby oral bioavailability. NanoCrySP technology is protected through patents in India, the USA, and the European Union. NanoCrySP can be utilized for (i) pharmaceutical development of new chemical entities, (ii) differentiated products of existing molecules, and (iii) generic drug products. The aggregation of drug nanocrystals generated using NanoCrySP poses significant challenges in the nanocrystal-based product development. Addition of stabilizers either during spray drying or during dissolution has shown beneficial effects.

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.

Bio-based topical system for enhanced salicylic acid delivery: preparation and performance of gels.

PubMed

Langasco, Rita; Spada, Gianpiera; Tanriverdi, Sakine Tuncay; Rassu, Giovanna; Giunchedi, Paolo; Özer, Özgen; Gavini, Elisabetta

2016-08-01

New salicylic acid (SA)-loaded gels were developed using excipients made from renewable materials, and our goal was to improve drug permeation in the topical treatment of acne vulgaris. We studied the preparation parameters to obtain suitable gel formulations. Only naturally occurring polymers were used as gelling agents. Two hydrogels and three lipogels were selected and characterized in terms of drug loading, pH, viability cells, rheology, mechanical properties and in vitro permeation; these hydrogels and lipogels were compared with the traditional ointment. We also evaluated skin parameters before and after gel application. The formulations that we studied are non-Newtonian fluids; they have high drug loading and suitable mechanical properties. Lipogels exhibit a slower and more linear in vitro permeation profile compared with hydrogels. The different vehicles that we used affected drug permeation and improve patient compliance. Cytotoxicity studies suggest that all of the formulations are non-toxic. Lipogels demonstrate appropriate technological features and improved performance compared with the traditional ointment with regard to their composition. Lipogels may represent a new bio-based topical system for SA delivery. The use of 'green' excipients leads to 'skin-friendly' formulations that are able to satisfy environmental safety. © 2016 Royal Pharmaceutical Society.

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.

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.

Extending residence time and stability of peptides by Protected Graft Copolymer (PGC) excipient: GLP-1 example

PubMed Central

Castillo, Gerardo M.; Reichstetter, Sandra; Bolotin, Elijah M.

2011-01-01

Purpose The purpose of this study is to determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes. Methods To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of 1) the binding of excipient to GLP-1, 2) the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, 3) the in vitro bio-activity of excipient-formulated GLP-1, 4) the in vivo pharmacokinetics of excipient-formulated GLP-1, and 5) the efficacy of the excipient-formulated GLP-1 in diabetic rats. Results We showed reproducible synthesis of PGC excipient, showed high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and showed that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day. Conclusions PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides. PMID:21830140

The application of uniplex, duplex, and multiplex PCR for the absence of specified microorganism testing of pharmaceutical excipients and drug products.

PubMed

Ragheb, Suzan M; Yassin, Aymen S; Amin, Magdy A

2012-01-01

Notable progress has been made in methods that encourage the use of polymerase chain reaction (PCR) as a rapid and accurate tool in microbiological testing of pharmaceuticals. In this study, the detection of the four main specified microorganisms according to the pharmacopeial recommendations, Salmonella spp, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, was optimized in different pharmaceutical dosage forms and raw materials. Uniplex PCR was performed for the detection of each microorganism individually targeting the conserved region in each bacterial genome. Further optimizations were done to perform duplex and multiplex PCR assays considering relative concentrations of competitor primers used in the reaction. The uniplex PCR amplicons were successfully sequenced, confirming the conservation of used primers. Other validation parameters such as specificity, sensitivity, and robustness were examined closely. The method provides a high-throughput screening method to test different pharmaceutical preparations for specified microorganisms for the detection of microbiological contamination. Strict regulations govern the production of pharmaceutical products whether they are sterile or nonsterile. Certain official tests are carried out in microbiology testing laboratory in any pharmaceutical production facility to ensure the pharmaceuticals microbiological quality according to the standard pharmacopeial recommendations. Nonsterile products must be free of specified microorganisms that are used as a check for their quality. Topical preparations must be free of Pseudomonas aeruginosa and Staphylococcus aureus, and oral preparations must be free of Salmonella spp and Escherichia coli. Conventional microbiological methods are time-consuming, labor-intensive, and require long incubation times, resulting in delaying the release of the products. In this study, we tested and validated a polymerase chain reaction identification approach to detect indicator bacteria in pharmaceutical preparations. The method depends on amplification of certain conserved genes located in the four specified bacteria. The method is optimized to be carried out individually or collectively to detect all indicator bacteria in a single reaction in different forms of pharmaceutical products.

Basics of Compounding: 3D Printing--Pharmacy Applications: Geometric Shape Effects on 3D Printing.

PubMed

Allen, Loyd V

2017-01-01

As patient therapy becomes more specialized and individualized, one applicable method of drug delivery is through 3D printing. With 3D printing, pharmacists can provide either immediate or modified drug release of either an individual drug or multiple drugs in a singledosage unit. The release rates can be varied, not only by excipients in the formulation, but also to some extent by the shapes of the finished-drug preparation. Some studies demonstrating these concepts are included in this article, along with their method of compounding using 3D printing. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Integrated LC-MS/MS Analytical Systems and Physical Inspection for the Analysis of a Botanical Herbal Preparation.

PubMed

Lai, Kuan-Ming; Cheng, Yung-Yi; Tsai, Tung-Hu

2015-06-09

The herbal decoction process is generally inconvenient and unpleasant. To avoid using herbal medicine decoctions, various high-quality industrial and pharmaceutical herbal decoction products have been used in clinical applications for more than ten years in Taiwan. However, the consistency and standardization of the quality of these herbal medicines are goals that remain to be achieved. The aim of study was to develop a validated liquid chromatography-tandem electrospray ionization mass spectrometry (LC-MS/MS) method to determine the biomarkers astragaloside I, astragaloside IV, formononetin, cinnamic acid, paeoniflorin and gingerol in the herbal preparation known as Huangqi-Guizhi-Wuwu (HGW). To investigate the physical quality of HGW, methods such as scanning electron microscopy, light microscopy with Congo red and potassium iodine staining, solubility measurements, swelling power tests, and crude fiber analysis were used to identify additives in commercial pharmaceutical products. The optimal LC-MS/MS multiple reaction-monitoring system included a gradient program using 5 mM ammonium acetate buffer with 0.05% formic acid/methanol. The results demonstrate deviations in biomarker content across different brands. In addition to the herbal extract, starch and excipients in the pharmaceutical granule, and crushed crude herb powder was added to the pharmaceutical products to increase their herbal ingredient content. In conclusion, a rigorous examination should be performed to certify the quality of the herbal products.

Diffusion and swelling measurements in pharmaceutical powder compacts using terahertz pulsed imaging.

PubMed

Yassin, Samy; Su, Ke; Lin, Hungyen; Gladden, Lynn F; Zeitler, J Axel

2015-05-01

Tablet dissolution is strongly affected by swelling and solvent penetration into its matrix. A terahertz-pulsed imaging (TPI) technique, in reflection mode, is introduced as a new tool to measure one-dimensional swelling and solvent ingress in flat-faced pharmaceutical compacts exposed to dissolution medium from one face of the tablet. The technique was demonstrated on three tableting excipients: hydroxypropylmethyl cellulose (HPMC), Eudragit RSPO, and lactose. Upon contact with water, HPMC initially shrinks to up to 13% of its original thickness before undergoing expansion. HPMC and lactose were shown to expand to up to 20% and 47% of their original size in 24 h and 13 min, respectively, whereas Eudragit does not undergo dimensional change. The TPI technique was used to measure the ingress of water into HPMC tablets over a period of 24 h and it was observed that water penetrates into the tablet by anomalous diffusion. X-ray microtomography was used to measure tablet porosity alongside helium pycnometry and was linked to the results obtained by TPI. Our results highlight a new application area of TPI in the pharmaceutical sciences that could be of interest in the development and quality testing of advanced drug delivery systems as well as immediate release formulations. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association.

Co-spray Drying with HPMC as a Platform to Improve Direct Compaction Properties of Various Tablet Fillers.

PubMed

Li, JinZhi; Zhao, LiJie; Lin, Xiao; Shen, Lan; Feng, Yi

2017-11-01

Many commonly used tablet fillers are not suitable for direct compaction process due to insufficient properties, mainly of flowability and compactability. This work therefore aimed to use co-spray drying with HPMC as a platform to improve direct compaction properties of various tablet fillers. Starch, calcium hydrogen phosphate dihydrate (DCPD), and mannitol were chosen as a representative of three types of commonly used fillers (i.e. organic macromolecules, water-insoluble inorganic salts, and water-soluble small molecular carbohydrates), respectively. The five-level central composite design-response surface methodology was used (i) to investigate the effects of HPMC level and solid content of the feed on various powder, tableting, and tablet properties of composite excipients, and (ii) to optimize the composition. The results showed that the impacts of the two factors on various properties of composite excipients showed great similarity, despite of significantly different primary properties of the parent fillers, and the HPMC level was the main contributor to the majority of the impacts. An increase in HPMC level significantly improved tablet tensile strength and various tableting parameters. For all the three fillers, their optimized composite excipients provided by the established models showed excellent performances as predicted. The platform suggested is confirmed to be effective and promising.

Viscosity-Lowering Effect of Amino Acids and Salts on Highly Concentrated Solutions of Two IgG1 Monoclonal Antibodies.

PubMed

Wang, Shujing; Zhang, Ning; Hu, Tao; Dai, Weiguo; Feng, Xiuying; Zhang, Xinyi; Qian, Feng

2015-12-07

Monoclonal antibodies display complicated solution properties in highly concentrated (>100 mg/mL) formulations, such as high viscosity, high aggregation propensity, and low stability, among others, originating from protein-protein interactions within the colloidal protein solution. These properties severely hinder the successful development of high-concentration mAb solution for subcutaneous injection. We hereby investigated the effects of several small-molecule excipients with diverse biophysical-chemical properties on the viscosity, aggregation propensity, and stability on two model IgG1 (JM1 and JM2) mAb formulations. These excipients include nine amino acids or their salt forms (Ala, Pro, Val, Gly, Ser, HisHCl, LysHCl, ArgHCl, and NaGlu), four representative salts (NaCl, NaAc, Na2SO4, and NH4Cl), and two chaotropic reagents (urea and GdnHCl). With only salts or amino acids in their salt-forms, significant decrease in viscosity was observed for JM1 (by up to 30-40%) and JM2 (by up to 50-80%) formulations, suggesting charge-charge interaction between the mAbs dictates the high viscosity of these mAbs formulations. Most of these viscosity-lowering excipients did not induce substantial protein aggregation or changes in the secondary structure of the mAbs, as evidenced by HPLC-SEC, DSC, and FT-IR analysis, even in the absence of common protein stabilizers such as sugars and surfactants. Therefore, amino acids in their salt-forms and several common salts, such as ArgHCl, HisHCl, LysHCl, NaCl, Na2SO4, and NaAc, could potentially serve as viscosity-lowering excipients during high-concentration mAb formulation development.

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.

Design of minocycline-containing starch nanocapsules for topical delivery.

PubMed

Marto, J; Gouveia, L F; Gonçalves, L M; Ribeiro, H M; Almeida, A J

2018-06-11

Pharmaceutical research has been focused on developing improved delivery systems while exploring new ways of using approved excipients. The present work investigated the potential of starch nanocapsules (StNC) as a topical delivery platform for hydrophilic antimicrobial drugs using minocycline hydrochloride (MH) as a model drug. Thus, a quality by design approach was used to assess the role of different factors that affect the main pharmaceutical properties of StNC prepared using an emulsification-solvent evaporation method. Full characterization was performed in terms of particle size, encapsulation efficiency, morphology and physical stability at 5 ± 3°C. Results show the surfactant and lipid contents play a major role in StNC particle size distribution. The MH loading only promoted minor changes upon StNC properties. Formulations were stable without variations on physicochemical properties. All tested formulations presented a zeta potential of +33.6±6.7 mV, indicating a good physical stability and evidencing that StNC are suitable nanocarriers for topical use.

Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

NASA Astrophysics Data System (ADS)

Nawroth, T.; Johnson, R.; Krebs, L.; Khoshakhlagh, P.; Langguth, P.; Hellmann, N.; Goerigk, G.; Boesecke, P.; Bravin, A.; Le Duc, G.; Szekely, N.; Schweins, R.

2016-09-01

T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation.

Cationic Thiolated Poly(aspartamide) Polymer as a Potential Excipient for Artificial Tear Formulations.

PubMed

Budai-Szűcs, Mária; Horvát, Gabriella; Szilágyi, Barnabás Áron; Gyarmati, Benjámin; Szilágyi, András; Berkó, Szilvia; Szabó-Révész, Piroska; Sandri, Giuseppina; Bonferoni, Maria Cristina; Caramella, Carla; Soós, Judit; Facskó, Andrea; Csányi, Erzsébet

2016-01-01

Dry eye disease is a relatively common ocular problem, which causes eye discomfort and visual disorders leading to a decrease in the quality of life. The aim of this study was to find a possible excipient for eye drop formulations, which is able to stabilize the tear film. A cationic thiolated polyaspartamide polymer, poly[(N-mercaptoethylaspartamide)-co-(N-(N',N'-dimethylaminoethyl)aspartamide)] (ThioPASP-DME), was used as a potential vehicle. Besides satisfying the basic requirements, the chemical structure of ThioPASP-DME is similar to those of ocular mucins as it is a protein-like polymer bearing a considerable number of thiol groups. The solution of the polymer is therefore able to mimic the physiological properties of the mucins and it can interact with the mucus layer via disulphide bond formation. The resultant mucoadhesion provides a prolonged residence time and ensures protective effect for the corneal/conjunctival epithelium. ThioPASP-DME also has an antioxidant effect due to the presence of the thiol groups. The applicability of ThioPASP-DME as a potential excipient in eye drops was determined by means of ocular compatibility tests and through examinations of the interactions with the mucosal surface. The results indicate that ThioPASP-DME can serve as a potential eye drop excipient for the therapy of dry eye disease.

Effect of pharmaceutical excipients on the stability of angiotensin-converting enzyme inhibitors in their solid dosage formulations.

PubMed

Stanisz, Beata; Regulska, Katarzyna; Kania, Jagoda; Garbacki, Piotr

2013-01-01

The compatibility studies of moexipril hydrochloride (MOXL), imidapril hydrochloride (IMD), enalapril maleate, (ENA) and lisinopril (LIS) in solid state with magnesium stearate and glyceryl behenate were performed. The aim of this study was to detect any possible drug-excipient interactions in order to optimize technological process conditions by the selection of the most adequate lubricant. Reversed-phase high-performance liquid chromatography was employed for studying drug-excipient binary mixtures in 1:1 ratio and pure drugs under forced ageing test conditions: temperature 318K (45 °C) and relative humidity range of 50.9%-75.4%. The method had been revalidated prior to use. The degradation rate constants for the binary mixtures and pure substances were calculated. The experimental results evidenced that moexipril and enalapril degradation accorded with autocatalytic-second-order kinetics, imidapril degradation followed first-order reaction mechanism, and LIS followed reversible first-order reaction mechanism. A degradation pathway for each substance was proposed to account for the observed decomposition products. It was determined that moexipril stability decreased threefold in the presence of magnesium stearate indicating an incompatibility--(4.15 ± 0.12) 10(-3) compared to (1.43 ± 0.32) 10(-6) for moexipril in pure. No interaction between magnesium stearate and the remaining studied compounds was observed. The stability studies of MOXL-glyceryl behenate binary mixture revealed no interaction. Magnesium stearate and increased relative humidity induce MOXL instability, while glyceryl behenate is an optimal lubricant, and therefore, it is recommended for moexipril-containing solid formulations. However, for the formulations containing moexipril and magnesium stearate, it is suggested to minimize the humidity level during storage.

Sensitive and selective spectrophotometric assay of piroxicam in pure form, capsule and human blood serum samples via ion-pair complex formation.

PubMed

Alizadeh, Nina; Keyhanian, Fereshteh

2014-09-15

A simple, accurate and highly sensitive spectrophotometric method has been developed for the rapid determination of piroxicam (PX) in pure and pharmaceutical formulations. The proposed method involves formation of stable yellow colored ion-pair complexes of the amino derivative (basic nitrogen) of PX with three sulphonphthalein acid dyes namely; bromocresol green (BCG), bromothymol blue (BTB), bromophenol blue (BPB) in acidic medium. The colored species exhibited absorption maxima at 438, 429 and 432 nm with molar absorptivity values of 9.400×10(3), 1.218×10(3) and 1.02×10(4) L mol(-1) cm(-1) for PX-BCG, PX-BTB and PX-BPB complexes, respectively. The effect of optimum conditions via acidity, reagent concentration, time and solvent were studied. The reactions were extremely rapid at room temperature and the absorbance values remained constant for 48h. Beer's law was obeyed with a good correlation coefficient in the concentration ranges 1-100 μg mL(-1) for BCG, BTB complexes and 1-95 μg mL(-1) for BPB complex. The composition ratio of the ion-pair complexes were found to be 1:1 in all cases as established by Job's method. No interference was observed from common additives and excipients which may be present in the pharmaceutical preparations. The proposed method was successfully applied for the determination of PX in capsule and human blood serum samples with good accuracy and precision. Copyright © 2014 Elsevier B.V. All rights reserved.

Use of molecular binding pair technology for definitive product marking and identification

NASA Astrophysics Data System (ADS)

Rittenburg, James H.

1998-04-01

Counterfeiting and diversion of brand name products is a significant worldwide problem. Loss of revenue to the manufacturers is obviously important, however erosion of consumer confidence, and liability for adverse health effects or performance caused by poor quality product can be of even greater significance. Biocode has developed a novel approach to product marking and identification that utilizes molecular binding pair technologies such as immunoassay. The sensitivity, specificity, and ease of use of immunoassay provides a powerful method for detecting trace levels of intentionally added chemical markers. Using the diversity of the immune response, Biocode has developed a library of binding molecules and highly sensitive immunoassay systems for detection and measurement of a variety of chemical markers. The markers have been selected based on their stability and compatibility within various types of products. For food, beverage, and pharmaceutical applications, common and naturally occurring food ingredients and pharmaceutical excipients provide markers which are safe, readily available, and already approved for use. For other applications such as fuel and lubricant marking. Solubility and chemical stability of the markers are a major consideration. In addition to incorporating markers directly into products, Biocode has also developed invisible inks that can be printed onto the surface of products, packaging, or labels. The trace levels of marker that is printed onto the surface of a product or package can only be revealed by using the complementary binding pair that has been developed by Biocode. This technology provides for simple field tests and very high level of security as it is virtually impossible to copy.

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.

Pharmaceutical Dispersion Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs.

PubMed

Zhang, Xingwang; Xing, Huijie; Zhao, Yue; Ma, Zhiguo

2018-06-23

Over the past decades, a large number of drugs as well as drug candidates with poor dissolution characteristics have been witnessed, which invokes great interest in enabling formulation of these active ingredients. Poorly water-soluble drugs, especially biopharmaceutical classification system (BCS) II ones, are preferably designed as oral dosage forms if the dissolution limit can be broken through. Minimizing a drug’s size is an effective means to increase its dissolution and hence the bioavailability, which can be achieved by specialized dispersion techniques. This article reviews the most commonly used dispersion techniques for pharmaceutical processing that can practically enhance the dissolution and bioavailability of poorly water-soluble drugs. Major interests focus on solid dispersion, lipid-based dispersion (nanoencapsulation), and liquisolid dispersion (drug solubilized in a non-volatile solvent and dispersed in suitable solid excipients for tableting or capsulizing), covering the formulation development, preparative technique and potential applications for oral drug delivery. Otherwise, some other techniques that can increase the dispersibility of a drug such as co-precipitation, concomitant crystallization and inclusion complexation are also discussed. Various dispersion techniques provide a productive platform for addressing the formulation challenge of poorly water-soluble drugs. Solid dispersion and liquisolid dispersion are most likely to be successful in developing oral dosage forms. Lipid-based dispersion represents a promising approach to surmounting the bioavailability of low-permeable drugs, though the technique needs to traverse the obstacle from liquid to solid transformation. Novel dispersion techniques are highly encouraged to develop for formulation of poorly water-soluble drugs.

Applying Multi-Criteria Decision Analysis (MCDA) Simple Scoring as an Evidence-based HTA Methodology for Evaluating Off-Patent Pharmaceuticals (OPPs) in Emerging Markets.

PubMed

Brixner, Diana; Maniadakis, Nikos; Kaló, Zoltán; Hu, Shanlian; Shen, Jie; Wijaya, Kalman

2017-09-01

Off-patent pharmaceuticals (OPPs) represent more than 60% of the pharmaceutical market in many emerging countries, where they are frequently evaluated primarily on cost rather than with health technology assessment. OPPs are assumed to be identical to the originators. Branded and unbranded generic versions can, however, vary from the originator in active pharmaceutical ingredients, dosage, consistency formulation, excipients, manufacturing processes, and distribution, for example. These variables can alter the efficacy and safety of the product, negatively impacting both the anticipated cost savings and the population's health. In addition, many health care systems lack the resources or expertise to evaluate such products, and current assessment methods can be complex and difficult to adapt to a health system's needs. Multicriteria decision analysis (MCDA) simple scoring is an evidence-based health technology assessment methodology for evaluating OPPs, especially in emerging countries in which resources are limited but decision makers still must balance affordability with factors such as drug safety, level interchangeability, manufacturing site and active pharmaceutical ingredient quality, supply track record, and real-life outcomes. MCDA simple scoring can be applied to pharmaceutical pricing, reimbursement, formulary listing, and drug procurement. In November 2015, a workshop was held at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting in Milan to refine and prioritize criteria that can be used in MCDA simple scoring for OPPs, resulting in an example MCDA process and 22 prioritized criteria that health care systems in emerging countries can easily adapt to their own decision-making processes. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Case studies with new excipients: development, implementation and regulatory approval.

PubMed

Koo, Otilia M Y; Varia, Sailesh A

2011-07-01

The purpose of this article is to describe the process whereby new excipients become accepted and to describe three case studies to illustrate the process. New excipients are defined according to the 2005 FDA Guidance on Nonclinical Safety Evaluation of New Excipients. The requirements for safety data submission for new excipients used in different classes of products for different durations are outlined in the guidance. Currently, the development of new excipients is linked to the development and approval of new drug products that contain them. New excipients that are used in US-approved drug products become listed in the FDA Inactive Ingredients Guide (IIG) database. Thereafter, US Pharmacopeia monographs for the new excipients are proposed. New excipients are reviewed and become accepted in the same way in Europe and Japan, except that there is no equivalent IIG database. Therefore, the focus of this article will be on the FDA review process. Three case studies, polyoxyl 15 hydroxystearate, sulfobutyl ether cyclodextrin and silicified microcrystalline cellulose, are used to illustrate how new excipients are accepted and implemented.

Low-viscosity hydroxypropylcellulose (HPC) grades SL and SSL: versatile pharmaceutical polymers for dissolution enhancement, controlled release, and pharmaceutical processing.

PubMed

Sarode, Ashish; Wang, Peng; Cote, Catherine; Worthen, David R

2013-03-01

Hydroxypropylcellulose (HPC)-SL and -SSL, low-viscosity hydroxypropylcellulose polymers, are versatile pharmaceutical excipients. The utility of HPC polymers was assessed for both dissolution enhancement and sustained release of pharmaceutical drugs using various processing techniques. The BCS class II drugs carbamazepine (CBZ), hydrochlorthiazide, and phenytoin (PHT) were hot melt mixed (HMM) with various polymers. PHT formulations produced by solvent evaporation (SE) and ball milling (BM) were prepared using HPC-SSL. HMM formulations of BCS class I chlorpheniramine maleate (CPM) were prepared using HPC-SL and -SSL. These solid dispersions (SDs) manufactured using different processes were evaluated for amorphous transformation and dissolution characteristics. Drug degradation because of HMM processing was also assessed. Amorphous conversion using HMM could be achieved only for relatively low-melting CBZ and CPM. SE and BM did not produce amorphous SDs of PHT using HPC-SSL. Chemical stability of all the drugs was maintained using HPC during the HMM process. Dissolution enhancement was observed in HPC-based HMMs and compared well to other polymers. The dissolution enhancement of PHT was in the order of SE>BM>HMM>physical mixtures, as compared to the pure drug, perhaps due to more intimate mixing that occurred during SE and BM than in HMM. Dissolution of CPM could be significantly sustained in simulated gastric and intestinal fluids using HPC polymers. These studies revealed that low-viscosity HPC-SL and -SSL can be employed to produce chemically stable SDs of poorly as well as highly water-soluble drugs using various pharmaceutical processes in order to control drug dissolution.

Water content determination of superdisintegrants by means of ATR-FTIR spectroscopy.

PubMed

Szakonyi, G; Zelkó, R

2012-04-07

Water contents of superdisintegrant pharmaceutical excipients were determined by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy using simple linear regression. Water contents of the investigated three common superdisintegrants (crospovidone, croscarmellose sodium, sodium starch glycolate) varied over a wide range (0-24%, w/w). In the case of crospovidone three different samples from two manufacturers were examined in order to study the effects of different grades on the calibration curves. Water content determinations were based on strong absorption of water between 3700 and 2800 cm⁻¹, other spectral changes associated with the different compaction of samples on the ATR crystal using the same pressure were followed by the infrared region between 1510 and 1050 cm⁻¹. The calibration curves were constructed using the ratio of absorbance intensities in the two investigated regions. Using appropriate baseline correction the linearity of the calibration curves was maintained over the entire investigated water content regions and the effect of particle size on the calibration was not significant in the case of crospovidones from the same manufacturer. The described method enables the water content determination of powdered hygroscopic materials containing homogeneously distributed water. Copyright © 2012 Elsevier B.V. All rights reserved.

Regulatory aspects in the pharmaceutical development of nanoparticle drug delivery systems designed to cross the intestinal epithelium and M-cells.

PubMed

Hussain, Nasir

2016-11-30

This article reviews the field of oral uptake of nanoparticles across the gastrointestinal epithelium for the period 2006-2016. Analysis is conducted from the viewpoint of i) M-cell genetics and model development, ii) drug targeting to Peyer's patches and M-cells, and iii) physicochemical interactions of nanoparticles in the intestinal milieu. In light of these recent developments, regulatory considerations in the development of orally-absorbable nanoparticle drug products are discussed and focused on Module 3.2.P sub-sections of the Common Technical Document. Particular attention is paid to novel excipients, ligands and the non-standard method of manufacture. The novelty of this drug delivery system demands not only a multi-disciplinary scientific and regulatory approach but also a risk-adjusted consideration for a system defined by both processes and specifications. Given the current state of scientific development in the field it is suggested (in the author's personal opinion) that the design of nanoparticulate drug delivery systems should be kept as simple as possible (from a regulatory and manufacturing perspective) and to target the entire gastrointestinal epithelium. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Simultaneous production and co-mixing of microparticles of nevirapine with excipients by supercritical antisolvent method for dissolution enhancement.

PubMed

Sanganwar, Ganesh P; Sathigari, Sateeshkumar; Babu, R Jayachandra; Gupta, Ram B

2010-01-31

Microparticles of a poorly water-soluble model drug, nevirapine (NEV) were prepared by supercritical antisolvent (SAS) method and simultaneously deposited on the surface of excipients such as lactose and microcrystalline cellulose in a single step to reduce drug-drug particle aggregation. In the proposed method, termed supercritical antisolvent-drug excipient mixing (SAS-DEM), drug particles were precipitated in supercritical CO(2) vessel containing excipient particles in suspended state. Drug/excipient mixtures were characterized for surface morphology, crystallinity, drug-excipient physico-chemical interactions, and molecular state of drug. In addition, the drug content uniformity and dissolution rate were determined. A highly ordered NEV-excipient mixture was produced. The SAS-DEM treatment was effective in overcoming drug-drug particle aggregation and did not affect the crystallinity or physico-chemical properties of NEV. The produced drug/excipient mixture has a significantly faster dissolution rate as compared to SAS drug microparticles alone or when physically mixed with the excipients. Copyright 2009 Elsevier B.V. All rights reserved.

Comparison of the effect of two excipients (karite nut butter and vaseline) on the efficacy of Cocos nucifera, Elaeis guineensis and Carapa procera oil-based repellents formulations against mosquitoes biting in Ivory Coast.

PubMed

Konan, Y L; Sylla, M S; Doannio, J M; Traoré, S

2003-06-01

Repellents in the form of dermal pomades are recommended as a protection against awakening and bedtime mosquito bites. If synthesis repellents are available, they are nevertheless not common and the prices remain out of reach for the communities concerned. The people therefore have to resort more and more to traditional concoctions, some of which have been shown to be effective. After demonstrating that oil-based formulations (lotions, creams, pomades) of Cocos nucifera (coconut), Elaeis guineensis (oil palm) and Carapa procera (gobi) were effective against mosquitoes, it became necessary to study the impact of the two excipients used in their manufacture, on the effectiveness of the repellents. Experiments were carried with Anopheles gambiae and Aedes aegypti under lobaratory conditions and any other mosquitoes collected under field conditions in Ivory Coast. The laboratory results indicate that the average protection times obtained with formulations with karite nut butter as excipient (54.8 +/- 37.0 mn and 74.6 +/- 26.4 mn respectively on An. gambiae and Ae. aegypti) are higher than those recorded with vaseline as excipient (respectively 42.7 +/- 30.0 mn and 60.8 +/- 33.9 mn). On the other hand, under field conditions, the biting rate percentage reduction obtained with the products with karite nut butter and vaseline excipient were similar (respectively 29.8% and 35.9% for all mosquitoes collected and 45.7% and 47.4% against An. gambiae). Nevertheless, the use of karite nut butter on repellent products should be encouraged because its sale price is very lower (10 time less) than the vaseline's.

Application of the ratio difference spectrophotometry to the determination of ibuprofen and famotidine in their combined dosage form: comparison with previously published spectrophotometric methods.

PubMed

Zaazaa, Hala E; Elzanfaly, Eman S; Soudi, Aya T; Salem, Maissa Y

2015-05-15

Ratio difference spectrophotometric method was developed for the determination of ibuprofen and famotidine in their mixture form. Ibuprofen and famotidine were determined in the presence of each other by the ratio difference spectrophotometric (RD) method where linearity was obtained from 50 to 600μg/mL and 2.5 to 25μg/mL for ibuprofen and famotidine, respectively. The suggested method was validated according to ICH guidelines and successfully applied for the analysis of ibuprofen and famotidine in their pharmaceutical dosage forms without interference from any additives or excipients. Copyright © 2015 Elsevier B.V. All rights reserved.

The effects of polar excipients transcutol and dexpanthenol on molecular mobility, permeability, and electrical impedance of the skin barrier.

PubMed

Björklund, Sebastian; Pham, Quoc Dat; Jensen, Louise Bastholm; Knudsen, Nina Østergaard; Nielsen, Lars Dencker; Ekelund, Katarina; Ruzgas, Tautgirdas; Engblom, Johan; Sparr, Emma

2016-10-01

In the development of transdermal and topical products it is important to understand how formulation ingredients interact with the molecular components of the upper layer of the skin, the stratum corneum (SC), and thereby influence its macroscopic barrier properties. The aim here was to investigate the effect of two commonly used excipients, transcutol and dexpanthenol, on the molecular as well as the macroscopic properties of the skin membrane. Polarization transfer solid-state NMR methods were combined with steady-state flux and impedance spectroscopy measurements to investigate how these common excipients influence the molecular components of SC and its barrier function at strictly controlled hydration conditions in vitro with excised porcine skin. The NMR results provide completely new molecular insight into how transcutol and dexpanthenol affect specific molecular segments of both SC lipids and proteins. The presence of transcutol or dexpanthenol in the formulation at fixed water activity results in increased effective skin permeability of the model drug metronidazole. Finally, impedance spectroscopy data show clear changes of the effective skin capacitance after treatment with transcutol or dexpanthenol. Based on the complementary data, we are able to draw direct links between effects on the molecular properties and on the macroscopic barrier function of the skin barrier under treatment with formulations containing transcutol or dexpanthenol. Copyright © 2016 Elsevier Inc. All rights reserved.

Solid-state mAbs and ADCs subjected to heat-stress stability conditions can be covalently modified with buffer and excipient molecules.

PubMed

Valliere-Douglass, John F; Lewis, Patsy; Salas-Solano, Oscar; Jiang, Shan

2015-02-01

We report that a unique type of chemical modification occurs on lyophilized proteins. Freeze-dried mAbs and antibody-drug conjugates (ADCs) can be covalently modified with buffer and excipient molecules on the side chains of Glu, Asp, Thr, and Ser amino acids when subjected to temperature stress. The reaction occurs primarily via condensation of common buffers and excipients such as histidine, tris, trehalose and sucrose, with Glu and Asp carboxylates in the primary sequence of proteins. The reaction was also found to proceed through condensation of carboxylate containing buffers such as citrate, with Thr and Ser hydroxyls in the primary sequence of proteins. Based on the mass of the covalent adducts observed on mAbs and ADCs, it is apparent that the reaction produces water as a product and is thus favored in a low moisture environments such as a lyophilized protein cake. Herein, we present the evidence for the covalent modification of proteins drawn from case studies of in-depth characterization of heat-stressed mAbs and ADCs in the solid state. We also demonstrate how common charge variant assays such as imaged capillary isoelectric focusing and mass spectrometry can be used to monitor this specific class of protein modification. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Measurements of elastic moduli of pharmaceutical compacts: a new methodology using double compaction on a compaction simulator.

PubMed

Mazel, Vincent; Busignies, Virginie; Diarra, Harona; Tchoreloff, Pierre

2012-06-01

The elastic properties of pharmaceutical powders play an important role during the compaction process. The elastic behavior can be represented by Young's modulus (E) and Poisson's ratio (v). However, during the compaction, the density of the powder bed changes and the moduli must be determined as a function of the porosity. This study proposes a new methodology to determine E and v as a function of the porosity using double compaction in an instrumented compaction simulator. Precompression is used to form the compact, and the elastic properties are measured during the beginning of the main compaction. By measuring the axial and radial pressure and the powder bed thickness, E and v can be determined as a function of the porosity. Two excipients were studied, microcrystalline cellulose (MCC) and anhydrous calcium phosphate (aCP). The values of E measured are comparable to those obtained using the classical three-point bending test. Poisson's ratio was found to be close to 0.24 for aCP with only small variations with the porosity, and to increase with a decreasing porosity for MCC (0.23-0.38). The classical approximation of a value of 0.3 for ν of pharmaceutical powders should therefore be taken with caution. Copyright © 2012 Wiley Periodicals, Inc.

A user-friendly model for spray drying to aid pharmaceutical product development.

PubMed

Grasmeijer, Niels; de Waard, Hans; Hinrichs, Wouter L J; Frijlink, Henderik W

2013-01-01

The aim of this study was to develop a user-friendly model for spray drying that can aid in the development of a pharmaceutical product, by shifting from a trial-and-error towards a quality-by-design approach. To achieve this, a spray dryer model was developed in commercial and open source spreadsheet software. The output of the model was first fitted to the experimental output of a Büchi B-290 spray dryer and subsequently validated. The predicted outlet temperatures of the spray dryer model matched the experimental values very well over the entire range of spray dryer settings that were tested. Finally, the model was applied to produce glassy sugars by spray drying, an often used excipient in formulations of biopharmaceuticals. For the production of glassy sugars, the model was extended to predict the relative humidity at the outlet, which is not measured in the spray dryer by default. This extended model was then successfully used to predict whether specific settings were suitable for producing glassy trehalose and inulin by spray drying. In conclusion, a spray dryer model was developed that is able to predict the output parameters of the spray drying process. The model can aid the development of spray dried pharmaceutical products by shifting from a trial-and-error towards a quality-by-design approach.

Anodic voltammetric behavior and determination of cefixime in pharmaceutical dosage forms and biological fluids.

PubMed

Golcu, Ayşegul; Dogan, Burcu; Ozkan, Sibel A

2005-10-15

The voltammetric behavior of cefixime was studied using cyclic, linear sweep, differential pulse and square wave voltammetric techniques. The oxidation of cefixime was irreversible and exhibited diffusion controlled process depending on pH. The oxidation mechanism was proposed and discussed. Different parameters were tested to optimize the conditions for the determination of cefixime. The dependence of current intensities and potentials on pH, concentration, scan rate, nature of the buffer was investigated. According to the linear relationship between the peak current and the concentration, differential pulse (DPV) and square wave (SWV) voltammetric methods for cefixime assay in pharmaceutical dosage forms and biological fluids were developed. For the determination of cefixime were proposed in acetate buffer at pH 4.5, which allows quantitation over the 6 x 10(-6)-2 x 10(-4)M range in supporting electrolyte and spiked serum sample; 8 x 10(-6)-2 x 10(-4)M range in urine sample; 6 x 10(-6)-1 x 10(-4)M range in breast milk samples for both techniques. The repeatability, reproducibility, precision and accuracy of the methods in all media were investigated. No electroactive interferences from the excipients and endogenous substances were found in the pharmaceutical dosage forms and in the biological samples, respectively.

How Deformation Behavior Controls Product Performance After Twin Screw Granulation With High Drug Loads and Crospovidone as Disintegrant.

PubMed

Meier, Robin; Moll, Klaus-Peter; Krumme, Markus; Kleinebudde, Peter

2017-01-01

This study addresses the quantitative influence of 12 different materials (active pharmaceutical ingredients and excipients as surrogate active pharmaceutical ingredients) on the critical quality attributes of twin screw granulated products and subsequently produced tablets. Prestudies demonstrated the significant influence of the chosen model materials (in combination with crospovidone) on the disintegration behavior of the resulting tablets, despite comparable tablet porosities. This study elucidates possible reasons for the varying disintegration behavior by investigating raw material, granule, and tablet properties. An answer could be found in the mechanical properties of the raw materials and the produced granules. Through compressibility studies, the materials could be classified into materials with high compressibility, which deform rather plastically under compression stress, and low compressibility, which display breakages under compression stress. In general, and apart from (pseudo)-polymorphic transformations, brittle materials featured excellent disintegration performance, even at low resulting tablet porosities <8%, whereas plastically deformable materials mostly did not reveal any disintegration. These findings must be considered in the development of simplified formulations with high drug loads, in which the active pharmaceutical ingredient predominantly defines the deformation behavior of the granule. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Validation and Uncertainty Estimation of an Ecofriendly and Stability-Indicating HPLC Method for Determination of Diltiazem in Pharmaceutical Preparations

PubMed Central

Sadeghi, Fahimeh; Navidpour, Latifeh; Bayat, Sima; Afshar, Minoo

2013-01-01

A green, simple, and stability-indicating RP-HPLC method was developed for the determination of diltiazem in topical preparations. The separation was based on a C18 analytical column using a mobile phase consisted of ethanol: phosphoric acid solution (pH = 2.5) (35 : 65, v/v). Column temperature was set at 50°C and quantitation was achieved with UV detection at 240 nm. In forced degradation studies, the drug was subjected to oxidation, hydrolysis, photolysis, and heat. The method was validated for specificity, selectivity, linearity, precision, accuracy, and robustness. The applied procedure was found to be linear in diltiazem concentration range of 0.5–50 μg/mL (r 2 = 0.9996). Precision was evaluated by replicate analysis in which % relative standard deviation (RSD) values for areas were found below 2.0. The recoveries obtained (99.25%–101.66%) ensured the accuracy of the developed method. The degradation products as well as the pharmaceutical excipients were well resolved from the pure drug. The expanded uncertainty (5.63%) of the method was also estimated from method validation data. Accordingly, the proposed validated and sustainable procedure was proved to be suitable for routine analyzing and stability studies of diltiazem in pharmaceutical preparations. PMID:24163778

Cationic Thiolated Poly(aspartamide) Polymer as a Potential Excipient for Artificial Tear Formulations

PubMed Central

Budai-Szűcs, Mária; Horvát, Gabriella; Szilágyi, Barnabás Áron; Gyarmati, Benjámin; Szilágyi, András; Berkó, Szilvia; Szabó-Révész, Piroska; Sandri, Giuseppina; Bonferoni, Maria Cristina; Caramella, Carla; Soós, Judit; Facskó, Andrea; Csányi, Erzsébet

2016-01-01

Dry eye disease is a relatively common ocular problem, which causes eye discomfort and visual disorders leading to a decrease in the quality of life. The aim of this study was to find a possible excipient for eye drop formulations, which is able to stabilize the tear film. A cationic thiolated polyaspartamide polymer, poly[(N-mercaptoethylaspartamide)-co-(N-(N′,N′-dimethylaminoethyl)aspartamide)] (ThioPASP-DME), was used as a potential vehicle. Besides satisfying the basic requirements, the chemical structure of ThioPASP-DME is similar to those of ocular mucins as it is a protein-like polymer bearing a considerable number of thiol groups. The solution of the polymer is therefore able to mimic the physiological properties of the mucins and it can interact with the mucus layer via disulphide bond formation. The resultant mucoadhesion provides a prolonged residence time and ensures protective effect for the corneal/conjunctival epithelium. ThioPASP-DME also has an antioxidant effect due to the presence of the thiol groups. The applicability of ThioPASP-DME as a potential excipient in eye drops was determined by means of ocular compatibility tests and through examinations of the interactions with the mucosal surface. The results indicate that ThioPASP-DME can serve as a potential eye drop excipient for the therapy of dry eye disease. PMID:27313866

Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure.

PubMed

Badal Tejedor, Maria; Nordgren, Niklas; Schuleit, Michael; Rutland, Mark W; Millqvist-Fureby, Anna

2015-01-01

Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture. Copyright © 2015 Elsevier B.V. All rights reserved.

Understanding the lipid-digestion processes in the GI tract before designing lipid-based drug-delivery systems.

PubMed

Bakala N'Goma, Jean-Claude; Amara, Sawsan; Dridi, Kaouthar; Jannin, Vincent; Carrière, Frédéric

2012-01-01

Many of the compounds present in lipid-based drug-delivery systems are esters, such as acylglycerols, phospholipids, polyethyleneglycol mono- and di-esters and polysorbate, which can be hydrolyzed by the various lipolytic enzymes present in the GI tract. Lipolysis of these compounds, along with dietary fats, affects the solubility, dispersion and bioavailibity of poorly water-soluble drugs. Pharmaceutical scientists have been taking a new interest in fat digestion in this context, and several studies presenting in vitro gastrointestinal lipolysis models have been published. In most models, it is generally assumed that pancreatic lipase is the main enzyme involved in the gastrointestinal lipolysis of lipid formulations. It was established, however, that gastric lipase, pancreatic carboxyl ester hydrolaze and pancreatic lipase-related protein 2 are the major players involved in the lipolysis of lipid excipients containing acylglycerols and polyethyleneglycol esters. These findings have shown that the lipolysis of lipid excipients may actually start in the stomach and involve several lipolytic enzymes. These findings should therefore be taken into account when testing in vitro the dispersion and bioavailability of poorly water-soluble drugs formulated with lipids. In this review, we present the latest data available about the lipolytic enzymes involved in gastrointestinal lipolysis and suggest tracks for designing physiologically relevant in vitro digestion models.

Differential heat of adsorption of water vapor on silicified microcrystalline cellulose (SMCC): an investigation using isothermal microcalorimetry.

PubMed

Qian, Ken K; Bogner, Robin H

2011-01-01

A novel dual-shaft configuration in isothermal microcalorimetry was developed to study the interaction of water vapor with pharmaceutical excipients. An instrument performance test is suggested to validate the experimental data. Reliable experimental results can be collected using a single perfusion shaft; however, there was limitation of the dual-shaft configuration, which resulted deviation in the experimental results. A periodic performance test is recommended. Silicified microcrystalline cellulose (SMCC) was used as a model system to study the interaction using the dual-shaft method. Enthalpy of water vapor adsorption on SMCC was determined and compared to literature data. The data collected using the dual-shaft configuration did not reflect the actual physical system. The deviation was most likely due to the lack of flow control caused by viscous resistance. The enthalpy of adsorption was then calculated using isothermal microcalorimetry coupled with a dynamic vapor sorption apparatus. The results, -55 kJ/mol at low relative humidity (RH) to -22 kJ/mol at high RH, were consistent with the physical phenomenon of water vapor adsorption. Enthalpy of adsorption showed surface heterogeneity of SMCC and suggested multilayer condensation of water at approximately 60% RH. However, at high RH, the results showed the moisture-excipient interaction can be more complex than the proposed mechanism.

Effect of milling on DSC thermogram of excipient adipic acid.

PubMed

Ng, Wai Kiong; Kwek, Jin Wang; Yuen, Aaron; Tan, Chin Lee; Tan, Reginald

2010-03-01

The purpose of this research was to investigate why and how mechanical milling results in an unexpected shift in differential scanning calorimetry (DSC) measured fusion enthalpy (Delta(fus)H) and melting point (T(m)) of adipic acid, a pharmaceutical excipient. Hyper differential scanning calorimetry (hyper-DSC) was used to characterize adipic acid before and after ball-milling. An experimental study was conducted to evaluate previous postulations such as electrostatic charging using the Faraday cage method, crystallinity loss using powder X-ray diffraction (PXRD), thermal annealing using DSC, impurities removal using thermal gravimetric analysis (TGA) and Karl Fischer titration. DSC thermograms showed that after milling, the values of Delta(fus)H and T(m) were increased by approximately 9% and 5 K, respectively. Previous suggestions of increased electrostatic attraction, change in particle size distribution, and thermal annealing during measurements did not explain the differences. Instead, theoretical analysis and experimental findings suggested that the residual solvent (water) plays a key role. Water entrapped as inclusions inside adipic acid during solution crystallization was partially evaporated by localized heating at the cleaved surfaces during milling. The correlation between the removal of water and melting properties measured was shown via drying and crystallization experiments. These findings show that milling can reduce residual solvent content and causes a shift in DSC results.

Modeling strategies for pharmaceutical blend monitoring and end-point determination by near-infrared spectroscopy.

PubMed

Igne, Benoît; de Juan, Anna; Jaumot, Joaquim; Lallemand, Jordane; Preys, Sébastien; Drennen, James K; Anderson, Carl A

2014-10-01

The implementation of a blend monitoring and control method based on a process analytical technology such as near infrared spectroscopy requires the selection and optimization of numerous criteria that will affect the monitoring outputs and expected blend end-point. Using a five component formulation, the present article contrasts the modeling strategies and end-point determination of a traditional quantitative method based on the prediction of the blend parameters employing partial least-squares regression with a qualitative strategy based on principal component analysis and Hotelling's T(2) and residual distance to the model, called Prototype. The possibility to monitor and control blend homogeneity with multivariate curve resolution was also assessed. The implementation of the above methods in the presence of designed experiments (with variation of the amount of active ingredient and excipients) and with normal operating condition samples (nominal concentrations of the active ingredient and excipients) was tested. The impact of criteria used to stop the blends (related to precision and/or accuracy) was assessed. Results demonstrated that while all methods showed similarities in their outputs, some approaches were preferred for decision making. The selectivity of regression based methods was also contrasted with the capacity of qualitative methods to determine the homogeneity of the entire formulation. Copyright © 2014. Published by Elsevier B.V.

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.

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane.

PubMed

Muankaew, Chutimon; Jansook, Phatsawee; Loftsson, Thorsteinn

2017-06-01

According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (J R ) and the apparent permeability coefficients (P app ) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased P app of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the P app of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

Official USP Reference Standards: metrology concepts, overview, and scientific issues and opportunities.

PubMed

Williams, Roger L

2006-01-23

The United States Pharmacopeia (USP) is a private standards-setting body created in 1820 by practitioners who wished to promote the quality of therapeutic products in commerce. The principal product of USP, then and now, is the United StatesPharmacopeia (USP), to which was added the National Formulary (NF) in 1975. The two compendia are published as a combined text annually (USP-NF). Originally a book of process standards, USP-NF evolved over time into compendia containing primarily product standards that are expressed in monographs for therapeutic ingredients, products, and excipients. As a public health service, USP supplies official USP Reference Standards to manufacturers and others who wish to test an article according to selected procedures of a monograph or General Chapter. During the past decade, understanding of USP monographs and official USP Reference Standards as a means of controlling the quality of a therapeutic article has evolved, based on advances in metrology, on activities in the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH), and on considerations by the USP Council of Experts and its Expert Committees and USP staff. This article discusses the evolution of this understanding, focusing on drug substances and excipients for well-characterized small molecules and their corresponding dosage forms.

A novel spectroscopic analysis to detect photochemical reaction of the bronchodilator - Doxofylline and its estimation in pharmaceutical formulation

NASA Astrophysics Data System (ADS)

Sasi Rekha, P.; Gunasekaran, S.

2018-02-01

Photostability studies of drugs and drug products are an integral part of the product development process in the pharmaceutical industry. These studies are carried out to ensure quality, efficacy and safety of the formulated products during manufacture, storage and use. In this investigation, a novel spectroscopic approach has been adopted by employing the FTIR-ATR and UV/Visible techniques to detect the photochemical reactions of the drug Doxofylline, chemically designated as 7-(1, 3 dioxolane-2-yl methyl) theophylline, in its raw (pure) form. Significant changes were observed in terms of optical density of the absorption bands and a satisfactory analysis has been performed using ANOVA Statistics. It highlights the role of the photochemistry of drugs with respect to its spectral profiles and also explains photo physical processes. In addition; the drug compatibility study was also undertaken by using FTIR-ATR technique which indicated that there were no interactions occurring between the raw sample of the drug and the excipients used in the preparation of the pharmaceutical formulation. With this, UV-visible spectroscopic method was validated for the quantitative estimation of Doxofylline in pharmaceutical dosage forms and was performed with λmax at 274 nm. Calibration curves were linear between the concentration range 10-50 μg/ml. The various parameters such as linearity, precision, accuracy, recovery and specificity were studied according to ICH guidelines (Ahmed et al., 2016; Jain et al., 2011; ICH, 1996).

Preparation and characterization of cross-linked excipient of coprocessed xanthan gum-acacia gum as matrix for sustained release tablets

NASA Astrophysics Data System (ADS)

Surini, Silvia; Wati, Dina Risma; Syahdi, Rezi Riadhi

2018-02-01

Sustained release tablet is solid dosage form which is designed to release drugs slowly in the body. This research was intended to prepare and characterize the cross-linked excipients of co-processed xanthan gum-acacia gum (CL-Co-XGGA) as matrices for sustained release tablets with gliclazide as a model drug. CL-Co-XGGA excipients were cross-linked materials of co-processed excipients of xanthan gum-acacia gum (Co-XGGA) using sodium trimetaphosphate. Co-processed excipients of xanthan gum-acacia gum were prepared in the ratio of each excipient 1:2, 1:1 and 2:1. Co-XGGA and CL-Co-XGGA excipients were characterized physically, chemically and functionally. Then, the sustained release (SR) tablets were formulated by wet granulation method using CL-Co-XGGA excipients as matrices. Also, the dissolution study of the gliclazide SR tablets was carried out in phosphate buffer medium pH 7,4 containing sodium lauryl sulphate 0.2% for 12 hours. The results showed that the degree of substitution (DS) of CL-Co-XGGA 1:2, 1:1, 2:1 excipients were respectively 0.067, 0.082 and 0.08. Besides that, the excipients gel strengths were 14.03, 17.27 and 20,70 gF, respectively. The cross-linked excipients had improved flow properties and swelling capability compared to the Co-XGGA excipients. The results of the gliclazide SR tablets evaluations showed that all tablets were passed all tablet requirements. Moreover, the gliclazide release from SR tablets F1 - F6 revealed the sustained release profile, which was following zero order kinetics (F1, F2, F3, F6) and Higuchi kinetics (F4 and F5). It could be concluded that the obtained CL-Co-XGGA excipients might be used as matrices for sustained release tablets and could retard drug release up to 8 until 32 hours.

Distribution of a low dose compound within pharmaceutical tablet by using multivariate curve resolution on Raman hyperspectral images.

PubMed

Boiret, Mathieu; de Juan, Anna; Gorretta, Nathalie; Ginot, Yves-Michel; Roger, Jean-Michel

2015-01-25

In this work, Raman hyperspectral images and multivariate curve resolution-alternating least squares (MCR-ALS) are used to study the distribution of actives and excipients within a pharmaceutical drug product. This article is mainly focused on the distribution of a low dose constituent. Different approaches are compared, using initially filtered or non-filtered data, or using a column-wise augmented dataset before starting the MCR-ALS iterative process including appended information on the low dose component. In the studied formulation, magnesium stearate is used as a lubricant to improve powder flowability. With a theoretical concentration of 0.5% (w/w) in the drug product, the spectral variance contained in the data is weak. By using a principal component analysis (PCA) filtered dataset as a first step of the MCR-ALS approach, the lubricant information is lost in the non-explained variance and its associated distribution in the tablet cannot be highlighted. A sufficient number of components to generate the PCA noise-filtered matrix has to be used in order to keep the lubricant variability within the data set analyzed or, otherwise, work with the raw non-filtered data. Different models are built using an increasing number of components to perform the PCA reduction. It is shown that the magnesium stearate information can be extracted from a PCA model using a minimum of 20 components. In the last part, a column-wise augmented matrix, including a reference spectrum of the lubricant, is used before starting MCR-ALS process. PCA reduction is performed on the augmented matrix, so the magnesium stearate contribution is included within the MCR-ALS calculations. By using an appropriate PCA reduction, with a sufficient number of components, or by using an augmented dataset including appended information on the low dose component, the distribution of the two actives, the two main excipients and the low dose lubricant are correctly recovered. Copyright © 2014 Elsevier B.V. All rights reserved.

Measurement of the Intertablet Coating Uniformity of a Pharmaceutical Pan Coating Process With Combined Terahertz and Optical Coherence Tomography In-Line Sensing.

PubMed

Lin, Hungyen; Dong, Yue; Markl, Daniel; Williams, Bryan M; Zheng, Yalin; Shen, Yaochun; Zeitler, J Axel

2017-04-01

We present in-line coating thickness measurements acquired simultaneously using 2 independent sensing modalities: terahertz pulsed imaging (TPI) and optical coherence tomography (OCT). Both techniques are sufficiently fast to resolve the coating thickness of individual pharmaceutical tablets in situ during the film coating operation, and both techniques are direct structural imaging techniques that do not require multivariate calibration. The TPI sensor is suitable to measure coatings greater than 50 μm and can penetrate through thick coatings even in the presence of pigments over a wide range of excipients. Due to the long wavelength, terahertz radiation is not affected by scattering from dust within the coater. In contrast, OCT can resolve coating layers as thin as 20 μm and is capable of measuring the intratablet coating uniformity and the intertablet coating thickness distribution within the coating pan. However, the OCT technique is less robust when it comes to the compatibility with excipients, dust, and potentially the maximum coating thickness that can be resolved. Using a custom-built laboratory scale coating unit, the coating thickness measurements were acquired independently by the TPI and OCT sensors throughout a film coating operation. Results of the in-line TPI and OCT measurements were compared against one another and validated with off-line TPI and weight gain measurements. Compared with other process analytical technology sensors, such as near-infrared and Raman spectroscopy, the TPI and OCT sensors can resolve the intertablet thickness distribution based on sampling a significant fraction of the tablet populations in the process. By combining 2 complementary sensing modalities, it was possible to seamlessly monitor the coating process over the range of film thickness from 20 μm to greater than 250 μm. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

[Preparation and application on compound excipient of sodium stearyl fumarate and plasdone S-630].

PubMed

Jiang, Yan-Rong; Zhang, Zhen-Hai; Jia, Xiao-Bin

2013-01-01

The compound excipient containing sodium stearyl fumarate and plasdone S-630 was prepared by applying spray drying method. The basic physical properties of compound excipient were studied by solubility test, scanning electron microscope, differential scanning calorimeter, X-ray diffraction and Fourier transform infra-red spectroscopy. The effect of compound excipient on moisture absorption and ferulic acid in vitro dissolution of spray drying power of angelica were investigated. The results showed that the chemical constituents of compound excipient did not change before and after spray drying. The water soluble compound excipient can improve significantly moisture absorption and has application prospect.

The application of terahertz pulsed imaging in characterising density distribution of roll-compacted ribbons.

PubMed

Zhang, Jianyi; Pei, Chunlei; Schiano, Serena; Heaps, David; Wu, Chuan-Yu

2016-09-01

Roll compaction is a commonly used dry granulation process in pharmaceutical, fine chemical and agrochemical industries for materials sensitive to heat or moisture. The ribbon density distribution plays an important role in controlling properties of granules (e.g. granule size distribution, porosity and strength). Accurate characterisation of ribbon density distribution is critical in process control and quality assurance. The terahertz imaging system has a great application potential in achieving this as the terahertz radiation has the ability to penetrate most of the pharmaceutical excipients and the refractive index reflects variations in density and chemical compositions. The aim of this study is to explore whether terahertz pulse imaging is a feasible technique for quantifying ribbon density distribution. Ribbons were made of two grades of microcrystalline cellulose (MCC), Avicel PH102 and DG, using a roll compactor at various process conditions and the ribbon density variation was investigated using terahertz imaging and section methods. The density variations obtained from both methods were compared to explore the reliability and accuracy of the terahertz imaging system. An average refractive index is calculated from the refractive index values in the frequency range between 0.5 and 1.5THz. It is shown that the refractive index gradually decreases from the middle of the ribbon towards to the edges. Variations of density distribution across the width of the ribbons are also obtained using both the section method and the terahertz imaging system. It is found that the terahertz imaging results are in excellent agreement with that obtained using the section method, demonstrating that terahertz imaging is a feasible and rapid tool to characterise ribbon density distributions. Copyright © 2016 Elsevier B.V. All rights reserved.

Spectrophotometric determination of sildenafil citrate in pure form and in pharmaceutical formulation using some chromotropic acid azo dyes

NASA Astrophysics Data System (ADS)

Issa, Y. M.; El-Hawary, W. F.; Youssef, A. F. A.; Senosy, A. R.

2010-04-01

Two simple and highly sensitive spectrophotometric methods were developed for the quantitative determination of the drug sildenafil citrate (SC), Viagra, in pure form and in pharmaceutical formulations, through ion-associate formation reactions (method A) with mono-chromotropic acid azo dyes, chromotrope 2B (I) and chromotrope 2R (II) and ion-pair reactions (method B) with bi-chromotropic acid azo dyes, 3-phenylazo-6-o-carboxyphenylazo-chromotropic acid (III), bis-3,6-(o-hydroxyphenylazo)-chromotropic acid (IV), bis-3,6-(p-N,N-dimethylphenylazo)-chromotropic acid (V) and 3-phenylazo-6-o-hydroxyphenylazo-chromotorpic acid (VI). The reaction products, extractable in methylene chloride, were quantitatively measured at 540, 520, 540, 570, 600 and 575 nm using reagents, I-VI, respectively. The reaction conditions were studied and optimized. Beer's plots were linear in the concentration ranges 3.3-87.0, 3.3-96.0, 5.0-115.0, 2.5-125.0, 8.3-166.7 and 0.8-15.0 μg mL -1 with corresponding molar absorptivities 1.02 × 10 4, 8.34 × 10 3, 6.86 × 10 3, 5.42 × 10 3, 3.35 × 10 3 and 2.32 × 10 4 L mol -1 cm -1 using reagents I-VI, respectively. The limits of detection and Sandell's sensitivities were calculated. The methods were successfully applied to the analysis of commercial tablets (Vigoran) and the recovery study reveals that there is no interference from the common excipients that are present in tablets. Statistical comparison of the results was performed with regard to accuracy and precision using Student's t- and F-tests at 95% confidence level. There is no significant difference between the reported and proposed methods with regard to accuracy and precision.

Spectrophotometric Determination of Distigmine Bromide, Cyclopentolate HCl, Diaveridine HCl and Tetrahydrozoline HCl via Charge Transfer Complex Formation with TCNQ and TCNE Reagents.

PubMed

Mohamed, Gehad Genidy; Rizk, Mahmoud Sabry; Zaky Frag, Eman Yousry

2015-01-01

The purpose of this investigation was directed to propose sensitive, accurate and reproducible methods of analysis that can be applied to determine distigmine bromide (DTB), cyclopentolate hydrochloride (CPHC), diaveridine hydrochloride (DVHC) and tetrahydrozoline hydrochloride (THHC) drugs in pure form and pharmaceutical preparations via charge-transfer complex formation with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and tetracyanoethylene (TCNE) reagents. Spectrophotometric method involve the addition a known excess of TCNQ or TCNE reagents to DTB, CPHC, DVHC and THHC drugs in acetonitrile, followed by the measurement of the absorbance of the CT complexes at the selected wavelength. The reaction stoichiometry is found to be 1:1 [drug]: [TCNQ or TCNE]. The absorbance is found to increase linearly with concentration of the drugs under investigation which is corroborated by the correlation coefficients of 0.9954-0.9981. The system obeys Beer's law for 6-400, 20-500, 1-180 and 60-560 µg mL(-1) and 80-600, 10-300, 1-60 and 80-640 µg mL(-1) for DTB, CPHC, DVHC and THHC drugs using TCNQ and TCNE reagents, respectively. The apparent molar absorptivity, sandell sensitivity, the limits of detection and quantification are also reported for the spectrophotometric method. Intra- and inter-day precision and accuracy of the method were evaluated as per ICH guidelines. The method was successfully applied to the assay of DTB, CPHC, DVHC and THHC drugs in formulations and the results were compared with those of a reference method by applying Student's t and F-tests. No interference was observed from common pharmaceutical excipients.

Spectrophotometric Determination of Distigmine Bromide, Cyclopentolate HCl, Diaveridine HCl and Tetrahydrozoline HCl via Charge Transfer Complex Formation with TCNQ and TCNE Reagents

PubMed Central

Mohamed, Gehad Genidy; Rizk, Mahmoud Sabry; Zaky Frag, Eman Yousry

2015-01-01

The purpose of this investigation was directed to propose sensitive, accurate and reproducible methods of analysis that can be applied to determine distigmine bromide (DTB), cyclopentolate hydrochloride (CPHC), diaveridine hydrochloride (DVHC) and tetrahydrozoline hydrochloride (THHC) drugs in pure form and pharmaceutical preparations via charge-transfer complex formation with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and tetracyanoethylene (TCNE) reagents. Spectrophotometric method involve the addition a known excess of TCNQ or TCNE reagents to DTB, CPHC, DVHC and THHC drugs in acetonitrile, followed by the measurement of the absorbance of the CT complexes at the selected wavelength. The reaction stoichiometry is found to be 1:1 [drug]: [TCNQ or TCNE]. The absorbance is found to increase linearly with concentration of the drugs under investigation which is corroborated by the correlation coefficients of 0.9954-0.9981. The system obeys Beer’s law for 6-400, 20-500, 1-180 and 60-560 µg mL-1 and 80-600, 10-300, 1-60 and 80-640 µg mL-1 for DTB, CPHC, DVHC and THHC drugs using TCNQ and TCNE reagents, respectively. The apparent molar absorptivity, sandell sensitivity, the limits of detection and quantification are also reported for the spectrophotometric method. Intra- and inter-day precision and accuracy of the method were evaluated as per ICH guidelines. The method was successfully applied to the assay of DTB, CPHC, DVHC and THHC drugs in formulations and the results were compared with those of a reference method by applying Student’s t and F-tests. No interference was observed from common pharmaceutical excipients. PMID:26330858

Development and Application of an MSALL-Based Approach for the Quantitative Analysis of Linear Polyethylene Glycols in Rat Plasma by Liquid Chromatography Triple-Quadrupole/Time-of-Flight Mass Spectrometry.

PubMed

Zhou, Xiaotong; Meng, Xiangjun; Cheng, Longmei; Su, Chong; Sun, Yantong; Sun, Lingxia; Tang, Zhaohui; Fawcett, John Paul; Yang, Yan; Gu, Jingkai

2017-05-16

Polyethylene glycols (PEGs) are synthetic polymers composed of repeating ethylene oxide subunits. They display excellent biocompatibility and are widely used as pharmaceutical excipients. To fully understand the biological fate of PEGs requires accurate and sensitive analytical methods for their quantitation. Application of conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) is difficult because PEGs have polydisperse molecular weights (MWs) and tend to produce multicharged ions in-source resulting in innumerable precursor ions. As a result, multiple reaction monitoring (MRM) fails to scan all ion pairs so that information on the fate of unselected ions is missed. This Article addresses this problem by application of liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry (LC-Q-TOF MS) based on the MS ALL technique. This technique performs information-independent acquisition by allowing all PEG precursor ions to enter the collision cell (Q2). In-quadrupole collision-induced dissociation (CID) in Q2 then effectively generates several fragments from all PEGs due to the high collision energy (CE). A particular PEG product ion (m/z 133.08592) was found to be common to all linear PEGs and allowed their total quantitation in rat plasma with high sensitivity, excellent linearity and reproducibility. Assay validation showed the method was linear for all linear PEGs over the concentration range 0.05-5.0 μg/mL. The assay was successfully applied to the pharmacokinetic study in rat involving intravenous administration of linear PEG 600, PEG 4000, and PEG 20000. It is anticipated the method will have wide ranging applications and stimulate the development of assays for other pharmaceutical polymers in the future.

Pharmaceutical Perspective on Opalescence and Liquid-Liquid Phase Separation in Protein Solutions.

PubMed

Raut, Ashlesha S; Kalonia, Devendra S

2016-05-02

Opalescence in protein solutions reduces aesthetic appeal of a formulation and can be an indicator of the presence of aggregates or precursor to phase separation in solution signifying reduced product stability. Liquid-liquid phase separation of a protein solution into a protein-rich and a protein-poor phase has been well-documented for globular proteins and recently observed for monoclonal antibody solutions, resulting in physical instability of the formulation. The present review discusses opalescence and liquid-liquid phase separation (LLPS) for therapeutic protein formulations. A brief discussion on theoretical concepts based on thermodynamics, kinetics, and light scattering is presented. This review also discusses theoretical concepts behind intense light scattering in the vicinity of the critical point termed as "critical opalescence". Both opalescence and LLPS are affected by the formulation factors including pH, ionic strength, protein concentration, temperature, and excipients. Literature reports for the effect of these formulation factors on attractive protein-protein interactions in solution as assessed by the second virial coefficient (B2) and the cloud-point temperature (Tcloud) measurements are also presented. The review also highlights pharmaceutical implications of LLPS in protein solutions.

Clay minerals: Properties and applications to dermocosmetic products and perspectives of natural raw materials for therapeutic purposes-A review.

PubMed

Moraes, Jemima Daniela Dias; Bertolino, Silvana Raquel Alina; Cuffini, Silvia Lucia; Ducart, Diego Fernando; Bretzke, Pedro Eriberto; Leonardi, Gislaine Ricci

2017-12-20

Clay minerals are layered materials with a number of peculiar properties, which find many relevant applications in various industries. Since they are easily found everywhere, they are particularly attractive due to their economic viability. In the cosmetic industry, clay minerals are often used as excipients to stabilize emulsions or suspensions and to modify the rheological behavior of these systems. They also play an important role as adsorbents or absorbents, not only in cosmetics but also in other industries, such as pharmaceuticals. This reviewer believes that since this manuscript is presented as covering topical applications that include pharmaceuticals, some types of clay minerals should be considered as a potential material to be used as drug delivery systems. We review several applications of clay minerals to dermocosmetic products, relating them to the underlying properties of these materials and exemplifying with a number of clay minerals available in the market. We also discuss the use of clay minerals in topically-applied products for therapeutic purposes, specially for skin treatment and protection. Copyright © 2017 Elsevier B.V. All rights reserved.

Flow, packing and compaction properties of novel coprocessed multifunctional directly compressible excipients prepared from tapioca starch and mannitol.

PubMed

Adeoye, Oluwatomide; Alebiowu, Gbenga

2014-12-01

Novel multifunctional excipients were prepared by coprocessing tapioca starch with mannitol using two methods viz; co-grinding and co-fusion. The flow, packing and compaction properties of the native and novel excipients were evaluated by using density, Hausner's ratio, angle of repose, the maximum volume reduction, consolidation index, the rate of consolidation, angle of internal friction, morphological properties, Heckel analysis, tensile strength and dilution potential as evaluation parameters. The study revealed that the method of coprocessing, particle size and particle shape influenced the properties of the resulting novel excipients. Co-grinding was less effective than co-fusion in the preparation of excipients with enhanced properties. The study concluded that coprocessing tapioca starch and mannitol will enhance the flow, packing and compaction properties of the novel excipient and that the co-fusion method of coprocessing would produce novel excipients with enhanced direct compression potential compared to the co-grinding method.

The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension.

PubMed

Tian, Fang; Saville, Dorothy J; Gordon, Keith C; Strachan, Clare J; Zeitler, J Axel; Sandler, Niklas; Rades, Thomas

2007-02-01

The influence of various excipients on the conversion of carbamazepine polymorphs to the dihydrate in aqueous suspension has been investigated. Ten excipients having functional groups which were potentially able to form hydrogen bonds with carbamazepine (group 1: methylcellulose, hypromellose (hydroxypropyl methylcellulose), hydroxypropylcellulose (HPC), 2-hydroxyethylcellulose (HEC), carmellose sodium (sodium carboxymethylcellulose), cellobiose; group 2: povidone (polyvinylpyrrolidone), povidone-vinyl acetate copolymer (povidone/VA) and N-methyl-2-pyrrolidone; group 3: macrogol (polyethylene glycol) and polyethylene oxide-polypropylene oxide copolymer (PEO/PPO)) were selected. Carbamazepine polymorphic forms III and I were dispersed separately into each aqueous excipient solution (0.1%, w/v) for 30 min at room temperature. The inhibition effect of each excipient was quantified using Raman spectroscopy combined with multivariate analyses. The solubility parameter of each excipient was calculated and used for categorizing excipients. Excipients in groups 1 and 2, which had both low solubility parameters (< 27.0 MPa(1/2)) and strong hydrogen bonding groups, inhibited the conversion completely. With increasing solubility parameter, the inhibition effect decreased for group 1 excipients, especially for carbamazepine form I, which had a higher specific surface area. Also, the excipients of group 3, lacking strong hydrogen bonding groups, showed poor inhibition although they had low solubility parameters (< 21.0 MPa(1/2)). This study indicated the importance of both hydrogen bonding interaction and a suitable hydrophobicity (expressed by the solubility parameter) in the inhibition of the conversion of carbamazepine to the dihydrate.

Pectin-based oral drug delivery to the colon.

PubMed

Sande, Sverre Arne

2005-05-01

This review presents an overview of studies concerning oral formulations intended for site-specific drug delivery to the colon with pectin as the main excipient. The biological aspects covered include gastrointestinal transit and the enzymatic degradation of pectin. Scintigraphic methods demonstrating the functionality of pectin formulations are discussed. The main focus is on the various formulations reported, including matrix tablets, multiparticulate formulations as pellets and hydrogel beads, and pectin-based coatings. Also included is an evaluation of common excipients employed to improve colon specificity by crosslinking or increasing the hydrophobicity. Finally, properties of the pectin molecules that are important for successful formulations are examined. The conclusion is that the studies found in the literature provide an excellent platform for the development of pectin-based colon delivery systems.

Development and validation of reversed phase high performance liquid chromatography method for determination of dexpanthenol in pharmaceutical formulations.

PubMed

Kulikov, A U; Zinchenko, A A

2007-02-19

This paper describes the validation of an isocratic HPLC method for the assay of dexpanthenol in aerosol and gel. The method employs the Vydac Proteins C4 column with a mobile phase of aqueous solution of trifluoroacetic acid and UV detection at 206 nm. A linear response (r>0.9999) was observed in the range of 13.0-130 microg mL(-1). The method shows good recoveries and intra and inter-day relative standard deviations were less than 1.0%. Validation parameters as specificity, accuracy and robustness were also determined. The method can be used for dexpanthenol assay of panthenol aerosol and gel with dexpanthenol as the method separates dexpanthenol from aerosol or gel excipients.

Safety and efficacy of generic drugs with respect to brand formulation.

PubMed

Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

2013-12-01

Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects.

[Prolonged-release drug formulations for parenteral administration. Part II. Microspheres and implants for injection].

PubMed

Płaczek, Margin; Jacyna, Julia; Sznitowska, Małgorzata

2014-01-01

Microspheres and implants are injectable drug forms, which by special design and selection of appropriate excipients, provide for a long time constant release rate of an active substance in the body. Development of both would not be possible without advances in polymer technology and invention of safe and biocompatible polymers such as: polyesters, vinyl acetate derivatives or silicones. Polymeric matrices provide retardation of drug release--for some implants up to a few years. In addition, this paper presents examples of all commercially available medicinal products containing microspheres and implants, currently registered in Poland, together with their characteristics: composition, time course and frequency of administration. Comments are also enclosed on frequently occurring inconsistent terminology in pharmaceutical forms.

New procedure for the determination of Hansen solubility parameters by means of inverse gas chromatography.

PubMed

Adamska, K; Bellinghausen, R; Voelkel, A

2008-06-27

The Hansen solubility parameter (HSP) seems to be a useful tool for the thermodynamic characterization of different materials. Unfortunately, estimation of the HSP values can cause some problems. In this work different procedures by using inverse gas chromatography have been presented for calculation of pharmaceutical excipients' solubility parameter. The new procedure proposed, based on the Lindvig et al. methodology, where experimental data of Flory-Huggins interaction parameter are used, can be a reasonable alternative for the estimation of HSP values. The advantage of this method is that the values of Flory-Huggins interaction parameter chi for all test solutes are used for further calculation, thus diverse interactions between test solute and material are taken into consideration.

Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets.

PubMed

Sadia, Muzna; Sośnicka, Agata; Arafat, Basel; Isreb, Abdullah; Ahmed, Waqar; Kelarakis, Antonios; Alhnan, Mohamed A

2016-11-20

This work aims to employ fused deposition modelling 3D printing to fabricate immediate release pharmaceutical tablets with several model drugs. It investigates the addition of non-melting filler to methacrylic matrix to facilitate FDM 3D printing and explore the impact of (i) the nature of filler, (ii) compatibility with the gears of the 3D printer and iii) polymer: filler ratio on the 3D printing process. Amongst the investigated fillers in this work, directly compressible lactose, spray-dried lactose and microcrystalline cellulose showed a level of degradation at 135°C whilst talc and TCP allowed consistent flow of the filament and a successful 3D printing of the tablet. A specially developed universal filament based on pharmaceutically approved methacrylic polymer (Eudragit EPO) and thermally stable filler, TCP (tribasic calcium phosphate) was optimised. Four model drugs with different physicochemical properties were included into ready-to-use mechanically stable tablets with immediate release properties. Following the two thermal processes (hot melt extrusion (HME) and fused deposition modelling (FDM) 3D printing), drug contents were 94.22%, 88.53%, 96.51% and 93.04% for 5-ASA, captopril, theophylline and prednisolone respectively. XRPD indicated that a fraction of 5-ASA, theophylline and prednisolone remained crystalline whilst captopril was in amorphous form. By combining the advantages of thermally stable pharmaceutically approved polymers and fillers, this unique approach provides a low cost production method for on demand manufacturing of individualised dosage forms. Copyright © 2016 Elsevier B.V. All rights reserved.

Three-dimensional printing in pharmaceutics: promises and problems.

PubMed

Yu, Deng Guang; Zhu, Li-Min; Branford-White, Christopher J; Yang, Xiang Liang

2008-09-01

Three-dimensional printing (3DP) is a rapid prototyping (RP) technology. Prototyping involves constructing specific layers that uses powder processing and liquid binding materials. Reports in the literature have highlighted the many advantages of the 3DP system over other processes in enhancing pharmaceutical applications, these include new methods in design, development, manufacture, and commercialization of various types of solid dosage forms. For example, 3DP technology is flexible in that it can be used in applications linked to linear drug delivery systems (DDS), colon-targeted DDS, oral fast disintegrating DDS, floating DDS, time controlled, and pulse release DDS as well as dosage form with multiphase release properties and implantable DDS. In addition 3DP can also provide solutions for resolving difficulties relating to the delivery of poorly water-soluble drugs, peptides and proteins, preparation of DDS for high toxic and potent drugs and controlled-release of multidrugs in a single dosage forms. Due to its flexible and highly reproducible manufacturing process, 3DP has some advantages over conventional compressing and other RP technologies in fabricating solid DDS. This enables 3DP to be further developed for use in pharmaceutics applications. However, there are some problems that limit the further applications of the system, such as the selections of suitable excipients and the pharmacotechnical properties of 3DP products. Further developments are therefore needed to overcome these issues where 3DP systems can be successfully combined with conventional pharmaceutics. Here we present an overview and the potential 3DP in the development of new drug delivery systems.

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.

Study of the use of axial viewed inductively coupled plasma atomic emission spectrometry with ultrasonic nebulization for the determination of select elemental impurities in oral drug products.

PubMed

Menoutis, James; Parisi, Angela; Verma, Natasha

2018-04-15

In efforts to control the potential presence of heavy metals in pharmaceuticals, the United States Pharmacopeia (USP) and International Conference on Harmonization (ICH) have put forth new requirements and guidelines for their control. The new requirements and guidelines establish specific daily exposures (PDE) for 24 heavy metals/elemental impurities (EI) based upon their toxicological properties. USP General Chapter 〈233〉 provides a general reference procedure for preparing pharmaceutical samples for analysis employing microwave assisted digestion (MWAD). It also provides two Compendial Procedures, Procedure 1 employing ICP-AES, and Procedure 2 employing ICP-MS. Given the extremely low detection limits afforded by ICP-MS, much work has been done in developing and evaluating analytical methods to support the analysis of elemental impurities in finished pharmaceutical products, active pharmaceutical ingredients, and excipients by this analytical technique. In this study, we have evaluated the use of axial ICP-AES. This employs ultrasonic nebulization (UN) for the determination of Class 1 and 2 EI, instead of traditional pneumatic nebulization. The study also employed closed vessel MWAD to prepare samples for analysis. Limits of quantitation were element specific and significantly lower than the PDEs for oral drugs. Spike recoveries for the elements studied ranged between 89.3% and 109.25%, except for Os, which was subject to OsO4 formation during MWAD. The use of axial ICP-AES UN provides an alternative to ICP-MS in the analysis of EI requiring low detection limits. Copyright © 2018 Elsevier B.V. All rights reserved.

Generalized in vitro-in vivo relationship (IVIVR) model based on artificial neural networks

PubMed Central

Mendyk, Aleksander; Tuszyński, Paweł K; Polak, Sebastian; Jachowicz, Renata

2013-01-01

Background The aim of this study was to develop a generalized in vitro-in vivo relationship (IVIVR) model based on in vitro dissolution profiles together with quantitative and qualitative composition of dosage formulations as covariates. Such a model would be of substantial aid in the early stages of development of a pharmaceutical formulation, when no in vivo results are yet available and it is impossible to create a classical in vitro-in vivo correlation (IVIVC)/IVIVR. Methods Chemoinformatics software was used to compute the molecular descriptors of drug substances (ie, active pharmaceutical ingredients) and excipients. The data were collected from the literature. Artificial neural networks were used as the modeling tool. The training process was carried out using the 10-fold cross-validation technique. Results The database contained 93 formulations with 307 inputs initially, and was later limited to 28 in a course of sensitivity analysis. The four best models were introduced into the artificial neural network ensemble. Complete in vivo profiles were predicted accurately for 37.6% of the formulations. Conclusion It has been shown that artificial neural networks can be an effective predictive tool for constructing IVIVR in an integrated generalized model for various formulations. Because IVIVC/IVIVR is classically conducted for 2–4 formulations and with a single active pharmaceutical ingredient, the approach described here is unique in that it incorporates various active pharmaceutical ingredients and dosage forms into a single model. Thus, preliminary IVIVC/IVIVR can be available without in vivo data, which is impossible using current IVIVC/IVIVR procedures. PMID:23569360

A novel approach to support formulation design on twin screw wet granulation technology: Understanding the impact of overarching excipient properties on drug product quality attributes.

PubMed

Willecke, N; Szepes, A; Wunderlich, M; Remon, J P; Vervaet, C; De Beer, T

2018-04-21

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models' validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes. Copyright © 2018 Elsevier B.V. All rights reserved.

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

PubMed

Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

2016-03-07

Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

The STEP (Safety and Toxicity of Excipients for Paediatrics) database: part 2 - the pilot version.

PubMed

Salunke, Smita; Brandys, Barbara; Giacoia, George; Tuleu, Catherine

2013-11-30

The screening and careful selection of excipients is a critical step in paediatric formulation development as certain excipients acceptable in adult formulations, may not be appropriate for paediatric use. While there is extensive toxicity data that could help in better understanding and highlighting the gaps in toxicity studies, the data are often scattered around the information sources and saddled with incompatible data types and formats. This paper is the second in a series that presents the update on the Safety and Toxicity of Excipients for Paediatrics ("STEP") database being developed by Eu-US PFIs, and describes the architecture data fields and functions of the database. The STEP database is a user designed resource that compiles the safety and toxicity data of excipients that is scattered over various sources and presents it in one freely accessible source. Currently, in the pilot database data from over 2000 references/10 excipients presenting preclinical, clinical, regulatory information and toxicological reviews, with references and source links. The STEP database allows searching "FOR" excipients and "BY" excipients. This dual nature of the STEP database, in which toxicity and safety information can be searched in both directions, makes it unique from existing sources. If the pilot is successful, the aim is to increase the number of excipients in the existing database so that a database large enough to be of practical research use will be available. It is anticipated that this source will prove to be a useful platform for data management and data exchange of excipient safety information. Copyright © 2013 Elsevier B.V. All rights reserved.

Diffusion and Swelling Measurements in Pharmaceutical Powder Compacts Using Terahertz Pulsed Imaging

PubMed Central

Yassin, Samy; Su, Ke; Lin, Hungyen; Gladden, Lynn F; Zeitler, J Axel

2015-01-01

Tablet dissolution is strongly affected by swelling and solvent penetration into its matrix. A terahertz-pulsed imaging (TPI) technique, in reflection mode, is introduced as a new tool to measure one-dimensional swelling and solvent ingress in flat-faced pharmaceutical compacts exposed to dissolution medium from one face of the tablet. The technique was demonstrated on three tableting excipients: hydroxypropylmethyl cellulose (HPMC), Eudragit RSPO, and lactose. Upon contact with water, HPMC initially shrinks to up to 13% of its original thickness before undergoing expansion. HPMC and lactose were shown to expand to up to 20% and 47% of their original size in 24 h and 13 min, respectively, whereas Eudragit does not undergo dimensional change. The TPI technique was used to measure the ingress of water into HPMC tablets over a period of 24 h and it was observed that water penetrates into the tablet by anomalous diffusion. X-ray microtomography was used to measure tablet porosity alongside helium pycnometry and was linked to the results obtained by TPI. Our results highlight a new application area of TPI in the pharmaceutical sciences that could be of interest in the development and quality testing of advanced drug delivery systems as well as immediate release formulations. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1658–1667, 2015 PMID:25645509

Development of qualitative and quantitative analysis methods in pharmaceutical application with new selective signal excitation methods for 13 C solid-state nuclear magnetic resonance using 1 H T1rho relaxation time.

PubMed

Nasu, Mamiko; Nemoto, Takayuki; Mimura, Hisashi; Sako, Kazuhiro

2013-01-01

Most pharmaceutical drug substances and excipients in formulations exist in a crystalline or amorphous form, and an understanding of their state during manufacture and storage is critically important, particularly in formulated products. Carbon 13 solid-state nuclear magnetic resonance (NMR) spectroscopy is useful for studying the chemical and physical state of pharmaceutical solids in a formulated product. We developed two new selective signal excitation methods in (13) C solid-state NMR to extract the spectrum of a target component from such a mixture. These methods were based on equalization of the proton relaxation time in a single domain via rapid intraproton spin diffusion and the difference in proton spin-lattice relaxation time in the rotating frame ((1) H T1rho) of individual components in the mixture. Introduction of simple pulse sequences to one-dimensional experiments reduced data acquisition time and increased flexibility. We then demonstrated these methods in a commercially available drug and in a mixture of two saccharides, in which the (13) C signals of the target components were selectively excited, and showed them to be applicable to the quantitative analysis of individual components in solid mixtures, such as formulated products, polymorphic mixtures, or mixtures of crystalline and amorphous phases. Copyright © 2012 Wiley Periodicals, Inc.

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization.

PubMed

Li, Shu; Yu, Tao; Tian, Yiwei; McCoy, Colin P; Jones, David S; Andrews, Gavin P

2016-09-06

Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.

A User-Friendly Model for Spray Drying to Aid Pharmaceutical Product Development

PubMed Central

Grasmeijer, Niels; de Waard, Hans; Hinrichs, Wouter L. J.; Frijlink, Henderik W.

2013-01-01

The aim of this study was to develop a user-friendly model for spray drying that can aid in the development of a pharmaceutical product, by shifting from a trial-and-error towards a quality-by-design approach. To achieve this, a spray dryer model was developed in commercial and open source spreadsheet software. The output of the model was first fitted to the experimental output of a Büchi B-290 spray dryer and subsequently validated. The predicted outlet temperatures of the spray dryer model matched the experimental values very well over the entire range of spray dryer settings that were tested. Finally, the model was applied to produce glassy sugars by spray drying, an often used excipient in formulations of biopharmaceuticals. For the production of glassy sugars, the model was extended to predict the relative humidity at the outlet, which is not measured in the spray dryer by default. This extended model was then successfully used to predict whether specific settings were suitable for producing glassy trehalose and inulin by spray drying. In conclusion, a spray dryer model was developed that is able to predict the output parameters of the spray drying process. The model can aid the development of spray dried pharmaceutical products by shifting from a trial-and-error towards a quality-by-design approach. PMID:24040240

Anodic voltammetric behavior and determination of rosiglitazone in pharmaceutical dosage forms and biological fluids on solid electrode.

PubMed

Dogan-Topal, Burcu; Tuncel, Secil; Ozkan, Sibel A

2010-09-01

The anodic voltammetric behavior and electroanalytical determination of rosiglitazone was studied using cyclic, linear sweep, differential pulse and square wave voltammetric techniques on glassy carbon electrode. The oxidation of rosiglitazone was irreversible and exhibited diffusion controlled process depending on pH. Different parameters were tested to optimize the conditions for the determination of the oxidation mechanism of rosiglitazone. The dependence of current intensities and potentials on pH, concentration, scan rate, nature of the buffer was also investigated. According to the linear relationship between the peak current and the concentration, differential pulse and square wave voltammetric methods for rosiglitazone assay in pharmaceutical dosage forms and biological fluids were developed. A linear response was obtained within the range of 1x10-6M - 6x10-5M in 0.1 M H2SO4 and acetate buffer at pH 5.70 for both voltammetric methods in human serum samples. The practical analytical value of the method is demonstrated by quantitative determination of rosiglitazon in pharmaceutical formulation and human serum, without the need for separation or complex sample preparation, since there was no interference from the excipients and endogenous substances. The methods were fully validated and successfully applied to the high throughput determination of the drug in tablets and human serum with good recoveries.

Evolution of the microstructure during the process of consolidation and bonding in soft granular solids.

PubMed

Yohannes, B; Gonzalez, M; Abebe, A; Sprockel, O; Nikfar, F; Kiang, S; Cuitiño, A M

2016-04-30

The evolution of microstructure during powder compaction process was investigated using a discrete particle modeling, which accounts for particle size distribution and material properties, such as plasticity, elasticity, and inter-particle bonding. The material properties were calibrated based on powder compaction experiments and validated based on tensile strength test experiments for lactose monohydrate and microcrystalline cellulose, which are commonly used excipient in pharmaceutical industry. The probability distribution function and the orientation of contact forces were used to study the evolution of the microstructure during the application of compaction pressure, unloading, and ejection of the compact from the die. The probability distribution function reveals that the compression contact forces increase as the compaction force increases (or the relative density increases), while the maximum value of the tensile contact forces remains the same. During unloading of the compaction pressure, the distribution approaches a normal distribution with a mean value of zero. As the contact forces evolve, the anisotropy of the powder bed also changes. Particularly, during loading, the compression contact forces are aligned along the direction of the compaction pressure, whereas the tensile contact forces are oriented perpendicular to direction of the compaction pressure. After ejection, the contact forces become isotropic. Copyright © 2016 Elsevier B.V. All rights reserved.

Cutaneous adverse reactions to amoxicillin-clavulanic acid suspension in children: the role of sodium benzoate.

PubMed

Mori, Francesca; Barni, Simona; Pucci, Neri; Rossi, Maria Elisabetta; de Martino, Maurizio; Novembre, Elio

2012-04-01

In Europe amoxicillin plus clavulanic acid is the most commonly prescribed antibiotic and sodium benzoate is contained in the suspension formulation as a preservative. We studied the relevance of sodium benzoate as the culprit agent. In a group of children with a history of adverse reactions to amoxicillin plus clavulanic acid suspension. A total of 89 children were enrolled over a period of 3 years (2006 - 2009). Single blind oral provocation tests (OPTs) with amoxicillin plus clavulanic acid, sodium benzoate and placebo were performed. 20 children with recurrent idiopathic urticaria were investigated as a control group. according to personal history: 70% of reactions were late in developing while 23% of reactions were immediate and for 5% of the cases it was not possible to define the timing. 8 children (8/89=9%) resulted positive to the provocation tests with amoxicillin plus clavulanic acid; ten children (10/89=11%) had positive results with sodium benzoate; 3% had a double positivity (i.e. excipient and active drug). The timing of reactions significantly differs between the Amoxicillin plus clavulanic acid and sodium benzoate groups (p=0.002). Sodium benzoate probably acts through a non-immunologic mechanism and care should be given to children allergic to sodium benzoate containing pharmaceutical formulations.

Challenges in detecting magnesium stearate distribution in tablets.

PubMed

Lakio, Satu; Vajna, Balázs; Farkas, István; Salokangas, Henri; Marosi, György; Yliruusi, Jouko

2013-03-01

Magnesium stearate (MS) is the most commonly used lubricant in pharmaceutical industry. During blending, MS particles form a thin layer on the surfaces of the excipient and drug particles prohibiting the bonding from forming between the particles. This hydrophobic layer decreases the tensile strength of tablets and prevents water from penetrating into the tablet restraining the disintegration and dissolution of the tablets. Although overlubrication of the powder mass during MS blending is a well-known problem, the lubricant distribution in tablets has traditionally been challenging to measure. There is currently no adequate analytical method to investigate this phenomenon. In this study, the distribution of MS in microcrystalline cellulose (MCC) tablets was investigated using three different blending scales. The crushing strength of the tablets was used as a secondary response, as its decrease is known to result from the overlubrication. In addition, coating of the MCC particles by MS in intact tablets was detected using Raman microscopic mapping. MS blending was more efficient in larger scales. Raman imaging was successfully applied to characterize MS distribution in MCC tablets despite low concentration of MS. The Raman method can provide highly valuable visual information about the proceeding of the MS blending process. However, the measuring set-up has to be carefully planned to establish reliable and reproducible results.

Investigating Structure and Dynamics of Proteins in Amorphous Phases Using Neutron Scattering.

PubMed

Castellanos, Maria Monica; McAuley, Arnold; Curtis, Joseph E

2017-01-01

In order to increase shelf life and minimize aggregation during storage, many biotherapeutic drugs are formulated and stored as either frozen solutions or lyophilized powders. However, characterizing amorphous solids can be challenging with the commonly available set of biophysical measurements used for proteins in liquid solutions. Therefore, some questions remain regarding the structure of the active pharmaceutical ingredient during freezing and drying of the drug product and the molecular role of excipients. Neutron scattering is a powerful technique to study structure and dynamics of a variety of systems in both solid and liquid phases. Moreover, neutron scattering experiments can generally be correlated with theory and molecular simulations to analyze experimental data. In this article, we focus on the use of neutron techniques to address problems of biotechnological interest. We describe the use of small-angle neutron scattering to study the solution structure of biological molecules and the packing arrangement in amorphous phases, that is, frozen glasses and freeze-dried protein powders. In addition, we discuss the use of neutron spectroscopy to measure the dynamics of glassy systems at different time and length scales. Overall, we expect that the present article will guide and prompt the use of neutron scattering to provide unique insights on many of the outstanding questions in biotechnology.

Pre-systemic metabolism of orally administered drugs and strategies to overcome it.

PubMed

Pereira de Sousa, Irene; Bernkop-Schnürch, Andreas

2014-10-28

The oral bioavailability of numerous drugs is not only limited by poor solubility and/or poor membrane permeability as addressed by the biopharmaceutical classification system (BCS) but also by a pre-systemic metabolism taking place to a high extent in the intestine. Enzymes responsible for metabolic reactions in the intestine include cytochromes P450 (CYP450), transferases, peptidases and proteases. Furthermore, in the gut nucleases, lipases as well as glycosidases influence the metabolic pathway of drugs and nutrients. A crucial role is also played by the intestinal microflora able to metabolize a wide broad of pharmaceutical compounds. Strategies to provide a protective effect towards an intestinal pre-systemic metabolism are based on the co-administration of enzyme inhibitor being optimally immobilized on unabsorbable and undegradable polymeric excipients in order to keep them concentrated there where an inhibitory effect is needed. Furthermore, certain polymeric excipients such as polyacrylates exhibit per se enzyme inhibitory properties. In addition, by incorporating drugs in cyclodextrines, in self-emulsifying drug delivery systems (SEDDS) or liposomes a protective effect towards an intestinal enzymatic attack can be achieved. Being aware of the important role of this pre-systemic metabolism by integrating it in the BCS as third dimension and keeping strategies to overcome this enzymatic barrier in mind, the therapeutic efficacy of many orally given drugs can certainly be substantially improved. Copyright © 2014 Elsevier B.V. All rights reserved.

Novel algorithm for simultaneous component detection and pseudo-molecular ion characterization in liquid chromatography-mass spectrometry.

PubMed

Zhang, Yufeng; Wang, Xiaoan; Wo, Siukwan; Ho, Hingman; Han, Quanbin; Fan, Xiaohui; Zuo, Zhong

2015-01-01

Resolving components and determining their pseudo-molecular ions (PMIs) are crucial steps in identifying complex herbal mixtures by liquid chromatography-mass spectrometry. To tackle such labor-intensive steps, we present here a novel algorithm for simultaneous detection of components and their PMIs. Our method consists of three steps: (1) obtaining a simplified dataset containing only mono-isotopic masses by removal of background noise and isotopic cluster ions based on the isotopic distribution model derived from all the reported natural compounds in dictionary of natural products; (2) stepwise resolving and removing all features of the highest abundant component from current simplified dataset and calculating PMI of each component according to an adduct-ion model, in which all non-fragment ions in a mass spectrum are considered as PMI plus one or several neutral species; (3) visual classification of detected components by principal component analysis (PCA) to exclude possible non-natural compounds (such as pharmaceutical excipients). This algorithm has been successfully applied to a standard mixture and three herbal extract/preparations. It indicated that our algorithm could detect components' features as a whole and report their PMI with an accuracy of more than 98%. Furthermore, components originated from excipients/contaminants could be easily separated from those natural components in the bi-plots of PCA. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Application of water-insoluble polymers to orally disintegrating tablets treated by high-pressure carbon dioxide gas.

PubMed

Ito, Yoshitaka; Maeda, Atsushi; Kondo, Hiromu; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

2016-09-10

The phase transition of pharmaceutical excipients that can be induced by humidifying or heating is well-known to increase the hardness of orally disintegrating tablets (ODTs). However, these conditions are not applicable to drug substances that are chemically unstable against such stressors. Here, we describe a system which enhances the hardness of tablets containing water-insoluble polymers by using high-pressure carbon dioxide (CO2). On screening of 26 polymeric excipients, aminoalkyl methacrylate copolymer E (AMCE) markedly increased tablet hardness (+155N) when maintained in a high-pressure CO2 environment. ODTs containing 10% AMCE were prepared and treatment with 4.0MPa CO2 gas at 25°C for 10min increased the hardness to +30N, whose level corresponded to heating at 70°C for 720min. In addition, we confirmed the effects of CO2 pressure, temperature, treatment time, and AMCE content on the physical properties of ODTs. Optimal pressure of CO2 gas was considered to be approximately 3.5MPa for an AMCE formula, as excessive pressure delayed the disintegration of ODTs. Combination of high-pressure CO2 gas and AMCE is a prospective approach for increasing the tablet hardness for ODTs, and can be conducted without additional heat or moisture stress using a simple apparatus. Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical stability of insulin. 3. Influence of excipients, formulation, and pH.

PubMed

Brange, J; Langkjaer, L

1992-01-01

The influence of auxiliary substances and pH on the chemical transformations of insulin in pharmaceutical formulation, including various hydrolytic and intermolecular cross-linking reactions, was studied. Bacteriostatic agents had a profound stabilizing effect--phenol > m-cresol > methylparaben--on deamidation as well as on insulin intermolecular cross-linking reactions. Of the isotonicity substances, NaCl generally had a stabilizing effect whereas glycerol and glucose led to increased chemical deterioration. Phenol and sodium chloride exerted their stabilizing effect through independent mechanisms. Zinc ions, in concentrations that promote association of insulin into hexamers, increase the stability, whereas higher zinc content had no further influence. Protamine gave rise to additional formation of covalent protamine-insulin products which increased with increasing protamine concentration. The impact of excipients on the chemical processes seems to be dictated mainly via an influence on the three-dimensional insulin structure. The effect of the physical state of the insulin on the chemical stability was also complex, suggesting an intricate dependence of intermolecular proximity of involved functional groups. At pH values below five and above eight, insulin degrades relatively fast. At acid pH, deamidation at residue A21 and covalent insulin dimerization dominates, whereas disulfide reactions leading to covalent polymerization and formation of A- and B-chains prevailed in alkaline medium. Structure-reactivity relationship is proposed to be a main determinant for the chemical transformation of insulin.

Evidence-Based Nanoscopic and Molecular Framework for Excipient Functionality in Compressed Orally Disintegrating Tablets

PubMed Central

Al-khattawi, Ali; Alyami, Hamad; Townsend, Bill; Ma, Xianghong; Mohammed, Afzal R.

2014-01-01

The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2–10 µm2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. PMID:25025427

Development of Coprocessed Chitin-Calcium Carbonate as Multifunctional Tablet Excipient for Direct Compression.

PubMed

Chaheen, Mohammad; Sanchez-Ballester, Noelia M; Bataille, Bernard; Yassine, Ahmad; Belamie, Emmanuel; Sharkawi, Tahmer

2018-04-24

Owing to the increasing interest in multifunctional excipients for tableting, coprocessing of individual excipients is regularly used to produce excipients of improved multifunctionality superior to individual excipients or their physical mix. The use of chitin as an excipient in tablet formulation is limited because of certain drawbacks such as poor flowability and low true density. The objective of this work is to improve these properties through coprocessing of chitin with calcium carbonate (CaCO 3 ) by precipitating CaCO 3 on chitin particles using different methods. In addition, optimization of the coprocessed chitin was carried out to improve the excipient's properties. Physicochemical (CaCO 3 content, true density, X-ray diffraction, infrared spectroscopy, and scanning electron microscopy) and functional testing (swelling force, flowability, tensile strength, deformation mechanism, and disintegration time) were used to characterize the coprocessed product. Results showed that the calcite CaCO 3 polymorph is precipitated on the chitin surface and that it interacts with chitin at carbonyl- and amide-group level. In addition, the coprocessed excipient has an improved true density and powder flowability, with CaCO 3 forming single layer on the chitin particles surface. Tableting studies showed that the coprocessed powder exhibited an intermediate deformation behavior between CaCO 3 (most brittle) and chitin (most plastic). Tablets showed acceptable tensile strength and rapid disintegration (2-4 s). These results show the potential use of coprocessed chitin-CaCO 3 as a multifunctional excipient for fast disintegration of tablets produced by direct compression. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Safety and efficacy of generic drugs with respect to brand formulation

PubMed Central

Gallelli, Luca; Palleria, Caterina; De Vuono, Antonio; Mumoli, Laura; Vasapollo, Piero; Piro, Brunella; Russo, Emilio

2013-01-01

Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side-effects. PMID:24347975

[Chocolate in some french pharmaceutical or medicinal books from XVIIth, XVIIIth and XIXth centuries. Its beneficent and inconvenient, proved or imaginary, effects].

PubMed

Paternotte, Stéphanie; Labrude, Pierre

2003-01-01

Rapidly after its appearance in France, interesting properties were attributed to chocolate and it was used in medicine,often wrongly, to treat digestive, pulmonary, nervous, even infectious diseases, and also for its nutritive and aphrodisiacal capability... But it was already charged with insomnia or constipation. During the XIXth century, chocolate was used as food and as an excipient for dissimulation and transportation of drugs. Medicinal chocolates were essentially nutritive and analeptic, pectoral, stomachic, purgative or anthelmintic. All of them have disappeared today, but the pharmacological interest of chocolate remains with its antidepressive activity and the promising proposes of some of its components. However, chocolate is still considered to be responsible of constipation, headache or pimples...

Individual and simultaneous spectrophotometric determination of dapsone and metoclopramide HCl in pharmaceutical dosage forms and synthetic binary mixtures.

PubMed

Omran, Ahmed Ahmed

2005-11-01

A rapid, sensitive and selective spectrophotometric method has been developed for the quantitative determination of dapsone (DAP) and metoclopramide hydrochloride (MCP) in both pure and dosage forms. Individual and simultaneous methods are based on the diazo coupling reaction of these drugs with benzoylacetone (BAC) in alkaline medium. The resulting azo dyes exhibit maximum absorption at 437 and 411 nm with a molar absorptivity of 4.14x10(4) and 2.97x10(4) l mol-1 cm-1 for DAP and MCP, respectively. Simultaneous determination of DAP and MCP was developed utilizing first-order digital derivative spectrophotometry. All variables have been optimized. No interferences were observed from drug excipients and the validity of the methods was tested against reference methods.

Studies on stercuia gum formulations in the form of osmotic core tablet for colon-specific drug delivery of azathioprine.

PubMed

Nath, Bipul; Nath, Lila Kanta

2013-01-01

The purpose of this research is to evaluate Sterculia urens gum as a carrier for a colon-targeted drug delivery system. Microflora degradation studies of Sterculia gum was conducted in phosphate-buffered saline pH 7.4 containing rat caecal medium under an anaerobic environment. Solubility, swelling index, viscosity, and pH of the polymer solution were determined. Different formulation aspects considered were gum concentration (10-40%) and concentration of citric acid (10-30%) on the swelling index and in-vitro dissolution release. The results of the isothermal stress testing showed that there is no degradation of samples of model drug, azathioprine, the drug polymer mixture, and the core tablet excipients. Differential scanning calorimetry and Fourier transform infrared spectroscopy study proved the compatibility of the drug with Sterculia gum and other tablet excipients. Microflora degradation study revealed that Sterculia gum can be used as tablet excipient for drug release in the colonic region by utilizing the action of enterobacteria. The swelling force of the Sterculia gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the mixed film coating under colonic microflora-activated environment. Sterculia gum gives premature drug release in the upper gastrointestinal tract without enteric coating and may not reach the colonic region. Sterculia gum as a colon-targeting carrier is possible via double-layer coating with chitosan/Eudragit RLPO (ammonio-methacrylate copolymer) mixed blend as well as enteric polymers, which would provide acid as well as intestinal resistance but undergo enzymatic degradation once reaching the colon. The aim of the research is to evaluate wheather Sterculia urens, which is a polysaccharide, is suitable as a carrier for colonic delivery of drugs acting locally in the colon. Sterculia gum has been reported to have wide pharmaceutical applications such as tablet binder, disintegrant, gelling agent, and as a controlled release polymer. Sterculia gum falls under the category of a polysaccharide and is yet to be evaluated as a carrier for colonic delivery of drugs. First the susceptibility of the polysaccharide gum in rat caecal microflora was investigated because true polysaccharides are degraded by the action of normal colonic bacteria. Bacterial degradation of the gum in the colonic environment was confirmed by adding a small quantity of the gum in rat caecal content mixed with phosphate-buffered saline pH 7.4 under an anaerobic environment. Solubility, swelling index, viscosity, and pH of the polymer solution were determined. Different formulation aspects considered were gum concentration (10-40%), concentration of citric acid (10-30%) on swelling index, and in vitro dissolution behavior. Isothermal stress testing was done to determine that there was no degradation of the model drug, azathioprine, with Sterculia gum excipient mixtures under stressed conditions. Differential scanning calorimetry and Fourier transform infrared spectroscopy study proved the compatibility of the drug with Sterculia gum and other tablet excipients. Microflora degradation study revealed that Sterculia gum is digested by the colonic microflora and therefore can be used as a tablet excipient for drug release in the colonic region utilizing the microflora degradation mechanism. Sterculia gum gives premature drug release in the upper gastrointestinal tract without enteric coating and may not reach the colonic region. Sterculia gum as colon-targeting carrier is possible via double-layer coating with chitosan/Eudragit RLPO (ammonio-methacrylate copolymer) and Eudragit L100 polymers, which would provide acid as well as intestinal resistance but undergo enzymatic degradation once reaching the colon.

Material and Compression Properties of Cedrela odorata Gum Co-Processed with Plantain Starch and Microcrystalline Cellulose.

PubMed

Adetunji, Oladapo Adewale; Odeniyi, Michael Ayodele

2016-01-01

Many excipients used in tableting exhibit some undesirable properties such as poor flow, cohesion and lubricating characteristics, thus necessitating some modification to achieve the desired product. The objective of this study was to enhance the material, flow and compressional properties of Cedrela odorata gum (COG) (Family: Meliaceae) by co-processing with plantain starch (PS) and microcrystalline cellulose (MCC). The COG was co-processed with PS (or MCC) by physical co-grinding at ratio 1 : 1, 1 : 2 and 1 : 4, and characterized using morphological analysis, swelling index viscosity measurements, particle size analysis and FTIR spectra. The material, flow and compressional properties of the co-processed excipients were also evaluated. Results were analyzed using mean and standard deviation of data. There was a decrease in the degree of agglomeration of COG and a reduction in the size of the powdered gum. The co-processed excipients were more spherical than the native excipients. The COG had the highest viscosity, while MCC and COG : PS (1 : 2) showed the highest and lowest degrees of swelling at 27.0 ± 0.05°C respectively. Water absorption capacity of the component excipients improved with co-processing COG : MCC increasing from 171.8 ± 1.54 (1 : 1) to 214.8 ± 1.07 (1 : 2), while COG : PS increased from 95.2 ± 0.08 (1 : 1) to 206.2 ± 0.13. There was a decrease in the percentage solubility of the co-processed excipients with the highest and lowest solubility observed in COG (54.1 ± 0.07%) and PS (3.7 ± 0.16%), respectively. The FTIR spectra indicate no significant interaction between the excipients. The poor flow of the component excipients did not improve with co-processing; however, there was a significant increase in compressibility. Generally, COG co-processed with MCC showed better compression properties when compared with COG co-processed with PS. Co-processing of COD with MC or PS enhanced the characters of the component excipients, thus making the co-processed excipients suitable for direct compression of tablets without altering the chemical nature of the component excipients.

Contribution to the rheological testing of pharmaceutical semisolids.

PubMed

Siska, B; Snejdrova, E; Machac, I; Dolecek, P; Martiska, J

2018-01-22

Rheological behaviour of pharmaceutical semisolid preparations significantly affects manufacturing process, administration, stability, homogeneity of incorporated drug, accuracy of dosing, adhesion in the place of application, drug release, and resulting therapeutic effect of the product. We performed test of consistency by penetrometry, rotational, oscillation and creep tests, and squeeze and tack tests of model samples to introduce methods suitable for characterization and comparison of semisolids in practice. Penetrometry is a simple method allowing sorting the semisolids to low and high stress-resistant materials but deficient for rheological characterization of semisolids. Value of yield stress, generally considered to be appropriate feature of semisolids, is significantly influenced by the method of testing and the way of evaluation. The hysteresis loops of model semisolids revealed incomplete thixotropy, therefore, three-step thixotropy test was employed. Semisolids showed nonlinear response in the creep phase of tests and partial recovery of structure by storing energy in the recovery phase. Squeeze and tack tests seem to be convenient ways for comparison of semisolids. Our study can contribute to a better understanding of different flow behaviour of semisolids given by different physicochemical properties of excipients and can bring useful approaches to evaluation and comparison of semisolids in practice.

Structural, functional and pH sensitive release characteristics of water-soluble polysaccharide from the seeds of Albizia lebbeck L.

PubMed

Kumar Varma, Chekuri Ashok; Jayaram Kumar, K

2017-11-01

Plant polysaccharides, generally regarded as safe (GRAS), are gaining importance as excipients in drug delivery. Therefore, the current paper presents the studies on structural, functional and drug release study of water soluble polysaccharide (ALPS) from seeds of Albizia lebbeck L. High swelling, water holding capacity, foam stability and lower moisture content suggests its use as additive in food preparations. The apparent molecular weight of polysaccharide was found to be 1.98×10 2 kDa. Monosaccharide composition analysis indicated that ALPS consists of mannose (4.06%), rhamnose (22.79%), glucose (38.9%), galactose (17.84%) and xylose (16.42%). Micromeritic properties revealed that the polysaccharide possess potential for pharmaceutical applications. From the surface charge analysis, ALPS was found to be non-ionic polysaccharide. Morphological study reveals the polysaccharide with irregular particle shape and rough surface. Fourier transformed infrared spectroscopy (FTIR) study confirms the carbohydrate nature of polysaccharide. From the thermogravimetric analysis (TGA) data, the second mass loss (243-340°C) attributed to polysaccharide degradation. The drug release profile reveals the use of polysaccharide for the preparation of pH sensitive pharmaceutical dosage forms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design Expert Supported Mathematical Optimization and Predictability Study of Buccoadhesive Pharmaceutical Wafers of Loratadine

PubMed Central

Dey, Surajit; Parcha, Versha; Bhattacharya, Shiv Sankar; Ghosh, Amitava

2013-01-01

Objective. The objective of this work encompasses the application of the response surface approach in the development of buccoadhesive pharmaceutical wafers of Loratadine (LOR). Methods. Experiments were performed according to a 32 factorial design to evaluate the effects of buccoadhesive polymer, sodium alginate (A), and lactose monohydrate as ingredient, of hydrophilic matrix former (B) on the bioadhesive force, disintegration time, percent (%) swelling index, and time taken for 70% drug release (t 70%). The effect of the two independent variables on the response variables was studied by response surface plots and contour plots generated by the Design-Expert software. The desirability function was used to optimize the response variables. Results. The compatibility between LOR and the wafer excipients was confirmed by differential scanning calorimetry, FTIR spectroscopy, and X-ray diffraction (XRD) analysis. Bioadhesion force, measured with TAXT2i texture analyzer, showed that the wafers had a good bioadhesive property which could be advantageous for retaining the drug into the buccal cavity. Conclusion. The observed responses taken were in agreement with the experimental values, and Loratadine wafers were produced with less experimental trials, and a patient compliant product was achieved with the concept of formulation by design. PMID:23781498

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.

To determine the end point of wet granulation by measuring powder energies and thermal properties.

PubMed

Dave, Rutesh H; Wu, Stephen H; Contractor, Labdhi D

2012-04-01

Wet granulation has been widely used in pharmaceutical industry as a tablet manufacturing process. However, end-point determination of wet granulation process has always remained a challenge. Many traditional methods are available for end-point determination, yet accuracy and reproducibility still remain a challenge. Microcrystalline cellulose, widely used as an excipient in pharmaceutical industry, was granulated using water. Wet mass was passed through sieve # 12 and dried till constant percentage loss on drying was obtained and dried granules were obtained. Wet and dried granules collected were subjected to basic flow energy, specific energy, bulk density, pressure drop, differential scanning calorimetry and effusivity measurements. Analysis of data revealed various stages of granule growth from initial seed formation by adding 200-400 g of water, granule growth was observed by adding 600-800 g of water and over wetting was observed at 1155 g of water. In this work, we have justified our work to properly identify and utilize this technique for practical purpose to correctly identify the end-point determination of microcrystalline cellulose and explain various principles underlying energies associated with powder and thermal measurements.

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.

A New Role of Fine Excipient Materials in Carrier-Based Dry Powder Inhalation Mixtures: Effect on Deagglomeration of Drug Particles During Mixing Revealed.

PubMed

Shalash, Ahmed O; Elsayed, Mustafa M A

2017-11-01

The potential of fine excipient materials to improve the performance of carrier-based dry powder inhalation mixtures is well acknowledged. The mechanisms underlying this potential are, however, open to question till date. Elaborate understanding of these mechanisms is a requisite for rational rather than empirical development of ternary dry powder inhalation mixtures. While effects of fine excipient materials on drug adhesion to and detachment from surfaces of carrier particle have been extensively investigated, effects on other processes, such as carrier-drug mixing, capsule/blister/device filling, or aerosolization in inhaler devices, have received little attention. We investigated the influence of fine excipient materials on the outcome of the carrier-drug mixing process. We studied the dispersibility of micronized fluticasone propionate particles after mixing with α-lactose monohydrate blends comprising different fine particle concentrations. Increasing the fine (D < 10.0 μm) excipient fraction from 1.84 to 8.70% v/v increased the respirable drug fraction in the excipient-drug mixture from 56.42 to 67.80% v/v (p < 0.05). The results suggest that low concentrations of fine excipient particles bind to active sites on and fill deep crevices in coarse carrier particles. As the concentration of fine excipient particles increases beyond that saturating active sites, they fill the spaces between and adhere to the surfaces of coarse carrier particles, creating projections and micropores. They thereby promote deagglomeration of drug particles during carrier-drug mixing. The findings pave the way for a comprehensive understanding of contributions of fine excipient materials to the performance of carrier-based dry powder inhalation mixtures.

Rheology as a tool for evaluation of melt processability of innovative dosage forms.

PubMed

Aho, Johanna; Boetker, Johan P; Baldursdottir, Stefania; Rantanen, Jukka

2015-10-30

Future manufacturing of pharmaceuticals will involve innovative use of polymeric excipients. Hot melt extrusion (HME) is an already established manufacturing technique and several products based on HME are on the market. Additionally, processing based on, e.g., HME or three dimensional (3D) printing, will have an increasingly important role when designing products for flexible dosing, since dosage forms based on compacting of a given powder mixture do not enable manufacturing of optimal pharmaceutical products for personalized treatments. The melt processability of polymers and API-polymer mixtures is highly dependent on the rheological properties of these systems, and rheological measurements should be considered as a more central part of the material characterization tool box when selecting suitable candidates for melt processing by, e.g., HME or 3D printing. The polymer processing industry offers established platforms, methods, and models for rheological characterization, and they can often be readily applied in the field of pharmaceutical manufacturing. Thoroughly measured and calculated rheological parameters together with thermal and mechanical material data are needed for the process simulations which are also becoming increasingly important. The authors aim to give an overview to the basics of rheology and summarize examples of the studies where rheology has been utilized in setting up or evaluating extrusion processes. Furthermore, examples of different experimental set-ups available for rheological measurements are presented, discussing each of their typical application area, advantages and limitations. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Development of rectal self-emulsifying suspension of a moisture-labile water-soluble drug.

PubMed

Kauss, Tina; Gaubert, Alexandra; Tabaran, Luc; Tonelli, Giovanni; Phoeung, Thida; Langlois, Marie-Hélène; White, Nick; Cartwright, Anthony; Gomes, Melba; Gaudin, Karen

2018-01-30

Self-emulsifying drug delivery systems, commonly used for oral delivery of poorly soluble compounds, were used to formulate water soluble but moisture labile compounds for rectal application. The objective was to use the oily phase of the system to formulate a liquid, non-aqueous product while obtaining the advantages of self-emulsification, rapid contact with the rectal mucosa and rapid absorption post-administration. Ceftriaxone was used as a model drug and the human bile salt sodium chenodeoxycholate was used as an absorption enhancer. After preliminary screening of 23 excipients, based on their emulsification ability and emulsion fineness in binary and ternary mixtures, a full factorial design was used to screen different formulations of three preselected excipients. The optimal formulation contained 60% of excipients, namely Capryol 90, Kolliphor EL and Kolliphor PS20 in 4 : 6 : 6 ratio and 40% of a powder blend that included 500 mg of ceftriaxone. Characterization of the system showed that it complied with the requirements for rectal administration, in particular rapid emulsification in a small quantity of liquid. Rabbit bioavailability showed rapid absorption of ceftriaxone, achieving 128% bioavailability compared to powder control formulation. These results demonstrated the potential of self-emulsifying formulations for rectal administration of Class 3 BCS drugs. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Evaluation of cellulose II powders as a potential multifunctional excipient in tablet formulations.

PubMed

de la Luz Reus Medina, Maria; Kumar, Vijay

2006-09-28

The use of UICEL-A/102 and UICEL-XL, the cellulose II powders, as a multifunctional direct compression excipient in the design of tablets containing hydrochlorothiazide (HCTZ) or ibuprofen (IBU), the model low and high dose drugs, respectively, has been reported. Commercial Oretic and Advil tablets containing HCTZ and IBU, respectively, and tablets made using Avicel PH-102 - the most commonly and widely used commercial direct compression excipient, were used in the study for comparison purposes. Tablets were made by first blending drug with the excipient and then with stearic acid, a lubricant, in a V-blender, followed by compressing into a tablet on a hydraulic press using 105 MPa of compression pressure and a dwell time of 30 s. The crushing strengths of HCTZ tablets decreased in the order Avicel PH-102>UICEL-XL, UICEL-A/102>Oretic and of IBU tablets in the order Avicel PH-102 > or = UICEL-XL approximately UICEL-A/102>Advil. The friability values for all tablets were well below the maximum 1% USP tolerance limit. UICEL-A/102 and UICEL-XL tablets containing HCTZ disintegrated rapidly (<25 s). Oretic tablets disintegrated in about 60 s, while Avicel PH-102 tablets remained intact during 1 h test period. The IBU tablets made using UICEL-A/102 disintegrated the fastest, UICEL-XL and Advil tablets the next, and Avicel PH-102 tablets remained intact. All tablets, except for those of Avicel PH-102, conformed to the USP drug release requirements. These results conclusively show that UICEL-A/102 and UICEL-XL have the potential to be used as filler, binder, and disintegrant, all-in-one, in the design of tablets containing either a low dose or high dose drug by the direct compression method.

A quality-by-design study for an immediate-release tablet platform: examining the relative impact of active pharmaceutical ingredient properties, processing methods, and excipient variability on drug product quality attributes.

PubMed

Kushner, Joseph; Langdon, Beth A; Hicks, Ian; Song, Daniel; Li, Fasheng; Kathiria, Lalji; Kane, Anil; Ranade, Gautam; Agarwal, Kam

2014-02-01

The impact of filler-lubricant particle size ratio variation (3.4-41.6) on the attributes of an immediate-release tablet was compared with the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8-114 μm), and drug type (theophylline or ibuprofen). All batches were successfully manufactured, except for direct compression of 25% drug loading of 8 μm (D[4,3]) drug, which exhibited very poor flow properties. All manufactured tablets possessed adequate quality attributes: tablet weight uniformity <4% RSD, tablet potency: 94%-105%, content uniformity <6% RSD, acceptance value ≤ 15, solid fraction: 0.82-0.86, tensile strength >1 MPa, friability ≤ 0.2% weight loss, and disintegration time < 4 min. The filler-lubricant particle size ratio exhibited the greatest impact on blend and granulation particle size and granulation flow, whereas drug property variation dominated blend flow, ribbon solid fraction, and tablet quality attributes. Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate-release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Physical characterization of polyethylene glycols by thermal analytical technique and the effect of humidity and molecular weight.

PubMed

Majumdar, R; Alexander, K S; Riga, A T

2010-05-01

Polyethylene glycols (PEGs) are well known as excipients in tablet dosage formulations. PEGs are generally known to be inert and have very few interactions with other components in the solid dosage forms. However, the physical nature of PEGs and how they affect the disintegration of tablets is not very well understood for the different molecular weights of PEGs. The knowledge of the effect of molecular weight of PEGs on their physical properties and the effect of humidity on the physical properties of PEGs are important parameters for the choice of a PEG to be acceptable as an excipient in pharmaceutical formulations. This study was done to determine the precision of the DSC physical properties for a wide range of PEGs with varying molecular weights from 194 to 23000 daltons. Nine different molecular weights of PEGs were examined in a DSC controlled Heat-Cool-Heat-Cool-Heat (HCHCH) cycle and the observed reproducible values of melting temperature, heat of fusion, crystallization temperature and the heat of crystallization were compared with values obtained from the literature and the observed percent crystallinity was again cross-checked by X-ray Diffraction (XRD) studies. The comparison values indicated acceptable precision. This study was also done to check the effect of humidity on the DSC physical properties for the entire range of PEGs. The results indicated that humidity probably has a higher effect on the physical properties of the low molecular weight PEGs as compared to the high molecular weight PEGs.

Improving oral bioavailability of resveratrol by a UDP-glucuronosyltransferase inhibitory excipient-based self-microemulsion.

PubMed

Yang, Fei-Fei; Zhou, Jing; Hu, Xiao; Cong, Zhao-Qing; Liu, Chun-Yu; Pan, Rui-Le; Chang, Qi; Liu, Xin-Min; Liao, Yong-Hong

2018-03-01

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Programming of Multicomponent Temporal Release Profiles in 3D Printed Polypills via Core-Shell, Multilayer, and Gradient Concentration Profiles.

PubMed

Haring, Alexander P; Tong, Yuxin; Halper, Justin; Johnson, Blake N

2018-06-10

Additive manufacturing (AM) appears poised to provide novel pharmaceutical technology and controlled release systems, yet understanding the effects of processing and post-processing operations on pill design, quality, and performance remains a significant barrier. This paper reports a study of the relationship between programmed concentration profile and resultant temporal release profile using a 3D printed polypill system consisting of a Food and Drug Administration (FDA) approved excipient (Pluronic F-127) and therapeutically relevant dosages of three commonly used oral agents for treatment of type 2 diabetes (300-500 mg per pill). A dual-extrusion hydrogel microextrusion process enables the programming of three unique concentration profiles, including core-shell, multilayer, and gradient structures. Experimental and computational studies of diffusive mass transfer processes reveal that programmed concentration profiles are dynamic throughout both pill 3D printing and solidification. Spectrophotometric assays show that the temporal release profiles could be selectively programmed to exhibit delayed, pulsed, or constant profiles over a 5 h release period by utilizing the core-shell, multilayer, and gradient distributions, respectively. Ultimately, this work provides new insights into the mass transfer processes that affect design, quality, and performance of spatially graded controlled release systems, as well as demonstrating the potential to create disease-specific polypill technology with programmable temporal release profiles. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stability-indicating spectrofluorimetric method for determination of itopride hydrochloride in raw material and pharmaceutical formulations.

PubMed

Walash, Mohamed I; Ibrahim, Fawzia; Eid, Manal I; El Abass, Samah Abo

2013-11-01

A simple, sensitive and rapid spectrofluorimetric method for determination of itopride hydrochloride in raw material and tablets has been developed. The proposed method is based on the measurement of the native fluorescence of the drug in water at 363 nm after excitation at 255 nm. The relative fluorescence intensity-concentration plot was rectilinear over the range of 0.1-2 μg/mL (2.5 × 10(-7)-5.06 × 10(-6) mole/L), with good correlation (r = 0.9999), limit of detection of 0.015 μg/mL and a lower limit of quantification of 0.045 μg/mL. The described method was successfully applied for the determination of itopride hydrochloride in its commercial tablets with average percentage recovery of 100.11 ± 0.32 without interference from common excipients. Additionally, the proposed method can be applied for determination of itopride in combined tablets with rabeprazole or pantoprazole without prior separation. The method was extended to stability study of itopride. The drug was exposed to acidic, alkaline, oxidative and photolytic degradation according to ICH guidelines. Moreover, the method was utilized to investigate the kinetics of the alkaline, acidic and oxidative degradation of the drug. A proposal for the degradation pathways was postulated.

Membrane formation and drug loading effects in high amylose starch tablets studied by NMR imaging.

PubMed

Thérien-Aubin, Héloïse; Zhu, X X; Ravenelle, François; Marchessault, Robert H

2008-04-01

Cross-linked high amylose starch is used as an excipient in the preparation of pharmaceutical tablets for the sustained release of drugs. NMR imaging with contrast enhanced by proton density and by self-diffusion coefficient was used to follow the water uptake and swelling, two critical parameters controlling the drug release of the cross-linked starch tablets containing 10 wt % of ciprofloxacin and of acetaminophen, respectively. The drug-loaded tablets were studied in a H2O/D2O mixture at 37 degrees C in comparison to the tablets without any drug loading. The diffusion of water in the tablets all showed a Fickian behavior, but the kinetics of water uptake was faster in the case of the drug-loaded tablets. The formation of a membrane at the water/tablet interface was observed.

Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study.

PubMed

Blaesi, Aron H; Saka, Nannaji

2017-11-01

In recent studies, we have introduced melt-processed polymeric cellular dosage forms to achieve both immediate drug release and predictable manufacture. Dosage forms ranging from minimally-porous solids to highly porous, open-cell and thin-walled structures were prepared, and the drug release characteristics investigated as the volume fraction of cells and the excipient molecular weight were varied. In the present study, both minimally-porous solid and cellular dosage forms consisting of various weight fractions of Acetaminophen drug and polyethylene glycol (PEG) excipient are prepared and analyzed. Microstructures of the solid forms and the cell walls range from single-phase solid solutions of the excipient and a small amount of drug molecules to two-phase composites of the excipient and tightly packed drug particles. Results of dissolution experiments show that the minimally-porous solid forms disintegrate and release drug by slow surface erosion. The erosion rate decreases as the drug weight fraction is increased. By contrast, the open-cell structures disintegrate rapidly by viscous exfoliation, and the disintegration time is independent of drug weight fraction. Drug release models suggest that the solid forms erode by convective mass transfer of the faster-eroding excipient if the drug volume fraction is small. At larger drug volume fractions, however, the slower-eroding drug particles hinder access of the free-flowing fluid to the excipient, thus slowing down erosion of the composite. Conversely, the disintegration rate of the cellular forms is limited by diffusion of the dissolution fluid into the excipient phase of the thin cell walls. Because the wall thickness is of the order of the drug particle size, and the particles are enveloped by the excipient during melt-processing, the drug particles cannot hinder diffusion through the excipient across the walls. Thus the disintegration time of the cellular forms is mostly unaffected by the volume fraction of drug in the walls. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemometric-assisted spectrophotometric methods and high performance liquid chromatography for simultaneous determination of seven β-blockers in their pharmaceutical products: A comparative study

NASA Astrophysics Data System (ADS)

Abdel Hameed, Eman A.; Abdel Salam, Randa A.; Hadad, Ghada M.

2015-04-01

Chemometric-assisted spectrophotometric methods and high performance liquid chromatography (HPLC) were developed for the simultaneous determination of the seven most commonly prescribed β-blockers (atenolol, sotalol, metoprolol, bisoprolol, propranolol, carvedilol and nebivolol). Principal component regression PCR, partial least square PLS and PLS with previous wavelength selection by genetic algorithm (GA-PLS) were used for chemometric analysis of spectral data of these drugs. The compositions of the mixtures used in the calibration set were varied to cover the linearity ranges 0.7-10 μg ml-1 for AT, 1-15 μg ml-1 for ST, 1-15 μg ml-1 for MT, 0.3-5 μg ml-1 for BS, 0.1-3 μg ml-1 for PR, 0.1-3 μg ml-1 for CV and 0.7-5 μg ml-1 for NB. The analytical performances of these chemometric methods were characterized by relative prediction errors and were compared with each other. GA-PLS showed superiority over the other applied multivariate methods due to the wavelength selection. A new gradient HPLC method had been developed using statistical experimental design. Optimum conditions of separation were determined with the aid of central composite design. The developed HPLC method was found to be linear in the range of 0.2-20 μg ml-1 for AT, 0.2-20 μg ml-1 for ST, 0.1-15 μg ml-1 for MT, 0.1-15 μg ml-1 for BS, 0.1-13 μg ml-1 for PR, 0.1-13 μg ml-1 for CV and 0.4-20 μg ml-1 for NB. No significant difference between the results of the proposed GA-PLS and HPLC methods with respect to accuracy and precision. The proposed analytical methods did not show any interference of the excipients when applied to pharmaceutical products.

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets.

PubMed

ElShaer, Amr; Kaialy, Waseem; Akhtar, Noreen; Iyire, Affiong; Hussain, Tariq; Alany, Raid; Mohammed, Afzal R

2015-10-01

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm(2) to 2.85±0.36N/mm(2) upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets. Copyright © 2015 Elsevier B.V. All rights reserved.

The Effect of Specific Surface Area of Chitin-Metal Silicate Coprocessed Excipient on the Chemical Decomposition of Cefotaxime Sodium.

PubMed

Al-Nimry, Suhair S; Alkhamis, Khouloud A; Alzarieni, Kawthar Z

2017-02-01

Chitin-metal silicates are multifunctional excipients used in tablets. Previously, a correlation between the surface acidity of chitin-calcium and chitin-magnesium silicate and the chemical decomposition of cefotaxime sodium was found but not with chitin-aluminum silicate. This lack of correlation could be due to the catalytic effect of silica alumina or the difference in surface area of the excipients. The objective of this study was to investigate the effect of the specific surface area of the excipient on the chemical decomposition of cefotaxime sodium in the solid state. Chitin was purified and coprocessed with different metal silicates to prepare the excipients. The specific surface area was determined using gas adsorption. The chemical decomposition was studied at constant temperature and relative humidity. Also, the degradation in solution was studied. A correlation was found between the degradation rate constant and the surface area of chitin-aluminum and chitin-calcium silicate but not with chitin-magnesium silicate. This was due to the small average pore diameter of this excipient. Also, the degradation in solution was slower than in solid state. In conclusion, the stability of cefotaxime sodium was dependent on the surface area of the excipient in contact with the drug. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Engineering Synergistically Active and Bioavailable Cost-effective Medicines for Neglected Tropical Diseases; The Role of Excipients.

PubMed

Serrano, Dolores R; Lalatsa, Aikaterini; Dea-Ayuela, M Auxiliadora

2017-07-19

Leishmaniasis is a neglected tropical disease responsible for the ninth largest disease burden in the world threatening 350 million people mostly in developing countries. The lack of efficacy, severe adverse effects, long duration, high cost and parenteral administration of the current therapies result in poor patient compliance and emergence of resistance. Leishmaniasis' unmet need for safer, affordable and more effective treatments is only partly addressed by today's global health product pipeline that focuses on products amenable to rapid clinical development, mainly by reformulating or repurposing existing drugs for new uses. Excipients are necessary for ensuring the stability and bioavailability of currently available antileishmaniasis drugs which in their majority are poorly soluble or have severe side-effects. Thus, selection of excipients that can ensure bioavailability and safety as well as elicit a synergistic effect against the Leishmania parasites without compromising safety will result in a more efficacious, safe and fast to market medicine. We have evaluated the in vitro activity of 30 commercially available generally regarded as safe (GRAS) excipients against different Leishmania spp., their cytotoxicity and potential use for inclusion in novel formulations. Amongst the tested excipients, the compounds with higher selectivity index were Eudragit E100 (cationic triblock copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate), CTAB (cetyltrimethylammonium bromide, cationic), lauric acid, Labrasol(non-ionic, caprylocaproyl polyoxyl- 8 glycerides) and sodium deoxycholate. An ideal excipient need to possess amphiphilic nature with ionic/polar groups and possess a short or medium fatty acid chain such as lauric (C12), capric C10) or caprylicacid (C8). Inclusion of these excipients and identification of the optimal combination of drug and excipients would lead to a more effective and safer antileishmanial therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Utilizing food matrix effects to enhance nutraceutical bioavailability: increase of curcumin bioaccessibility using excipient emulsions.

PubMed

Zou, Liqiang; Liu, Wei; Liu, Chengmei; Xiao, Hang; McClements, David Julian

2015-02-25

Excipient foods have compositions and structures specifically designed to improve the bioaccessibility of bioactive agents present in other foods coingested with them. In this study, an excipient emulsion was shown to improve the solubility and bioaccessibility of curcumin from powdered rhizome turmeric (Curcuma longa). Corn oil-in-water emulsions were mixed with curcumin powder, and the resulting mixtures were incubated at either 30 °C (to simulate a salad dressing) or 100 °C (to simulate a cooking sauce). There was an appreciable transfer of curcumin into the excipient emulsions at both incubation temperatures, but this effect was much more pronounced at 100 °C. The bioaccessibility of curcumin measured using a simulated gastrointestinal tract model was greatly improved in the presence of the excipient emulsion, particularly in the system held at 100 °C. This effect was attributed to the higher initial amount of curcumin solubilized within the oil droplets, as well as that solubilized in the mixed micelles formed by lipid digestion. This study highlights the potential of designing excipient food emulsions that increase the oral bioavailability of lipophilic nutraceuticals, such as curcumin.

In situ 3D topographic and shape analysis by synchrotron radiation X-ray microtomography for crystal form identification in polymorphic mixtures

PubMed Central

Yin, Xian-Zhen; Xiao, Ti-Qiao; Nangia, Ashwini; Yang, Shuo; Lu, Xiao-Long; Li, Hai-Yan; Shao, Qun; He, You; York, Peter; Zhang, Ji-Wen

2016-01-01

Polymorphism denotes the existence of more than one crystal structure of a substance, and great practical and theoretical interest for the chemical and pharmaceutical industries. In many cases, it is challenging to produce a pure crystal form and establish a sensitive detection method for the identification of crystal form in a mixture of polymorphs. In this study, an accurate and sensitive method based on synchrotron radiation X-ray computed microtomography (SR-μCT) was devised to identify the polymorphs of clopidogrel bisulphate (CLP). After 3D reconstruction, crystal particles were extracted and dozens of structural parameters were calculated. Whilst, the particle shapes of the two crystal forms were all irregular, the surface of CLP II was found to be rougher than CLP I. In order to classify the crystal form based on the quantitative morphological property of particles, Volume Bias Percentage based on Surface Smoothing (VBP) was defined and a new method based on VBP was successfully developed, with a total matching rate of 99.91% for 4544 particles and a lowest detectable limit of 1%. More important for the mixtures in solid pharmaceutical formulations, the interference of excipients can be avoided, a feature cannot achieved by other available analytical methods. PMID:27097672

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.

Effect of permeability enhancers on paracellular permeability of acyclovir.

PubMed

Ates, Muge; Kaynak, Mustafa Sinan; Sahin, Selma

2016-06-01

According to Biopharmaceutics Classification System (BCS), acyclovir is a class III (high solubility, low permeability) compound, and it is transported through paracellular route by passive diffusion. The aim of this study was to investigate the effect of various pharmaceutical excipients on the intestinal permeability of acyclovir. The single-pass in-situ intestinal perfusion (SPIP) method was used to estimate the permeability values of acyclovir and metoprolol across different intestinal segments (jejunum, ileum and colon). Permeability coefficient (Peff ) of acyclovir was determined in the absence and presence of a permeation enhancer such as dimethyl β-cyclodextrin (DM-β-CD), sodium lauryl sulfate (SLS), sodium caprate (Cap-Na) and chitosan chloride. All enhancers increased the permeability of paracellularly transported acyclovir. Although Cap-Na has the highest permeability-enhancing effect in all segments, permeation-enhancing effect of chitosan and SLS was only significant in ileum. On the other hand, DM-β-CD slightly decreased the permeability in all intestinal segments. These findings have potential implication concerning the enhancement of absorption of paracellularly transported compounds with limited oral bioavailability. In the case of acyclovir, Cap-Na either alone or in combination with SLS or chitosan has the potential to improve its absorption and bioavailability and has yet to be explored. © 2016 Royal Pharmaceutical Society.

A novel use of oxidative coupling reactions for determination of some statins (cholesterol-lowering drugs) in pharmaceutical formulations

NASA Astrophysics Data System (ADS)

Ashour, Safwan; Bahbouh, Mahmoud; Khateeb, Mouhammed

2011-03-01

New, accurate and reliable spectrophotometric methods for the assay of three statin drugs, atorvastatin calcium (AVS), fluvastatin sodium (FVS) and pravastatin sodium (PVS) in pure form and pharmaceutical formulations have been described. All methods involve the oxidative coupling reaction of AVS, FVS and PVS with 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate (MBTH) in the presence of Ce(IV) in an acidic medium to form colored products with λmax at 566, 615 and 664 nm, respectively. Beer's law was obeyed in the ranges of 2.0-20.0, 4.9-35.4 and 7.0-30.0 μg mL -1 for AVS-MBTH, FVS-MBTH and PVS-MBTH, respectively. Molar absorptivities for the above three methods were found to be 3.24 × 10 4, 1.05 × 10 4 and 0.68 × 10 4 L mol -1 cm -1, respectively. Statistical treatment of the experimental results indicates that the methods are precise and accurate. The proposed methods have been applied to the determination of the components in commercial forms with no interference from the excipients. A comparative study between the suggested procedures and the official methods for these compounds in the commercial forms showed no significant difference between the two methods.

Rapid and sensitive spectrofluorimetric determination of enrofloxacin, levofloxacin and ofloxacin with 2,3,5,6-tetrachloro- p-benzoquinone

NASA Astrophysics Data System (ADS)

Ulu, Sevgi Tatar

2009-06-01

A highly sensitive spectrofluorimetric method was developed for the first time, for the analysis of three fluoroquinolones (FQ) antibacterials, namely enrofloxacin (ENR), levofloxacin (LEV) and ofloxacin (OFL) in pharmaceutical preparations through charge transfer (CT) complex formation with 2,3,5,6-tetrachloro- p-benzoquinone (chloranil,CLA). At the optimum reaction conditions, the FQ-CLA complexes showed excitation maxima ranging from 359 to 363 nm and emission maxima ranging from 442 to 488 nm. Rectilinear calibration graphs were obtained in the concentration range of 50-1000, 50-1000 and 25-500 ng mL -1 for ENR, LEV and OFL, respectively. The detection limit was found to be 17 ng mL -1 for ENR, 17 ng mL -1 for LEV, 8 ng mL -1 for OFL, respectively. Excipients used as additive in commercial formulations did not interfere in the analysis. The method was validated according to the ICH guidelines with respect to specificity, linearity, accuracy, precision and robustness. The proposed method was successfully applied to the analysis of pharmaceutical preparations. The results obtained were in good agreement with those obtained using the official method; no significant difference in the accuracy and precision as revealed by the accepted values of t- and F-tests, respectively.

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.

From sticky stuff to sweet receptors--achievements, limits and novel approaches to bioadhesion.

PubMed

Lehr, C M

1996-01-01

About 10 years ago, the concept of bioadhesion was introduced into the pharmaceutical literature and has since stimulated much research and development both in academia and in industry. The first generation of bioadhesive drug delivery systems (BBDS) were based on so-called mucoadhesive polymers, i.e. natural or synthetic macromolecules, often already well accepted and used as pharmaceutical excipients for other purposes, which show the remarkable ability to 'stick' to humid or wet mucosal tissue surfaces. While these novel dosage forms were mainly expected to allow for a possible prolongation, better localization or intensified contact to mucosal tissue surfaces, it had to be realized that these goals were often not so easily accomplished, at least not by means of such relatively straightforward technology. However, although not always convincing as a 'pharmaceutical glue', some of the mucoadhesive polymers were found to display other, possibly even more important biological activities, namely to inhibit proteolytic enzymes and/or to modulate the permeability of usually tight epithelial tissue barriers. Such features were found to be particularly useful in the context of peptide and protein drug delivery. But still, the interest in realizing 'true' bioadhesion continues: instead of mucoadhesive polymers, plant or bacterial lectins, i.e. adhesion molecules which specifically bind to sugar moieties of the epithelial cell membrane, are now widely being investigated as drug delivery adjuvants. These second-generation bioadhesives not only provide for cellular binding, but also for subsequent endo- and transcytosis. This makes the novel, specifically bioadhesive molecules particularly interesting for the controlled delivery of DNA/RNA molecules in the context of antisense or gene therapy.

Sensitive inexpensive spectrophotometric and spectrofluorimetric analysis of ezogabine, levetiracetam and topiramate in tablet formulations using Hantzsch condensation reaction

NASA Astrophysics Data System (ADS)

Ibrahim, F. A.; El-Yazbi, A. F.; Wagih, M. M.; Barary, M. A.

2017-09-01

Two highly sensitive, simple and selective spectrophotometric and spectrofluorimetric assays have been investigated for the analysis of ezogabine, levetiracetam and topiramate in their pure and in pharmaceutical dosage forms. The suggested methods depend on the condensation of the primary amino-groups in the three drugs with acetylacetone and formaldehyde according to Hantzsch reaction yielding highly fluorescent yellow colored dihydropyridine derivatives. The reaction products of ezogabine, levetiracetam and topiramate were measured spectrophotometrically at 418, 390 and 380 nm or spectrofluorimetrically at λem/ex of 495/425 nm, 490/415 nm and 488/410 nm, respectively. Various experimental conditions have been carefully studied to maximize the reaction yield. At the optimum reaction conditions, the calibration curves were rectilinear over the concentration ranges of 8-25, 60-180 and 80-200 μg/mL spectrophotometrically and 0.02-0.2, 0.2-1.2 and 0.2-1.5 μg/mL spectrofluorimetrically for ezogabine, levetiracetam and topiramate, respectively with good correlation coefficients. The suggested methods were applied successfully for the analysis of ezogabine, levetiracetam and topiramate in their commercial tablets with high percentage recoveries and negligible interference from various excipients in pharmaceutical dosage forms. The results were statistically analyzed and showed the absence of any significant difference between both developed and published methods. The procedures were validated and evaluated by the ICH guidelines revealing good reproducibility and accuracy. Therefore, the two proposed methods may be considered of high interest for practical and reliable analysis of ezogabine, levetiracetam and topiramate in pharmaceutical dosage forms.

An accurate and precise representation of drug ingredients.

PubMed

Hanna, Josh; Bian, Jiang; Hogan, William R

2016-01-01

In previous work, we built the Drug Ontology (DrOn) to support comparative effectiveness research use cases. Here, we have updated our representation of ingredients to include both active ingredients (and their strengths) and excipients. Our update had three primary lines of work: 1) analysing and extracting excipients, 2) analysing and extracting strength information for active ingredients, and 3) representing the binding of active ingredients to cytochrome P450 isoenzymes as substrates and inhibitors of those enzymes. To properly differentiate between excipients and active ingredients, we conducted an ontological analysis of the roles that various ingredients, including excipients, have in drug products. We used the value specification model of the Ontology for Biomedical Investigations to represent strengths of active ingredients and then analyzed RxNorm to extract excipient and strength information and modeled them according to the results of our analysis. We also analyzed and defined dispositions of molecules used in aggregate as active ingredients to bind cytochrome P450 isoenzymes. Our analysis of excipients led to 17 new classes representing the various roles that excipients can bear. We then extracted excipients from RxNorm and added them to DrOn for branded drugs. We found excipients for 5,743 branded drugs, covering ~27% of the 21,191 branded drugs in DrOn. Our analysis of active ingredients resulted in another new class, active ingredient role. We also extracted strengths for all types of tablets, capsules, and caplets, resulting in strengths for 5,782 drug forms, covering ~41% of the 14,035 total drug forms and accounting for ~97 % of the 5,970 tablets, capsules, and caplets in DrOn. We represented binding-as-substrate and binding-as-inhibitor dispositions to two cytochrome P450 (CYP) isoenzymes (CYP2C19 and CYP2D6) and linked these dispositions to 65 compounds. It is now possible to query DrOn automatically for all drug products that contain active ingredients whose molecular grains inhibit or are metabolized by a particular CYP isoenzyme. DrOn is open source and is available at http://purl.obolibrary.org/obo/dron.owl.

Soil Materials and Health: An new experience for teaching

NASA Astrophysics Data System (ADS)

Del Hoyo Martínez, Carmen

2014-05-01

Cationic clays are very extended compounds on the earth surface so they constitute the main component of soils and sedimentary rocks. Due to their presence and special properties that they have, mankind has used them with therapeutic aims from Prehistory, not being rare to find references to this subject in works of classic authors. During the Renaissance and with the appearance of the first Pharmacopeia, its use was regulated to a certain extent. The scientific development reached during the XXth century has allowed to understand and to study the reasons of the useful and peculiar properties of clays, directly related to their colloidal size and crystalline structure. These properties are translated in a high specific surface area, optimal rheological properties and/or excellent sorptive capacity; everything makes cationic clays very useful for a wide range of applications. In the field of health, cationic clays are used in Pharmaceutical Technology and Dermopharmacy as ideal excipients and substances of suitable biological activity due to their chemical inertness and low or null toxicity for the patient (Carretero, 2002; Lopez Galindo et al., 2005; Choy et al., 2007; del Hoyo, 2007). Cationic clays can be used in a wide range of applications in health. However, it must be also considered that the risk exposure to cationic clays may cause several diseases, as it has been seen above. Cationic clays have been used as excipients and active principles in the pharmaceutical industry. The last tendencies are their use in geomedicine, as much to come up as to treat diseases. One stands out his presence in spas and aesthetic medicine. Development of new pharmaceutical formulations is observed, based on cationic clays, for cancer therapy. It has to emphasize the importance in the synthesis of biosensors with cationic clays. Cationic clays can be considered a group of promising materials in the development of new health applications. The study of the use of the cationic clays in the field of the health is a source to develop numerous studies of cases in the teaching of different subjects related to the geoscience and a new opportunity to connect the learning with the reality. References -Carretero, MI 2002. Clay Minerals and Their Beneficial Effects upon Human Health. A review. Appl. Clay Sci. 21, pp. 155-163. -Choy, J.H., Choi, S.J., Oh, J.M., Park, T. 2007. Clay minerals and layered double hydroxides for novel biological applications. Appl. Clay Sci. 36 pp. 122-132. -Del Hoyo, C. 2007. Layered double hydroxides and human health: An overview. Appl. Clay Sci. 36, pp. 103-121. -Lopez-Galindo, A., Viseras Iborra, C. & Cerezo Gonzalez, P. 2005. Arcillas y salud. In: Conferencias de la XIX Reunion de la Sociedad Espanola de Arcillas. Rives, Ed., pp. 15-18.

Solutions as solutions--synthesis and use of a liquid polyester excipient to dissolve lipophilic drugs and formulate sustained-release parenterals.

PubMed

Asmus, Lutz R; Gurny, Robert; Möller, Michael

2011-11-01

Solid poly(lactides) and poly(lactide-co-glycolides) are widely used polymers for sustained-release parenterals. However, they have some unfavorable properties regarding manufacturing of the formulations and administration to the patient due to their solid aggregate state. In contrast, hexyl-substituted poly(lactic acid) (hexPLA, poly(2-hydroxyoctanoic acid)) is a viscous degradable polyester. To date, a two-step ring-opening polymerization was used for its synthesis. Here, we investigated a novel one-pot one-step melt polycondensation method to prepare hexPLA for biomedical applications by a simple green chemistry process. No catalyst or solely pharmaceutically acceptable catalysts and environmentally friendly purification methods without organic solvents were used. The resulting hexPLA polymers are stable under dry heat sterilization conditions. Low molecular weight hexPLAs with less than 5000 g/mol are less viscous than high molecular weight polymers. HexPLA can dissolve lipophilic active substances, with generally high incorporation capacities in low molecular weight polymers. The incorporation of solid compounds increases the viscosity and glass transition temperature, whereas the addition of small amounts of plasticizers or sparse warming significantly decreases the viscosity. Loratadine is soluble in hexPLA up to 28%. This highly concentrated Loratadine-hexPLA formulation released the active compound entirely over 14 days without initial burst in a zero order kinetic, matching the clinical requirements for such a sustained-release formulation. This demonstrates the potential of hexPLA as an excipient for injectable sustained-release formulations. Copyright © 2011 Elsevier B.V. All rights reserved.

Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal.

PubMed

Mai, Yang; Afonso-Pereira, Francisco; Murdan, Sudaxshina; Basit, Abdul W

2017-09-30

The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (p<0.05) the bioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (p<0.05), and to a greater extent in males, but had no influence on the bioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp. Copyright © 2017 Elsevier B.V. All rights reserved.

Cyclodextrins: A Weapon in the Fight Against Antimicrobial Resistance

NASA Astrophysics Data System (ADS)

Wong, Chew Ee; Dolzhenko, Anton V.; Lee, Sui Mae; Young, David James

Antimicrobial resistance poses one of the most serious global challenges of our age. Cyclodextrins (CDs) are widely utilized excipients in formulations because of their solubilizing properties, low toxicity, and low inflammatory response. This review summarizes recent investigations of antimicrobial agents involving CDs and CD-based antimicrobial materials. CDs have been employed for antimicrobial applications either through formation of inclusion complexes or by chemical modification of their hydroxyl groups to tailor pharmaceutically active compounds. Applications of these CD inclusion complexes include drug delivery, antimicrobial coatings on materials (e.g., biomedical devices and implants) and antimicrobial dressings that help to prevent wound infections. There are relatively limited studies of chemically modified CDs with antimicrobial activity. The mechanism of action of antimicrobial CD inclusion complexes and derivatives needs further elucidation, but activity of CDs and their derivatives is often associated with their interaction with bacterial cell membranes.

Preparation and Characterization of Novel Montmorillonite Nanocomposites

NASA Astrophysics Data System (ADS)

Mansa, Rola

Clay minerals have historically played a consequential role in human health. While the beginnings were rooted in geophagy, a primitive act of consuming earth, the health-related uses of clay minerals have evolved and diversified over time.. As excipients in pharmaceutical formulations, clay minerals can attribute novel properties onto intercalated compounds. Intercalating oxybenzone, a UV filter, within the interlamellar space of montmorillonite is desirable in order to minimize direct contact with skin. Intercalating resveratrol, a compound known for attributing beneficial effects onto human health, may be advantageous since this compound is susceptible to cis-trans isomerisation. The strategy of using alkylammonium--modified clay was undertaken and proved successful for the intercalation of oxybenzone. The field of biopolymer/layered silicate nanocomposites is heavily researched for use in a multitude of applications. Novel montmorillonite nanocomposites were prepared with neutral guar gum and cationic guar gum, using an environmentally friendly process and are fully characterized.

Thermal Stability and Kinetic Study of Fluvoxamine Stability in Binary Samples with Lactose.

PubMed

Ghaderi, Faranak; Nemati, Mahboob; Siahi-Shadbad, Mohammad Reza; Valizadeh, Hadi; Monajjemzadeh, Farnaz

2017-04-01

Purpose: In the present study the incompatibility of FLM (fluvoxamine) with lactose in solid state mixtures was investigated. The compatibility was evaluated using different physicochemical methods such as differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy and mass spectrometry. Methods: Non-Isothermally stressed physical mixtures were used to calculate the solid-state kinetic parameters. Different thermal models such as Friedman, Flynn-Wall-Ozawa (FWO) and Kissinger-Akahira-Sunose (KAS) were used for the characterization of the drug-excipient interaction. Results: Overall, the incompatibility of FLM with lactose as a reducing carbohydrate was successfully evaluated and the activation energy of this interaction was calculated. Conclusion: In this research the lactose and FLM Maillard interaction was proved using physicochemical techniques including DSC and FTIR. It was shown that DSC- based kinetic analysis provides fast and versatile kinetic comparison of Arrhenius activation energies for different pharmaceutical samples.

Thiolated chitosans: useful excipients for oral drug delivery.

PubMed

Werle, Martin; Bernkop-Schnürch, Andreas

2008-03-01

To improve the bioavailability of orally administered drugs, formulations based on polymers are of great interest for pharmaceutical technologists. Thiolated chitosans are multifunctional polymers that exhibit improved mucoadhesive, cohesive and permeation-enhancing as well as efflux-pump-inhibitory properties. They can be synthesized by derivatization of the primary amino groups of chitosan with coupling reagents bearing thiol functions. Various data gained in-vitro as well as in-vivo studies clearly demonstrate the potential of thiolated chitosans for oral drug delivery. Within the current review, the synthesis and characterization of thiolated chitosans so far developed is summarized. Features of thiolated chitosans important for oral drug delivery are discussed as well. Moreover, different formulation approaches, such as matrix tablets and micro-/nanoparticles, as well as the applicability of thiolated chitosans for the oral delivery of various substance classes including peptides and efflux pump substrates, are highlighted.

Powder and compaction characteristics of pregelatinized starches.

PubMed

Rojas, J; Uribe, Y; Zuluaga, A

2012-06-01

Pregelatinized starch is widely used as a pharmaceutical aid, especially as a filler-binder. It is known that the tableting performance of excipients could be affected by their source. The aim of this study was to evaluate the powder and tableting properties of pregelatinized starches obtained from yucca, corn and rice and compare those properties with those of Starch 1500. This material had the lowest particle size, and porosity and largest density and best flow. However, yucca starch and corn starch showed an irregular granule morphology, better compactibility and compressibility than Starch 1500. Their onset of plastic deformation and their strain rate sensitivity was comparable to that of Starch 1500. These two materials showed compact disintegration slower that Starch 1500. Conversely, rice starch showed a high elasticity, and friability, low compactibility, which are undesirable for direct compression. This study demonstrated the potential use of pregelatinized starches, especially those obtained from yucca and corn as direct compression filler-binders.

Comprehensive review on additives of topical dosage forms for drug delivery.

PubMed

Garg, Tarun; Rath, Goutam; Goyal, Amit K

2015-12-01

Skin is the largest organ of the human body and plays the most important role in protecting against pathogen and foreign matter. Three important modes such as topical, regional and transdermal are widely used for delivery of various dosage forms. Among these modes, the topical dosage forms are preferred because it provides local therapeutic activity when applied to the skin or mucous membranes. Additives or pharmaceutical excipients (non-drug component of dosage form) are used as inactive ingredients in dosage form or tools for structuring dosage forms. The main use of topical dosage form additives are controling the extent of absorption, maintaining the viscosity, improving the stability as well as organoleptic property and increasing the bulk of the formulation. The overall goal of this article is to provide the clinician with information related to the topical dosage form additives and their current major applications against various diseases.

Skin rash during treatment with generic itraconazole.

PubMed

De Vuono, Antonio; Palleria, Caterina; Scicchitano, Francesca; Squillace, Aida; De Sarro, Giovambattista; Gallelli, Luca

2014-04-01

Generic drugs have the same active substance, the same pharmaceutical form, the same therapeutic indications and a similar bioequivalence with the reference medicinal product (branded). Although a similar efficacy is postulated, some cases of clinical inefficacy during treatment with generic formulations have been reported. In this case, we describe a woman with onychomycosis that developed a skin rash during treatment with a generic formulation of itraconazole. Drug administration and its re-challenge confirmed the association between itraconazole and skin rash. Both Naranjo probability scale and World Health Organization causality assessment scale documented a probable association between generic-itraconazole and skin rash. The switch from generic formulation to brand one induced an improvement of symptoms. Since we are unable to evaluate the role of each excipient in the development of skin rash, we cannot rule out their involvement. However, more data are necessary to better define the similarities or differences between branded and generic formulations.

Skin rash during treatment with generic itraconazole

PubMed Central

De Vuono, Antonio; Palleria, Caterina; Scicchitano, Francesca; Squillace, Aida; De Sarro, Giovambattista; Gallelli, Luca

2014-01-01

Generic drugs have the same active substance, the same pharmaceutical form, the same therapeutic indications and a similar bioequivalence with the reference medicinal product (branded). Although a similar efficacy is postulated, some cases of clinical inefficacy during treatment with generic formulations have been reported. In this case, we describe a woman with onychomycosis that developed a skin rash during treatment with a generic formulation of itraconazole. Drug administration and its re-challenge confirmed the association between itraconazole and skin rash. Both Naranjo probability scale and World Health Organization causality assessment scale documented a probable association between generic-itraconazole and skin rash. The switch from generic formulation to brand one induced an improvement of symptoms. Since we are unable to evaluate the role of each excipient in the development of skin rash, we cannot rule out their involvement. However, more data are necessary to better define the similarities or differences between branded and generic formulations. PMID:24799820

Thermal Stability and Kinetic Study of Fluvoxamine Stability in Binary Samples with Lactose

PubMed Central

Ghaderi, Faranak; Nemati, Mahboob; Siahi-Shadbad, Mohammad Reza; Valizadeh, Hadi; Monajjemzadeh, Farnaz

2017-01-01

Purpose: In the present study the incompatibility of FLM (fluvoxamine) with lactose in solid state mixtures was investigated. The compatibility was evaluated using different physicochemical methods such as differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy and mass spectrometry. Methods: Non-Isothermally stressed physical mixtures were used to calculate the solid–state kinetic parameters. Different thermal models such as Friedman, Flynn–Wall–Ozawa (FWO) and Kissinger–Akahira–Sunose (KAS) were used for the characterization of the drug-excipient interaction. Results: Overall, the incompatibility of FLM with lactose as a reducing carbohydrate was successfully evaluated and the activation energy of this interaction was calculated. Conclusion: In this research the lactose and FLM Maillard interaction was proved using physicochemical techniques including DSC and FTIR. It was shown that DSC- based kinetic analysis provides fast and versatile kinetic comparison of Arrhenius activation energies for different pharmaceutical samples. PMID:28507936

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.

Physical aging in pharmaceutical polymers and the effect on solid oral dosage form stability.

PubMed

Kucera, Shawn A; Felton, Linda A; McGinity, James W

2013-12-05

The application of a polymeric film to a solid oral dosage form can be an effective technique to modify drug release. Most polymers used for such purposes are amorphous in nature and are subject to physical aging. This physical aging phenomenon has been shown to cause changes not only in the mechanical and drug release properties of polymeric films, but also the permeability of these films due to a densification and decrease in free volume of the polymer as the material relaxes to an equilibrated thermodynamic state. Temperature, humidity, and additional excipients in the coating formulations have been shown to influence the aging process. This review article discusses the process of physical aging in films prepared from aqueous dispersions, describes various analytical techniques that can be used to investigate the aging process, and highlights strategies to prevent such aging. Copyright © 2013 Elsevier B.V. All rights reserved.

Dissolution rate enhancement of gliclazide by ordered mixing.

PubMed

Saharan, Vikas A; Choudhury, Pratim K

2011-09-01

The poorly water soluble antidiabetic drug gliclazide was selected to study the effect of excipients on dissolution rate enhancement. Ordered mixtures of micronized gliclazide with lactose, mannitol, sorbitol, maltitol and sodium chloride were prepared by manual shaking of glass vials containing the drug and excipient(s). Different water soluble excipients, addition of surfactant and superdisintegrant, drug concentration and carrier particle size influenced the dissolution rate of the drug. Dissolution rate studies of the prepared ordered mixtures revealed an increase in drug dissolution with all water soluble excipients. The order of dissolution rate improvement for gliclazide was mannitol > lactose > maltitol > sorbitol > sodium chloride. Composite granules of the particle size range 355-710 μm were superior in increasing the drug dissolution rate from ordered mixtures. Reducing the carrier particle size decreased the dissolution rate of the drug as well as the increase in drug concentration. Kinetic modeling of drug release data fitted best the Hixson-Crowell model, which indicates that all the ordered mixture formulations followed the cube root law fairly well.

Immediate-type hypersensitivity reaction to Mannitol as drug excipient (E421): a case report.

PubMed

Calogiuri, G F; Muratore, L; Nettis, E; Casto, A M; Di Leo, E; Vacca, A

2015-05-01

Allergic reactions to mannitol have been reported rarely, despite its widespread use as a drug and as a food excipient. This is the first case report in which oral mannitol induces an immediate type hypersensitivity as a drug excipient, in a 42 year old man affected by rhinitis to olive tree pollen. Unusual and undervalued risk factors for mannitol hypersensitivity are examined.

Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets.

PubMed

Rahman, Ziyaur; Zidan, Ahmed S; Korang-Yeboah, Maxwell; Yang, Yang; Siddiqui, Akhtar; Shakleya, Diaa; Khan, Mansoor A; Cruz, Celia; Ashraf, Muhammad

2017-01-30

The objective of the present investigation was to understand the effects of excipients and curing process on the abuse deterrent properties (ADP) of Polyox™ based directly compressible abuse deterrent tablet formulations (ADFs). The excipients investigated were lactose (monohydrate or anhydrous), microcrystalline cellulose and hydroxypropyl methylcellulose. The ADPs studied were tablet crush resistance or hardness, particle size distribution following mechanical manipulation, drug extraction in water and alcohol, syringeability and injectability. Other non-ADPs such as surface morphology and tablet dissolution were also studied. It was found that presence of 50% or more of water soluble or swellable excipient in the ADF tablets significantly affected the tablet hardness, particle size distribution following mechanical manipulation and drug extraction while small amount (5%) of excipients had either minimal or no effect on ADPs of these tablets. Addition of high molecular weight HPMC (K 100M) affected syringeability and injectability of ADF. Curing process was found to affect ADPs (hardness, particle size distribution, drug extraction and syringeability and injectability) when compared with uncured tablet. In conclusion, addition of large amount of excipients, especially water soluble ones in Polyox™ based ADF tablets increase the risk of abuse by various routes of administration. Published by Elsevier B.V.

ANALYSIS OF TRENDS IN LIFE EXPECTANCIES AND PER CAPITA GROSS DOMESTIC PRODUCT AS WELL AS PHARMACEUTICAL AND NON-PHARMACEUTICAL HEALTHCARE EXPENDITURES.

PubMed

Hermanowski, Tomasz; Bystrov, Victor; Staszewska-Bystrova, Anna; Szafraniec-Buryło, Sylwia I; Rabczenko, Daniel; Kolasa, Katarzyna; Orlewska, Ewa

2015-01-01

Life expectancy is a common measure of population health. Macro-perspective based on aggregated data makes it possible to approximate the impact of different levels of pharmaceutical expenditure on general population health status and is often used in cross-country comparisons. The aim of the study was to determine whether there are long-run relations between life expectancy, total healthcare expenditures, and pharmaceutical expenditures in OECD countries. Common trends in per capita gross domestic products (GDPs) (excluding healthcare expenditures), per capita healthcare expenditures (excluding pharmaceutical expenditures), per capita pharmaceutical expenditures, and life expectancies of women and men aged 60 and 65 were analyzed across OECD countries. Short-term effect of pharmaceutical expenditure onto life expectancy was also estimated by regressing the deviations of life expectancies from their long-term trends onto the deviations of pharmaceutical and non-pharmaceutical health expenditures, as well as GDP from their trends. The dataset was created on the basis of OECD Health Data for 34 countries and the years 1991-2010. Life expectancy variables were used as proxies for the health outcomes, whereas the pharmaceutical and healthcare expenditures represented drug and healthcare consumption, respectively. In general, both expenditures and life expectancies tended to increase in all of the analyzed countries; however, the growth rates differed across the countries. The analysis of common trends indicated the existence of common long-term trends in life expectancies and per capita GDP as well as pharmaceutical and non-pharmaceutical healthcare expenditures. However, there was no evidence that pharmaceutical expenditures provided additional information about the long-term trends in life expectancies beyond that contained in the GDP series. The analysis based on the deviations of variables from their long-term trends allowed concluding that pharmaceutical expenditures significantly influenced life expectancies in the short run. Non-pharmaceutical healthcare expenditures were found to be significant in one out of four models (for life expectancy of women aged 65), while GDPs were found to be insignificant in all four models. The results of the study indicate that there are common long-term trends in life expectancies and per capita GDP as well as pharmaceutical and non-pharmaceutical healthcare expenditures. The available data did not reveal any cause- effect relationship. Other factors, for which the systematic data were not available, may have determined the increase in life expectancy in OECD countries. Significant positive short-term relations between pharmaceutical expenditures and life expectancies in OECD countries were found. The significant short-term effect of pharmaceutical expenditures onto life expectancy means that an increase of pharmaceutical expenditures above long-term trends would lead to a temporary increase in life expectancy above its corresponding long-term trend. However, this effect would not persist as pharmaceutical expenditures and life expectancy would converge to levels determined by the long-term trends.

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.

The influence of excipients commonly used in freeze drying on whole blood coagulation dynamics assessed by rotational thromboelastometry.

PubMed

Erber, Matthias; Lee, Geoffrey

2015-09-01

Lyophilized reagents are used on a daily basis in coagulation diagnostics. They often contain a number of excipients in addition to the active compound. Some of these excipients may, however, influence coagulation dynamics. Besides from plasmatic coagulation bulking agents may influence platelet properties. We therefore studied the influence of a variety of bulking agents (glycine, mannitol, sucrose and trehalose) as well as a surfactant (Tween® 80) on whole blood coagulation using thromboelastometry (ROTEM®) and platelet function analysis (ROTEM® platelet). Both disaccharides as well as Tween® 80 did not influence whole blood coagulation in the concentration range investigated. The addition of glycine and mannitol solutions to the ROTEM® measurement leads to an impaired clot formation as well as overall clot strength while clotting initiation remained barely influenced. Hypertonic glycine and mannitol solutions exhibit different clot formation impairment when correlated to their osmolar concentration and compared to equally osmolar NaCl-solutions. The effect of glycine was assigned to fibrin formation impairment identified with the FIBTEM assay. Platelet function analysis revealed that hypertonic glycine solutions do not alter platelet function but hypertonic mannitol and NaCl solutions do. While the influence observed for glycine may be due to fibrinogen precipitation, the mechanism of mannitol appears to be more complex as platelet function as well as fibrin-based clot formation are influenced. This study therefore demonstrates the necessity to check for coagulation impairment due to compounds contained in lyophilized reagents.

Boosting the bioavailability of hydrophobic nutrients, vitamins, and nutraceuticals in natural products using excipient emulsions.

PubMed

McClements, David Julian; Saliva-Trujillo, Laura; Zhang, Ruojie; Zhang, Zipei; Zou, Liqiang; Yao, Mingfei; Xiao, Hang

2016-10-01

Many highly hydrophobic bioactives, such as non-polar nutrients, nutraceuticals, and vitamins, have a relatively low or variable oral bioavailability. The poor bioavailability profile of these bioactives may be due to limited bioaccessibility, poor absorption, and/or chemical transformation within the gastrointestinal tract (GIT). The bioavailability of hydrophobic bioactives can be improved using specially designed oil-in-water emulsions consisting of lipid droplets dispersed within an aqueous phase. The bioactives may be isolated from their natural environment and then incorporated into the lipid phase of emulsion-based delivery systems. Alternatively, the bioactives may be left in their natural environment (e.g., fruits or vegetables), and then ingested with emulsion-based excipient systems. An excipient emulsion may have no inherent health benefits itself, but it boosts the biological activity of bioactive ingredients co-ingested with it by altering their bioaccessibility, absorption, and/or chemical transformation. This review discusses the design and fabrication of excipient emulsions, and gives some examples of recent research that demonstrates their potential efficacy for improving the bioavailability of hydrophobic bioactives. The concept of excipient emulsions could be used to formulate emulsion-based food products (such as excipient sauces, dressings, dips, creams, or yogurts) specifically designed to increase the bioavailability of bioactive agents in natural foods, such as fruits and vegetables. Copyright © 2015 Elsevier Ltd. All rights reserved.

The reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland.

PubMed

Heiskanen, Kati; Ahonen, Riitta; Kanerva, Risto; Karttunen, Pekka; Timonen, Johanna

2017-01-01

The aim of this study was to explore the reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland. The study took the form of semi-structured interviews. Forty-one pharmaceutical companies and pharmaceutical wholesalers were invited to participate in the study. The pharmaceutical companies were the member organizations of Pharma Industry Finland (PIF) (N = 30) and the Finnish Generic Pharmaceutical Association (FGPA) (N = 7). One company which is a central player in the pharmaceutical market in Finland but does not belong to PIF or FGPA was also invited. The pharmaceutical wholesalers were those with a nationwide distribution network (N = 3). A total of 30 interviews were conducted between March and June 2016. The data were subjected to qualitative thematic analysis. The most common reasons behind medicine shortages in Finland were the small size of the pharmaceutical market (29/30), sudden or fluctuating demand (28/30), small stock sizes (25/30), long delivery time (23/30) and a long or complex production chain (23/30). The reasons for the medicine shortages were supply-related more often than demand-related. However, the reasons were often complex and there was more than one reason behind a shortage. Supply-related reasons behind shortages commonly interfaced with the country-specific characteristics of Finland, whereas demand-related reasons were commonly associated with the predictability and attractiveness of the market. Some reasons, such as raw material shortages, were considered global and thus had similar effects on other countries.

Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients.

PubMed

Buckley, Lorrene A; Salunke, Smita; Thompson, Karen; Baer, Gerri; Fegley, Darren; Turner, Mark A

2018-02-05

A public workshop entitled "Challenges and strategies to facilitate formulation development of pediatric drug products" focused on current status and gaps as well as recommendations for risk-based strategies to support the development of pediatric age-appropriate drug products. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary, panel, and case-study breakout sessions. By enabling practical and meaningful discussion between scientists representing the diversity of involved disciplines (formulators, nonclinical scientists, clinicians, and regulators) and geographies (eg, US, EU), the Excipients Safety workshop session was successful in providing specific and key recommendations for defining paths forward. Leveraging orthogonal sources of data (eg. food industry, agro science), collaborative data sharing, and increased awareness of the existing sources such as the Safety and Toxicity of Excipients for Paediatrics (STEP) database will be important to address the gap in excipients knowledge needed for risk assessment. The importance of defining risk-based approaches to safety assessments for excipients vital to pediatric formulations was emphasized, as was the need for meaningful stakeholder (eg, patient, caregiver) engagement. Copyright © 2017 Elsevier B.V. All rights reserved.

Microencapsulated Dopamine (DA)-Induced Restitution of Function in 6-OHDA-Denervated Rat Striatum in vivo: Comparison Between Two Microsphere Excipients

PubMed Central

McRae, Amanda; Hjorth, Stephan; Mason, David W.; Dillon, Lynn; Tice, Thomas R.

1991-01-01

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated- striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application. PMID:1782252

Evaluation of a rotary tablet press simulator as a tool for the characterization of compaction properties of pharmaceutical products.

PubMed

Michaut, F; Busignies, V; Fouquereau, C; de Barochez, B Huet; Leclerc, B; Tchoreloff, P

2010-06-01

The Stylcam 100R, a rotary press simulator, was designed to simulate speed profiles of rotary tablet presses. Such a simulator was qualified by numerous laboratories and, actually, its ability to be used for studying the behaviour of powders under pressure should be examined. Then, the purpose of this work was to investigate the performances of the Stylcam 100R for characterizing the compaction behaviour and the tabletting properties of pharmaceutical powders. The compressibility of three pharmaceutical excipients (microcrystalline cellulose, dicalcium phosphate dihydrate and alpha-lactose monohydrate) was studied. Four compression speeds were used on the compaction simulator. Force-displacement cycles were associated with two energy parameters, the specific total energy (Es(tot)) and the specific expansion energy (Es(exp)). The mean yield pressure was calculated from Heckel's plots obtained with the in-die method. The diametral tensile strength of compacts was measured in order to evaluate mechanical properties. To evaluate the accuracy of all these parameters, a comparative study was carried out on an eccentric instrumented press. The values of energy parameters and tensile strengths of tablets are close between the eccentric press and the compaction simulator, whatever the compression speed on the latter. The mean yield pressure values obtained using the two presses are different. Finally, the Stylcam 100R seems to be a good tool for characterising tabletting properties of powders, except for the Heckel's model probably due to an unadapted equation of deformation and a lack of accuracy of the displacement transducers. Future improvements should allow correcting these two points. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

Liquid chromatographic method for the simultaneous determination of captopril, piroxicam, and amlodipine in bulk drug, pharmaceutical formulation, and human serum by programming the detector.

PubMed

Sultana, Najma; Arayne, M Saeed; Ali, Saeeda Nadir

2013-10-01

A highly sensitive LC method with UV detection has been developed for the simultaneous determination of coadministered drugs captopril, piroxicam, and amlodipine in bulk drug, pharmaceutical formulations, and human serum at the isosbestic point (235 nm) and at individual λmax (220, 255, and 238 nm, respectively) by programming the detector with time to match the individual analyte's chromophore, which enhanced the sensitivity with linear range. The assay involved an isocratic elution of analytes on a Bondapak C18 (10 μm, 25 × 0.46 cm) column at ambient temperature using a mobile phase of methanol/water 80:20 at pH 2.9 and a flow rate of 1.0 mL/min. Linearity was found to be 0.25-25, 0.10-6.0, and 0.20-13.0 μg/mL with correlation coefficient >0.998 and detection limits of 7.39, 3.90, and 9.38 ng/mL, respectively, whereas calibration curves for wavelength-programmed analysis were 0.10-6.0, 0.04-2.56, and 0.10-10.0 μg/mL with correlation coefficient >0.998 and detection limits of 5.79, 2.68, and 3.87 ng/mL, respectively. All the validated parameters were in the acceptable range. The recovery of drugs was 99.32-100.39 and 98.65-101.96% in pharmaceutical formulation and human serum, respectively, at the isosbestic point and at individual λmax . This method is applicable for the analysis of drugs in bulk drug, tablets, serum, and in clinical samples without interference of excipients or endogenous serum components. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sub-1min separation in sequential injection chromatography for determination of synthetic water-soluble dyes in pharmaceutical formulation.

PubMed

Davletbaeva, Polina; Chocholouš, Petr; Bulatov, Andrey; Šatínský, Dalibor; Solich, Petr

2017-09-05

Sequential Injection Chromatography (SIC) evolved from fast and automated non-separation Sequential Injection Analysis (SIA) into chromatographic separation method for multi-element analysis. However, the speed of the measurement (sample throughput) is due to chromatography significantly reduced. In this paper, a sub-1min separation using medium polar cyano monolithic column (5mm×4.6mm) resulted in fast and green separation with sample throughput comparable with non-separation flow methods The separation of three synthetic water-soluble dyes (sunset yellow FCF, carmoisine and green S) was in a gradient elution mode (0.02% ammonium acetate, pH 6.7 - water) with flow rate of 3.0mLmin -1 corresponding with sample throughput of 30h -1 . Spectrophotometric detection wavelengths were set to 480, 516 and 630nm and 10Hz data collection rate. The performance of the separation was described and discussed (peak capacities 3.48-7.67, peak symmetries 1.72-1.84 and resolutions 1.42-1.88). The method was represented by validation parameters: LODs of 0.15-0.35mgL -1 , LOQs of 0.50-1.25mgL -1 , calibration ranges 0.50-150.00mgL -1 (r>0.998) and repeatability at 10.0mgL -1 of RSD≤0.98% (n=6). The method was used for determination of the dyes in "forest berries" colored pharmaceutical cough-cold formulation. The sample matrix - pharmaceuticals and excipients were not interfering with vis determination because of no retention in the separation column and colorless nature. The results proved the concept of fast and green chromatography approach using very short medium polar monolithic column in SIC. Copyright © 2017 Elsevier B.V. All rights reserved.

Present and future medical applications of microbial exopolysaccharides

PubMed Central

Moscovici, Misu

2015-01-01

Microbial exopolysaccharides (EPS) have found outstanding medical applications since the mid-20th century, with the first clinical trials on dextran solutions as plasma expanders. Other EPS entered medicine firstly as conventional pharmaceutical excipients (e.g., xanthan – as suspension stabilizer, or pullulan – in capsules and oral care products). Polysaccharides, initially obtained from plant or animal sources, became easily available for a wide range of applications, especially when they were commercially produced by microbial fermentation. Alginates are used as anti-reflux, dental impressions, or as matrix for tablets. Hyaluronic acid and derivatives are used in surgery, arthritis treatment, or wound healing. Bacterial cellulose is applied in wound dressings or scaffolds for tissue engineering. The development of drug controlled-release systems and of micro- and nanoparticulated ones, has opened a new era of medical applications for biopolymers. EPS and their derivatives are well-suited potentially non-toxic, biodegradable drug carriers. Such systems concern rating and targeting of controlled release. Their large area of applications is explained by the available manifold series of derivatives, whose useful properties can be thereby controlled. From matrix inclusion to conjugates, different systems have been designed to solubilize, and to assure stable transport in the body, target accumulation and variable rate-release of a drug substance. From controlled drug delivery, EPS potential applications expanded to vaccine adjuvants and diagnostic imaging systems. Other potential applications are related to the bioactive (immunomodulator, antitumor, antiviral) characteristics of EPS. The numerous potential applications still wait to be developed into commercial pharmaceuticals and medical devices. Based on previous and recent results in important medical-pharmaceutical domains, one can undoubtedly state that EPS medical applications have a broad future ahead. PMID:26483763

Ephemeral profiles of prescription drug and formulation tampering: evolving pseudoscience on the Internet.

PubMed

Cone, Edward J

2006-06-01

The magnitude of non-therapeutic use, or misuse of prescription pharmaceuticals now rivals that of illicit drug abuse. Drug and formulation tampering enables misusers to administer higher doses by intended and non-intended routes. Perceived motives appear to be a combination of interests in achieving a faster onset and enhancing psychoactive effects. Narcotic analgesics, stimulants, and depressants are widely sought, examined, and tampered with for recreational use. This review examines tampering methods reported on the Internet for selected pharmaceutical products. The Internet provides broad and varied guidance on tampering methods that are specific to drug classes and unique formulations. Instructions are available on crushing, separating, purifying and chemically altering specific formulations to allow changes in dosage, route of administration, and time course of effects. Many pharmaceutical formulations contain features that serve as "barriers" to tampering. The nature and effectiveness of formulation barriers vary widely with many being overcome by adventurous misusers. Examples of successes and failures in tampering attempts are frequently described on Internet sites that support recreational drug use. Successful tampering methods that have widespread appeal evolve into recipes and become archived on multiple websites. Examples of tampering methods include: (1) how to separate narcotic drugs (codeine, hydrocodone, oxycodone) from excipients and non-desirable actives (aspirin, acetaminophen, ibuprofen); (2) overcoming time-release formulations (beads, layers, matrices); (3) removal of active drug from high-dose formulations (patches, pills); (4) alteration of dosage forms for alternate routes of administration. The development of successful formulations that inhibit or prevent drug/formulation tampering with drugs of abuse should take into consideration the scope and practice of tampering methods available to recreational drug users on the Internet.

Stability indicating validated HPLC method for quantification of levothyroxine with eight degradation peaks in the presence of excipients.

PubMed

Shah, R B; Bryant, A; Collier, J; Habib, M J; Khan, M A

2008-08-06

A simple, sensitive, accurate, and robust stability indicating analytical method is presented for identification, separation, and quantitation of l-thyroxine and eight degradation impurities with an internal standard. The method was used in the presence of commonly used formulation excipients such as butylated hydroxyanisole, povidone, crospovidone, croscarmellose sodium, mannitol, sucrose, acacia, lactose monohydrate, confectionary sugar, microcrystalline cellulose, sodium laurel sulfate, magnesium stearate, talc, and silicon dioxide. The two active thyroid hormones: 3,3',5,5'-tetra-iodo-l-thyronine (l-thyroxine-T4) and 3,3',5-tri-iodo-l-thyronine (T3) and degradation products including di-iodothyronine (T2), thyronine (T0), tyrosine (Tyr), di-iodotyrosine (DIT), mono-iodotyrosine (MIT), 3,3',5,5'-tetra-iodothyroacetic acid (T4AA) and 3,3',5-tri-iodothyroacetic acid (T3AA) were assayed by the current method. The separation of l-thyroxine and eight metabolites along with theophylline (internal standard) was achieved using a C18 column (25 degrees C) with a mobile phase of trifluoroacetic acid (0.1%, v/v, pH 3)-acetonitrile in gradient elution at 0.8 ml/min at 223 nm. The sample diluent was 0.01 M methanolic NaOH. Method was validated according to FDA, USP, and ICH guidelines for inter-day accuracy, precision, and robustness after checking performance with system suitability. Tyr (4.97 min), theophylline (9.09 min), MIT (9.55 min), DIT (11.37 min), T0 (11.63 min), T2 (14.47 min), T3 (16.29 min), T4 (17.60 min), T3AA (22.71 min), and T4AA (24.83 min) separated in a single chromatographic run. Linear relationship (r2>0.99) was observed between the peak area ratio and the concentrations for all of the compounds within the range of 2-20 microg/ml. The total time for analysis, equilibration and recovery was 40 min. The method was shown to separate well from commonly employed formulation excipients. Accuracy ranged from 95 to 105% for T4 and 90 to 110% for all other compounds. Precision was <2% for all the compounds. The method was found to be robust with minor changes in injection volume, flow rate, column temperature, and gradient ratio. Validation results indicated that the method shows satisfactory linearity, precision, accuracy, and ruggedness and also stress degradation studies indicated that the method can be used as stability indicating method for l-thyroxine in the presence of excipients.

[The excipient properties of shea butter compared with vaseline and lanolin].

PubMed

Thioune, Oumar; Khouma, Barham; Diarra, Mounibé; Diop, Alioune B; Lô, Issa

2003-01-01

A shea butter ointment containing 3% aureomycin (clortetracyclin hydrocloride) was prepared and some of its macroscopic and microscopic characteristics were evaluated. Then, the release of the active ingredient was compared by UV spectrophotometry with those obtained when excipients such as petroleum jelly and lanoline were used. Results had shown that the shea butter ointment had satisfactory characteristics. In the other hand, it was found that shea butter released the aureomycin easily and at a faster rate than the other excipients.

Rapid screening of guar gum using portable Raman spectral identification methods.

PubMed

Srivastava, Hirsch K; Wolfgang, Steven; Rodriguez, Jason D

2016-01-25

Guar gum is a well-known inactive ingredient (excipient) used in a variety of oral pharmaceutical dosage forms as a thickener and stabilizer of suspensions and as a binder of powders. It is also widely used as a food ingredient in which case alternatives with similar properties, including chemically similar gums, are readily available. Recent supply shortages and price fluctuations have caused guar gum to come under increasing scrutiny for possible adulteration by substitution of cheaper alternatives. One way that the U.S. FDA is attempting to screen pharmaceutical ingredients at risk for adulteration or substitution is through field-deployable spectroscopic screening. Here we report a comprehensive approach to evaluate two field-deployable Raman methods--spectral correlation and principal component analysis--to differentiate guar gum from other gums. We report a comparison of the sensitivity of the spectroscopic screening methods with current compendial identification tests. The ability of the spectroscopic methods to perform unambiguous identification of guar gum compared to other gums makes them an enhanced surveillance alternative to the current compendial identification tests, which are largely subjective in nature. Our findings indicate that Raman spectral identification methods perform better than compendial identification methods and are able to distinguish guar gum from other gums with 100% accuracy for samples tested by spectral correlation and principal component analysis. Published by Elsevier B.V.

Probing Pharmaceutical Mixtures during Milling: The Potency of Low-Frequency Raman Spectroscopy in Identifying Disorder.

PubMed

Walker, Greg; Römann, Philipp; Poller, Bettina; Löbmann, Korbinian; Grohganz, Holger; Rooney, Jeremy S; Huff, Gregory S; Smith, Geoffrey P S; Rades, Thomas; Gordon, Keith C; Strachan, Clare J; Fraser-Miller, Sara J

2017-12-04

This study uses a multimodal analytical approach to evaluate the rates of (co)amorphization of milled drug and excipient and the effectiveness of different analytical methods in detecting these changes. Indomethacin and tryptophan were the model substances, and the analytical methods included low-frequency Raman spectroscopy (785 nm excitation and capable of measuring both low- (10 to 250 cm -1 ) and midfrequency (450 to 1800 cm -1 ) regimes, and a 830 nm system (5 to 250 cm -1 )), conventional (200-3000 cm -1 ) Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD). The kinetics of amorphization were found to be faster for the mixture, and indeed, for indomethacin, only partial amorphization occurred (after 360 min of milling). Each technique was capable of identifying the transformations, but some, such as low-frequency Raman spectroscopy and XRPD, provided less ambiguous signatures than the midvibrational frequency techniques (conventional Raman and FTIR). The low-frequency Raman spectra showed intense phonon mode bands for the crystalline and cocrystalline samples that could be used as a sensitive probe of order. Multivariate analysis has been used to further interpret the spectral changes. Overall, this study demonstrates the potential of low-frequency Raman spectroscopy, which has several practical advantages over XRPD, for probing (dis-)order during pharmaceutical processing, showcasing its potential for future development, and implementation as an in-line process monitoring method.

Dendrimers: a class of polymers in the nanotechnology for the delivery of active pharmaceuticals.

PubMed

Samad, Abdus; Alam, Md Intakhab; Saxena, Kinshuk

2009-01-01

Dendrimers represent a class of novel polymers having unique molecular architectures characterized by their well-defined structure, with a high degree of molecular uniformity, low polydispersity and properties that make them attractive materials for the development of nanomedicines. The dendrimer drug delivery can be achieved by coupling a drug through one of two approaches. Hydrophobic drugs can be complexed within the hydrophobic dendrimer interior to make them water-soluble or drugs can be covalently coupled onto the surface of the dendrimer. In addition, dendrimers have been shown to be capable of bypassing efflux transporters. A new generation of dendrimer-based delivery systems will enable the efficient transport of drugs across cellular barriers. This review deals principally with the synthesis, characterization and recent applications of dendrimers. In future it will only ever be possible to designate a dendrimer as safe means of drug delivery related to a specific application. However, so far limited clinical experience using dendrimers makes it impossible to designate any particular system which is safe and non toxic. Although there is widespread concern as to the safety of nanosized particles, preclinical and clinical experience gained during the development of polymeric excipients, biomedical polymers and polymer therapeutics showed that judicious development of dendrimer chemistry for each specific application will ensure development of safe and important materials for biomedical and pharmaceutical use.

Spectrophotometric determination of β-adrenergic antagonists drugs via ion-pair complex formation using MO and EBT

NASA Astrophysics Data System (ADS)

El-Didamony, A. M.; Shehata, A. M.

2014-09-01

Two simple, rapid and sensitive spectrophotometric methods have been proposed for the assay of bisoprolol fumarate (BSF), propranolol hydrochloride (PRH), and timolol maleate (TIM) either in bulk or in pharmaceutical formulations. The methods are based on the reaction of the selected drugs with methyl orange (MO) and eriochrome black T in acidic buffers, after extracting in dichloromethane and measured quantitatively with maximum absorption at 428 and 518 nm for MO and EBT, respectively. The analytical parameters and their effects on the reported systems are investigated. The extracts are intensely colored and very stable at room temperature. The calibration graphs were linear over the concentration range of 0.8-6.4, 0.4-3.6, 0.8-5.6 μg/mL for BSF, PRH, and TIM, respectively, with MO and 0.8-6.4, 0.4-3.2, and 0.8-8.0 μg/mL for BSF, PRH, and TIM, respectively, with EBT. The stoichiometry of the complexes was found to be 1 : 1 in all cases. The proposed methods were successfully extended to pharmaceutical preparations. Excipients used as additive in commercial formulations did not interfere in the analysis. The proposed methods can be recommended for quality control and routine analysis where time, cost effectiveness and high specificity of analytical technique are of great importance.

Characteristics of Tacca leontopetaloides L. Kuntze collected from An Giang in Vietnam

NASA Astrophysics Data System (ADS)

Vu, Quan Thi Hong; Le, Phung Thi Kim; Vo, Huy Pham Hoang; Nguyen, Triet Thanh; Nguyen, Tam Kim Minh

2017-09-01

Tacca leontopetaloides L. Kuntze has been known as a remedy in folk medicine and also a staple food source in many tropical countries. Nonetheless, there are currently few literature and research on the potential pharmaceutical benefits of this herbal plant. In this study, the constituents of leaves, peels and peeled tubers as well as its antioxidant and antimicrobial activities of Tacca cultivated from mountainous regions in Tinh Bien, An Giang Province, Vietnam were investigated. The results indicated that the highest of total phenolic content (TPC) and total flavonoid content (TFC) were presented in leaves of Tacca which were 16.69 mg GAE (gallic acid equivalent)/g dried weight, 57.24 mg QE (quercetin equivalent)/g dried weight, respectively. Besides, the yield of flour recovery process from Tacca tuber estimated from 18%-20%. The chemical compositions of Tacca flour were 0.66 % total of nitrogen, 0.91% lipid, 0.05% ash and 85.7% starch content on dried weight. Furthermore, the extract of peels possessed potential antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus faecalis whilst the extract of others did not show any significant inhibition at the same concentration. As a results, with high starch content (nearly 20% in tuber) is a highly promising new starch for food and pharmaceutical excipient industry, while the usefullness of peel in treatment need further investigation.

Absorption enhancement studies of clopidogrel hydrogen sulphate in rat everted gut sacs.

PubMed

Lassoued, Mohamed Ali; Sfar, Souad; Bouraoui, Abderrahman; Khemiss, Fathia

2012-04-01

Clopidogrel, a thienopyridine antiplatelet agent, is a poor aqueous soluble compound and a P-glycoprotein (P-gp) efflux pump substrate. These two factors are responsible for its incomplete intestinal absorption. In this study, we have attempted to enhance the absorption of clopidogrel by improving its solubility and by inhibiting intestinal P-gp activity.   Solubility enhancement was achieved by preparing solid dispersions. Quinidine and naringin were selected as P-gp inhibitors, whilst tartaric acid was selected as the intestinal absorption enhancer. Absorption studies were performed using the everted gut sac model prepared from rat jejunum. The determination of clopidogrel was performed by high performance liquid chromatography. We noticed an enhancement of clopidogrel absorption by improving its solubility or by inhibiting the P-gp activity. The greatest results were obtained for solid dispersions in the presence of P-gp inhibitors at their highest concentrations, with an absorption improvement of 3.41- and 3.91-fold for naringin (15mg/kg) and quinidine (200µm), respectively. However, no clopidogrel absorption enhancement occurred in the presence of tartaric acid. Naringin, a natural compound which has no undesirable side effects as compared with quinidine, could be used as a pharmaceutical excipient in the presence of clopidogrel solid dispersions to increase clopidogrel intestinal absorption and therefore its oral bioavailability. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics.

PubMed

Shetab Boushehri, Maryam Alsadat; Stein, Valentin; Lamprecht, Alf

2018-06-01

Nanoparticles create exciting platforms for anticancer immunotherapy and vaccination, though their inherent immunomodulatory properties have remained underexploited. Ammonio methacrylate copolymers (AMC) are well-established excipients in pharmaceutical industry and components of controlled-release oral formulations. Here, we demonstrate that nanoscaling of type A and B AMC (Eudragit ® RL and RS) endows these inactive ingredients immunostimulatory properties exploitable for cancer therapy. The particles induce the secretion of various pro-inflammatory cytokines and chemokines from the cells of innate immunity. Though the underlying mechanisms are not fully uncovered, the current work established the partial involvement of Toll-like Receptor 4 (TLR4) and Nuclear factor κB (NF-κB). The size and charge-dependency of the particles' pro-inflammatory properties and cytokine/chemokine induction profile was also demonstrated. Within the context of cancer immunotherapy, biweekly peritumoral nanoparticle injection led to a complete regression of the syngeneic colorectal tumor, or a significant growth retardation thereof, considerably extending the survival of tumor-bearing animals. Additionally, presence of the immunological memory in treated animals was established. Given their better economical and relatively safer profile compared to well-established chemo- and immunotheraputics, and their ability to serve as carriers for drug targeting, vaccination and combination therapy, AMC nanoparticles (AMCNP) are fascinating subjects for further research in the field of cancer therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Production of Highly Charged Pharmaceutical Aerosols Using a New Aerosol Induction Charger

PubMed Central

Golshahi, Laleh; Longest, P. Worth; Holbrook, Landon; Snead, Jessica; Hindle, Michael

2015-01-01

Purpose Properly charged particles can be used for effective lung targeting of pharmaceutical aerosols. The objective of this study was to characterize the performance of a new induction charger that operates with a mesh nebulizer for the production of highly charged submicrometer aerosols to bypass the mouth-throat and deliver clinically relevant doses of medications to the lungs. Methods Variables of interest included combinations of model drug (i.e. albuterol sulfate) and charging excipient (NaCl) as well as strength of the charging field (1–5 kV/cm). Aerosol charge and size were measured using a modified electrical low pressure impactor system combined with high performance liquid chromatography. Results At the approximate mass median aerodynamic diameter (MMAD) of the aerosol (~ 0.4 μm), the induction charge on the particles was an order of magnitude above the field and diffusion charge limit. The nebulization rate was 439.3 ± 42.9 μl/min, which with a 0.1 % w/v solution delivered 419.5 ± 34.2 μg of medication per minute. A new correlation was developed to predict particle charge produced by the induction charger. Conclusions The combination of the aerosol induction charger and predictive correlations will allow for the practical generation and control of charged submicrometer aerosols for targeting deposition within the lungs. PMID:25823649

The reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland

PubMed Central

Ahonen, Riitta; Kanerva, Risto; Karttunen, Pekka; Timonen, Johanna

2017-01-01

The aim of this study was to explore the reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland. The study took the form of semi-structured interviews. Forty-one pharmaceutical companies and pharmaceutical wholesalers were invited to participate in the study. The pharmaceutical companies were the member organizations of Pharma Industry Finland (PIF) (N = 30) and the Finnish Generic Pharmaceutical Association (FGPA) (N = 7). One company which is a central player in the pharmaceutical market in Finland but does not belong to PIF or FGPA was also invited. The pharmaceutical wholesalers were those with a nationwide distribution network (N = 3). A total of 30 interviews were conducted between March and June 2016. The data were subjected to qualitative thematic analysis. The most common reasons behind medicine shortages in Finland were the small size of the pharmaceutical market (29/30), sudden or fluctuating demand (28/30), small stock sizes (25/30), long delivery time (23/30) and a long or complex production chain (23/30). The reasons for the medicine shortages were supply-related more often than demand-related. However, the reasons were often complex and there was more than one reason behind a shortage. Supply-related reasons behind shortages commonly interfaced with the country-specific characteristics of Finland, whereas demand-related reasons were commonly associated with the predictability and attractiveness of the market. Some reasons, such as raw material shortages, were considered global and thus had similar effects on other countries. PMID:28658307

Spray-dried high-amylose sodium carboxymethyl starch: impact of α-amylase on drug-release profile.

PubMed

Nabais, Teresa; Zaraa, Sarra; Leclair, Grégoire

2016-11-01

Spray-dried high-amylose sodium carboxymethyl starch (SD HASCA) is a promising pharmaceutical excipient for sustained-release (SR) matrix tablets produced by direct compression. The presence of α-amylase in the gastrointestinal tract and the variations of the gastric residence time of non-disintegrating dosage forms may affect the presystemic metabolism of this excipient and, consequently, the drug-release profile from formulations produced with SD HASCA. In this study, the influence of α-amylase and the residence time in acidic conditions on the drug-release profile was evaluated for a once-daily acetaminophen formulation (Acetaminophen SR) and a once-daily tramadol hydrochloride formulation (Tramadol SR). Both formulations were based on SD HASCA. α-Amylase concentrations ranging from 0 IU/L to 20000 IU/L did not significantly affect the drug-release profiles of acetaminophen and tramadol hydrochloride from SD HASCA tablets (f2 > 50) for all but only one of the studied conditions (f2 = 47). Moreover, the drug-release properties from both SD HASCA formulations were not significantly different when the residence time in acidic medium was 1 h or 3 h. An increase in α-amylase concentration led to an increase in the importance of polymer erosion as the main mechanism of drug-release instead of drug diffusion, for both formulations and both residence times, even if release profiles remained comparable. As such, it is expected that α-amylase concentration and residence time in the stomach will not clinically affect the performance of both SD HASCA SR formulations, even if the mechanism of release itself may be affected.

A study on maize proteins as a potential new tablet excipient.

PubMed

Georget, Dominique M R; Barker, Susan A; Belton, Peter S

2008-06-01

This investigation has examined the use of zein proteins from maize as the major component in oral controlled-release tablets, such formulations often being required to improve patient compliance. Tablets containing ground zein proteins, calcium hydrogen orthophosphate, polyvinyl pyrrolidone, theophylline and magnesium stearate were produced by wet granulation and compression on a single station tablet press and were compared to directly compressed tablets based on zein proteins, calcium hydrogen orthophosphate and theophylline. Non invasive techniques such as Fourier Transform infrared spectroscopy and Fourier Transform Raman spectroscopy were employed to investigate any changes in the secondary structure of zein proteins during tablet production. Random coils, alpha helices and beta sheets predominated and their relative content remained unaffected during grinding, wet granulation and compression, indicating that formulations based on zeins will be robust, i.e. insensitive to minor changes in the production conditions. Drug release from the tablets was studied using a standard pharmacopoeial dissolution test. Dissolution profiles in water, 0.1M HCl (pH=1) and phosphate buffer (pH=6.8) show that only a limited amount of theophylline was released after 4.5h, suggesting that zein proteins could act as a potential vehicle for oral controlled drug release. Analysis of the theophylline release profiles using the Peppas and Sahlin model reveals that diffusion and polymer relaxation occurred in acidic (pH=1) and buffered (pH=6.8) conditions for wet granulated tablets, whereas diffusion was predominant in directly compressed tablets. In conclusion, the present study has shown that zeins can be successfully used as a pharmaceutical excipient, and in particular as a matrix in monolithic controlled release tablets.

The Influence of Tablet Formulation, Drug Concentration, and pH Modification on the Stability of Extemporaneously Compounded Levothyroxine Suspensions.

PubMed

Svirskis, Darren; Lin, Shao-Wei; Brown, Helen; Sangaroomthong, Annie; Shin, Daniel; Wang, Ziqi; Xu, Hongtao; Dean, Rebecca; Vareed, Preetika; Jensen, Maree; Wu, Zimei

2018-01-01

Three brands of levothyroxine tablets are currently available in New Zealand (Eltroxin, Mercury Pharma, Synthroid) for extemporaneous compounding into suspensions. This study aims to determine whether tablet brand (i.e., formulation), concentration, storage conditions, as well as pH, impact the stability of compounded levothyroxine suspensions. Using the three available brands of levothyroxine tablets, suspensions were compounded at concentrations of 15 µg/mL and 25 µg/mL and stored at 4°C and 22°C. Samples were withdrawn weekly for 4 weeks, and chemical stability was evaluated using high-performance liquid chromatographic analysis. Physical appearance, ease of resuspension, and pH were also monitored weekly. To evaluate the effect on drug stability, pH modifiers were added to a suspension. As demonstrated by high-performance liquid chromatographic analysis, the suspensions compounded from the Eltroxin and Mercury Pharma tablets were more stable (>90% remaining after 4 weeks) than Synthroid across both storage conditions and concentrations. The drug was more stable at the higher concentration of 25 µg/mL than at 15 µg/mL. Levothyroxine was stable when pH was increased to pH 8 through the addition of sodium citrate; stability was reduced at a lower pH. Storage temperature did not affect the stability of the suspensions during the 4-week study. This is the first study demonstrating the impact of tablet brand, with different excipients, and drug concentrations on stability, and thus the beyond-use date of the compounded levothyroxine liquid formulations. The pH control achieved by sodium citrate, either as an excipient in tablets or an additive during compounding, improved drug stability. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

PubMed Central

Neurath, A Robert; Strick, Nathan; Li, Yun-Yao; Debnath, Asim K

2004-01-01

Background For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. Methods Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. Results HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. Conclusion These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored. PMID:15485580

The effects of excipients and particle engineering on the biophysical stability and aerosol performance of parathyroid hormone (1-34) prepared as a dry powder for inhalation.

PubMed

Shoyele, Sunday A; Sivadas, Neeraj; Cryan, Sally-Ann

2011-03-01

Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH. © 2011 American Association of Pharmaceutical Scientists

Simultaneous Determination of Acetaminophen and Synthetic Color(s) by Derivative Spectroscopy in Syrup Formulations and Validation by HPLC: Exposure Risk of Colors to Children.

PubMed

Rastogi, Shanya Das; Dixit, Sumita; Tripathi, Anurag; Das, Mukul

2015-06-01

Color additives are used in pediatric syrup formulations as an excipient; though not pre-requisite, but pediatric syrup formulations are normally colored. An attempt has been made to measure simultaneously the single drug, acetaminophen (AT), along with the colors, carmoisine (CA), erythrosine (ET), and sunset yellow FCF (SSY) added in it by three derivative spectroscopy methods namely, 1st order, ratio, and differential derivative methods. Moreover, evaluation has been made for the exposure assessment of the colors added as excipient because some colors have been reported to cause allergic reactions and hypersensitivity in children. The present methods provide simple, accurate, and reproducible quantitative determination of the drug, AT, along with the color in synthetic mixtures and commercial drug formulations without any interference. The limit of detection varied from 0.0001-0.31 μg/ml while limit of quantification ranged from 0.002-1.04 μg/ml in all the three methods. The calibration curve of all the three derivative methods exhibited good linear relationship with excellent regression coefficients (0.9986-1.000). Both intra-day and inter-day precisions showed %RSD value less than 2% while the percentage recovery was found between 96.8-103.8%. The sensitivity of the proposed methods is almost comparable to HPLC and thus, can be used for determination of drug AT, and color simultaneously in pharmaceutical formulation on routine basis. The present methods also showed that colors like SSY and ET are saturating more than 50% of acceptable daily intake (ADI) value which is alarming and needs to be considered for modification by regulatory authorities to safeguard the health of children.

Evaluation about wettability, water absorption or swelling of excipients through various methods and the correlation between these parameters and tablet disintegration.

PubMed

Yang, Baixue; Wei, Chen; Yang, Yang; Wang, Qifang; Li, Sanming

2018-04-06

To evaluate parameters about wettability, water absorption or swelling of excipients in forms of powders or dosage through various methods systematically and explore its correlation with tablet disintegration. The water penetration and swelling of powders with different proportions of excipients including microcrystalline cellulose (MCC), mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), croscarmellose sodium (CCMC-Na) and magnesium stearate (MgSt) were determined by Washburn capillary rise. Both contact angle of water on the excipient compacts and surface swelling volume were measured by sessile drop technique. Moreover, the test about water absorption and swelling of compacts was fulfilled by a modified method. Eventually, the disintegration of tablets with or without loratadine was performed according to the method described in USP. These parameters were successfully identified by the methods above, which proved that excipient wettability or swelling properties varied with the structure of excipients. For example, MgSt could improve the water uptake, while impeded tablet swelling. Furthermore, in the present study it is verified that tablet disintegration was closely related to these parameters, especially wetting rate and initial water absorption rate. The higher wetting rate of water on tablet or initial water absorption rate, the faster swelling it be, resulting in the shorter tablet disintegration time. The methods utilized in the present study were feasible and effective. The disintegration of tablets did relate to these parameters, especially wetting rate and initial water absorption rate.

NIR analysis of cellulose and lactose--application to ecstasy tablet analysis.

PubMed

Baer, Ines; Gurny, Robert; Margot, Pierre

2007-04-11

Cellulose and lactose are the most frequently used excipients in illicit ecstasy production. The aim of this project was to use near infrared reflectance spectroscopy (NIRS) for the determination of the different chemical forms of these two substances, as well as for the differentiation of their origin (producer). It was possible to distinguish between the different chemical forms of both compounds, as well as between their origins (producers), although within limits. Furthermore, the possibilities to apply NIR for the analysis of substances such as found in illicit tablets were studied. First, a few cellulose and lactose samples were chosen to make mixtures with amphetamine at three degrees of purity (5, 10 and 15%), in order to study the resulting changes in the spectra as well as to simultaneously quantify amphetamine and identify the excipient. A PLS2 model could be build to predict concentrations and excipient. Secondarily, the technique was to be applied to real ecstasy tablets. About 40 ecstasy seizures were analysed with the aim to determine the excipient and to check them against each other. Identification of the excipients was not always obvious, especially when more than one excipient were present. However, a comparison between tablets appeared to give groups of similar samples. NIR analysis results in spectra representing the tablet blend as a whole taking into account all absorbing compounds. Although NIRS seems to be an appropriate method for ecstasy profiling, little is known about intra- and intervariability of compression batches.

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy.

PubMed

Mah, Pei T; Novakovic, Dunja; Saarinen, Jukka; Van Landeghem, Stijn; Peltonen, Leena; Laaksonen, Timo; Isomäki, Antti; Strachan, Clare J

2017-05-01

To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods. Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy. Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage. SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.

Enhancing Nutraceutical Bioavailability from Raw and Cooked Vegetables Using Excipient Emulsions: Influence of Lipid Type on Carotenoid Bioaccessibility from Carrots.

PubMed

Zhang, Ruojie; Zhang, Zipei; Zou, Liqiang; Xiao, Hang; Zhang, Guodong; Decker, Eric Andrew; McClements, David Julian

2015-12-09

The influence of the nature of the lipid phase in excipient emulsions on the bioaccessibility and transformation of carotenoid from carrots was investigated using a gastrointestinal tract (GIT) model. Excipient emulsions were fabricated using whey protein as an emulsifier and medium-chain triglycerides (MCT), fish oil, or corn oil as the oil phase. Changes in particle size, charge, and microstructure were measured as the carrot-emulsion mixtures were passed through simulated mouth, stomach, and small intestine regions. Carotenoid bioaccessibility depended on the type of lipids used to form the excipient emulsions (corn oil > fish oil ≫ MCT), which was attributed to differences in the solubilization capacity of mixed micelles formed from different lipid digestion products. The transformation of carotenoids was greater for fish oil and corn oil than for MCT, which may have been due to greater oxidation or isomerization. The bioaccessibility of the carotenoids was higher from boiled than raw carrots, which was attributed to greater disruption of the plant tissue facilitating carotenoid release. In conclusion, excipient emulsions are highly effective at increasing carotenoid bioaccessibility from carrots, but lipid type must be optimized to ensure high efficacy.

Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

PubMed

Campiñez, María Dolores; Caraballo, Isidoro; Puchkov, Maxim; Kuentz, Martin

2017-07-01

The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers.

PubMed

Jämstorp, Erik; Yarra, Tejaswi; Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne; Strømme, Maria

2012-01-01

Improving acid resistance, while maintaining the excellent mechanical stability is crucial in the development of a sustained and safe oral geopolymer dosage form for highly potent opioids. In the present work, commercially available Methacrylic acid-ethyl acrylate copolymer, Polyethylene-glycol (PEG) and Alginate polymer excipients were included in dissolved or powder form in geopolymer pellets to improve the release properties of Zolpidem, herein acting as a model drug for the highly potent opioid Fentanyl. Scanning electron microscopy, compression strength tests and drug release experiments, in gastric pH 1 and intestinal pH 6.8 conditions, were performed. The polymer excipients, with an exception for PEG, reduced the drug release rate in pH 1 due to their ability to keep the pellets in shape, in combination with the introduction of an insoluble excipient, and thereby maintain a barrier towards drug diffusion and release. Neither geopolymer compression strength nor the release in pH 6.8 was considerably impaired by the incorporation of the polymer excipients. The geopolymer/polymer composites combine high mechanical strength and good release properties under both gastric and intestinal pH conditions, and are therefore promising oral dosage forms for sustained release of highly potent opioids.

Evaluation of Gum of Moringa oleifera as a Binder and Release Retardant in Tablet Formulation

PubMed Central

Panda, D. S.; Choudhury, N. S. K.; Yedukondalu, M.; Si, S.; Gupta, R.

2008-01-01

The present study was undertaken to find out the potential of gum from Moringa oleifera to act as a binder and release retardant in tablet formulations. The effect of calcium sulphate dihydrate (water insoluble) and lactose (water soluble) diluent on the release of propranolol hydrochloride was studied. The DSC thermograms of drug, gum and mixture of gum/drug indicated no chemical interaction. Tablets (F1, F2, F3, and F4) were prepared containing calcium sulphate dihydrate as diluent, propranolol hydrochloride as model drug using 10%, 8%, 6% and 4% w/v of gum solution as binder. Magnesium stearate was used as lubricant. Physical and technological properties of granules and tablets like flow rate, Carr index, Hausner ratio, angle of repose, hardness, friability and disintegration time were determined and found to be satisfactory. Tablets were prepared by wet granulation method containing calcium sulphate dihydrate as excipient, propranolol hydrochloride as model drug using 10%, 20% and 30% of gum as release retardant, magnesium stearate was used as lubricant. Similarly tablets were prepared replacing lactose with calcium sulphate dihydrate. Despite of the widely varying physico-chemical characteristics of the excipients, the drug release profiles were found to be similar. The drug release increased with increasing proportions of the excipient and decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The values of release exponent ‘n’ are between 0.37 and 0.54. This implies that the release mechanism is Fickian. There is no evidence that the dissolution or erosion of the excipient has got any effect on the release of the drug. The t50% values for tablets containing calcium sulphate dihydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t50% values suggest that the nature of excipient used appeared to play a minor role in regulating the release, while the gum content was a major factor. PMID:21394258

Release of indomethacin from ultrasound dry granules containing lactose-based excipients.

PubMed

Cavallari, Cristina; Albertini, Beatrice; Rodriguez, Lorenzo; Rabasco, Antonio M; Fini, Adamo

2005-01-20

Physical mixtures were prepared containing indomethacin and beta-lactose and alpha-lactose-based excipients (Ludipress and Cellactose). The mixtures were compacted with the aid of ultrasound, obtaining tablets, which were milled and sieved. Granules thus obtained were examined by optical microscopy and differential scanning calorimetry. The intense yellow color of the granules and the absence of indomethacin peak in thermograms suggest important modifications of indomethacin physical state; the drug thus modified appears to be spread on the excipient particle surface as a thin film, giving a lustrous appearance. No influence of ultrasound was observed on phase transition concerning lactose; only loss of water was important under high energy ultrasound. Dissolution profiles suggest an increased release of the drug from the systems treated with ultrasound at high energy, with respect to a traditional compaction; while no difference could be evidenced among the three excipients that, however, appear all suitable for this ultrasound-aided direct compression process.

A new approach to accelerated drug-excipient compatibility testing.

PubMed

Sims, Jonathan L; Carreira, Judith A; Carrier, Daniel J; Crabtree, Simon R; Easton, Lynne; Hancock, Stephen A; Simcox, Carol E

2003-01-01

The purpose of this study was to develop a method of qualitatively predicting the most likely degradants in a formulation or probing specific drug-excipient interactions in a significantly shorter time frame than the typical 1 month storage testing. In the example studied, accelerated storage testing of a solid dosage form at 50 degrees C, the drug substance SB-243213-A degraded via the formation of two oxidative impurities. These impurities reached a level of 1% PAR after 3 months. Various stressing methods were examined to try to recreate this degradation and in doing so provide a practical and reliable method capable of predicting drug-excipient interactions. The technique developed was able to mimic the 1-month's accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable of multisample stressing, and ideal for use in drug-excipient compatibility screening.

Development and validation of spectrophotometric, atomic absorption and kinetic methods for determination of moxifloxacin hydrochloride.

PubMed

Abdellaziz, Lobna M; Hosny, Mervat M

2011-01-01

Three simple spectrophotometric and atomic absorption spectrometric methods are developed and validated for the determination of moxifloxacin HCl in pure form and in pharmaceutical formulations. Method (A) is a kinetic method based on the oxidation of moxifloxacin HCl by Fe(3+) ion in the presence of 1,10 o-phenanthroline (o-phen). Method (B) describes spectrophotometric procedures for determination of moxifloxacin HCl based on its ability to reduce Fe (III) to Fe (II), which was rapidly converted to the corresponding stable coloured complex after reacting with 2,2' bipyridyl (bipy). The formation of the tris-complex formed in both methods (A) and (B) were carefully studied and their absorbance were measured at 510 and 520 nm respectively. Method (C) is based on the formation of ion- pair associated between the drug and bismuth (III) tetraiodide in acidic medium to form orange-red ion-pair associates. This associate can be quantitatively determined by three different procedures. The formed precipitate is either filtered off, dissolved in acetone and quantified spectrophotometrically at 462 nm (Procedure 1), or decomposed by hydrochloric acid, and the bismuth content is determined by direct atomic absorption spectrometric (Procedure 2). Also the residual unreacted metal complex in the filtrate is determined through its metal content using indirect atomic absorption spectrometric technique (procedure 3). All the proposed methods were validated according to the International Conference on Harmonization (ICH) guidelines, the three proposed methods permit the determination of moxifloxacin HCl in the range of (0.8-6, 0.8-4) for methods A and B, (16-96, 16-96 and 16-72) for procedures 1-3 in method C. The limits of detection and quantitation were calculated, the precision of the methods were satisfactory; the values of relative standard deviations did not exceed 2%. The proposed methods were successfully applied to determine the drug in its pharmaceutical formulations without interference from the common excipients. The results obtained by the proposed methods were comparable with those obtained by the reference method.

Development and Validation of Spectrophotometric, Atomic Absorption and Kinetic Methods for Determination of Moxifloxacin Hydrochloride

PubMed Central

Abdellaziz, Lobna M.; Hosny, Mervat M.

2011-01-01

Three simple spectrophotometric and atomic absorption spectrometric methods are developed and validated for the determination of moxifloxacin HCl in pure form and in pharmaceutical formulations. Method (A) is a kinetic method based on the oxidation of moxifloxacin HCl by Fe3+ ion in the presence of 1,10 o-phenanthroline (o-phen). Method (B) describes spectrophotometric procedures for determination of moxifloxacin HCl based on its ability to reduce Fe (III) to Fe (II), which was rapidly converted to the corresponding stable coloured complex after reacting with 2,2′ bipyridyl (bipy). The formation of the tris-complex formed in both methods (A) and (B) were carefully studied and their absorbance were measured at 510 and 520 nm respectively. Method (C) is based on the formation of ion- pair associated between the drug and bismuth (III) tetraiodide in acidic medium to form orange—red ion-pair associates. This associate can be quantitatively determined by three different procedures. The formed precipitate is either filtered off, dissolved in acetone and quantified spectrophotometrically at 462 nm (Procedure 1), or decomposed by hydrochloric acid, and the bismuth content is determined by direct atomic absorption spectrometric (Procedure 2). Also the residual unreacted metal complex in the filtrate is determined through its metal content using indirect atomic absorption spectrometric technique (procedure 3). All the proposed methods were validated according to the International Conference on Harmonization (ICH) guidelines, the three proposed methods permit the determination of moxifloxacin HCl in the range of (0.8–6, 0.8–4) for methods A and B, (16–96, 16–96 and 16–72) for procedures 1–3 in method C. The limits of detection and quantitation were calculated, the precision of the methods were satisfactory; the values of relative standard deviations did not exceed 2%. The proposed methods were successfully applied to determine the drug in its pharmaceutical formulations without interference from the common excipients. The results obtained by the proposed methods were comparable with those obtained by the reference method. PMID:22219661

Immunoglobulin G particles manufacturing by spray drying process for pressurised metered dose inhaler formulations.

PubMed

Carli, V; Menu-Bouaouiche, L; Cardinael, P; Benissan, L; Coquerel, G

2018-07-01

The objective of this work is to show the feasibility of manufacturing from a spray drying process particles containing immunoglobulin G capable of being administered by inhalation via a pressurized metered dose inhaler. Spray drying were made from aqueous solutions containing IgG and two types of excipients, mannitol and trehalose, with two ratios: 25% w/w and 75%w/w. The physicochemical and aerodynamic properties of the powders obtained were characterized just after manufacturing and after 1 month of storage at 40°C/75% RH according to criteria defined as needed to satisfy an inhaled formulation with a pressurized metered dose inhaler. Maintain of the biological activity and the structure of IgG after atomization was also tested by slot blot and circular dichroism. All spray-dried powders presented a median diameter lower than 5μm. The powders atomized with trehalose showed a solid state more stable than those atomized with mannitol. All atomized powders were in the form of wrinkled particles regardless the nature and the ratios of excipients. The results showed that the aerosolisation properties were compliant with the target, independently of the excipient used at a ratio of 25% w/w IgG-excipient. Moreover, the addition of excipient during the atomization process the denaturation of IgG was limited. This study showed that the use of trehalose as excipient could satisfy the requirements of an inhaled formulation with a pressurized metered dose inhaler. Copyright © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Extractive colorimetric method for the determination of dothiepin hydrochloride and risperidone in pure and in dosage forms.

PubMed

Hassan, Wafaa El-Sayed

2008-08-01

Three rapid, simple, reproducible and sensitive extractive colorimetric methods (A--C) for assaying dothiepin hydrochloride (I) and risperidone (II) in bulk sample and in dosage forms were investigated. Methods A and B are based on the formation of an ion pair complexes with methyl orange (A) and orange G (B), whereas method C depends on ternary complex formation between cobalt thiocyanate and the studied drug I or II. The optimum reaction conditions were investigated and it was observed the calibration curves resulting from the measurements of absorbance concentration relations of the extracted complexes were linear over the concentration range 0.1--12 microg ml(-1) for method A, 0.5--11 mug ml(-1) for method B, and 3.2--80 microg ml(-1) for method C with a relative standard deviation (RSD) of 1.17 and 1.28 for drug I and II, respectively. The molar absorptivity, Sandell sensitivity, Ringbom optimum concentration ranges, and detection and quantification limits for all complexes were calculated and evaluated at maximum wavelengths of 423, 498, and 625 nm, using methods A, B, and C, respectively. The interference from excipients commonly present in dosage forms and common degradation products was studied. The proposed methods are highly specific for the determination of drugs I and II, in their dosage forms applying the standard additions technique without any interference from common excipients. The proposed methods have been compared statistically to the reference methods and found to be simple, accurate (t-test) and reproducible (F-value).

Interpenetrating Polymer Networks as Innovative Drug Delivery Systems

PubMed Central

Lohani, Alka; Singh, Garima; Bhattacharya, Shiv Sankar; Verma, Anurag

2014-01-01

Polymers have always been valuable excipients in conventional dosage forms, also have shown excellent performance into the parenteral arena, and are now capable of offering advanced and sophisticated functions such as controlled drug release and drug targeting. Advances in polymer science have led to the development of several novel drug delivery systems. Interpenetrating polymer networks (IPNs) have shown superior performances over the conventional individual polymers and, consequently, the ranges of applications have grown rapidly for such class of materials. The advanced properties of IPNs like swelling capacity, stability, biocompatibility, nontoxicity and biodegradability have attracted considerable attention in pharmaceutical field especially in delivering bioactive molecules to the target site. In the past few years various research reports on the IPN based delivery systems showed that these carriers have emerged as a novel carrier in controlled drug delivery. The present review encompasses IPNs, their types, method of synthesis, factors which affects the morphology of IPNs, extensively studied IPN based drug delivery systems, and some natural polymers widely used for IPNs. PMID:24949205

In-vitro Drug Dissolution Studies in Medicinal Compounds.

PubMed

Bozal-Palabiyik, Burcin; Uslu, Bengi; Ozkan, Yalcin; Ozkan, Sibel A

2018-03-22

After oral administration, drug absorption from solid dosage forms depend on the release of the drug active compounds from the dosage form, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Dissolution testing is an essential part of designing more effective solid dosage forms in pharmaceutical industry. Moreover dissolution testing contributes to the selection of appropriate formulation excipients for improving the dosage form efficiency. This study aims to analyze in-vitro drug dissolution testing in solid dosage forms since 2010 in order to present a comprehensive outlook of recent trends. In doing that the previous studies in the literature are summarized in the form of a table to demonstrate the apparatuses used for dissolution testing, the media in which the solid dosage form is dissolved, the method preferred for analysis from dissolution media, the conditions of analyses and the results obtained. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

New FDA draft guidance on immunogenicity.

PubMed

Parenky, Ashwin; Myler, Heather; Amaravadi, Lakshmi; Bechtold-Peters, Karoline; Rosenberg, Amy; Kirshner, Susan; Quarmby, Valerie

2014-05-01

A "Late Breaking" session was held on May 20 at the 2013 American Association of Pharmaceutical Scientists-National Biotech Conference (AAPS-NBC) to discuss the US Food and Drug Administration's (FDA) 2013 draft guidance on Immunogenicity Assessment for Therapeutic Protein Products. The session was initiated by a presentation from the FDA which highlighted several key aspects of the 2013 draft guidance pertaining to immunogenicity risk, the potential impact on patient safety and product efficacy, and risk mitigation. This was followed by an open discussion on the draft guidance which enabled delegates from biopharmaceutical companies to engage the FDA on topics that had emerged from their review of the draft guidance. The multidisciplinary audience fostered an environment that was conducive to scientific discussion on a broad range of topics such as clinical impact, immune mitigation strategies, immune prediction and the role of formulation, excipients, aggregates, and degradation products in immunogenicity. This meeting report highlights several key aspects of the 2013 draft guidance together with related dialog from the session.

Salt disproportionation: A material science perspective.

PubMed

Thakral, Naveen K; Kelly, Ron C

2017-03-30

While screening the counter-ions for salt selection for an active pharmaceutical substance, there is often an uncertainty about disproportionation of the salt and hence physical stability of the final product formulation to provide adequate shelf life. Several examples of disproportionation reactions are reviewed to explain the concepts of pHmax, microenvironmental pH, and buffering capacity of excipients and APIs to gain mechanistic understanding of disproportionation reaction. Miscellaneous factors responsible for disproportionation are examined. In addition to the dissolution failure due to the formation of less soluble unionized form, various implications of the disproportionation are evaluated with specific examples. During lead optimization and early stages of development, when only a limited amount of material is available, use of predictive tools like mathematical models and model free kinetics to rank order the various counter-ions are discussed in detail. Finally, analytical methods and mitigation strategies are discussed to prevent the disproportionation by detecting it during early stages of drug development. Copyright © 2017 Elsevier B.V. All rights reserved.

[In vitro evaluation of the gels properties prepared on Pluronic F-127 as vehicles for administration prolactin by injection].

PubMed

Karolewicz, Bozena; Pawlik-Gałczyńska, Anna; Pluta, Janusz; Ryszka, Florian

2011-01-01

The aim of this study was to prepare a thermoresponsive formulations, which are a carrier for proteins--prolactin administered directly into solid tumor and which obtain sol-gel transitions at physiological ranges of temperature. Prolactin (PRL) is a hormone that in vivo and in vitro exhibits antiangiogenic properties. Application of this protein in the proposed formulations can be particularly advantageous because of its relatively low stability and limited ability to transmembrane penetration. The paper prepared thermoresponsive carriers, based on nonionic polymer Pluronic F-127 with selected excipients such as dextran 7000, PEG 400, Tween 20 and Tween 80. The sol-gel transition temperature of the formulations was investigated and their physicochemical properties such as pH, density, osmotic pressure were studied. In the remainder of the work carried out tests of prolactin release from the proposed media. The results obtained indicate that a significant influence on the theological parameters obtained carriers and the availability of pharmaceutical composition of prolactin was developed formulation.

Effect of polacrilin potassium as disintegrant on bioavailability of diclofenac potassium in tablets : a technical note.

PubMed

Bele, Mrudula H; Derle, Diliprao V

2012-09-01

Polacrilin potassium is an ion exchange resin used in oral pharmaceutical formulations as a tablet disintegrant. It is a weakly acidic cation exchange resin. Chemically, it is a partial potassium salt of a copolymer of methacrylic acid with divinyl benzene. It ionizes to an anionic polymer chain and potassium cations. It was hypothesized that polacrilin potassium may be able to improve the permeability of anionic drugs according to the Donnan membrane phenomenon. The effect of polacrilin potassium on the permeability of diclofenac potassium, used as a model anionic drug, was tested in vitro using diffusion cells and in vivo by monitoring serum levels in rats. The amount of drug permeated across a dialysis membrane in vitro was significantly more in the presence of polacrilin potassium. Significant improvement was found in the extent of drug absorption in vivo. It could be concluded that polacrilin potassium may be used as a high-functionality excipient for improving the bioavailability of anionic drugs having poor gastrointestinal permeability.

Rediscovery and Revival of Analytical Refractometry for Protein Determination: Recombining Simplicity With Accuracy in the Digital Era.

PubMed

Anderle, Heinz; Weber, Alfred

2016-03-01

Among "vintage" methods of protein determination, quantitative analytical refractometry has received far less attention than well-established pharmacopoeial techniques based on protein nitrogen content, such as Dumas combustion (1831) and Kjeldahl digestion (1883). Protein determination by quantitative refractometry dates back to 1903 and has been extensively investigated and characterized in the following 30 years, but has since vanished into a few niche applications that may not require the degree of accuracy and precision essential for pharmaceutical analysis. However, because high-resolution and precision digital refractometers have replaced manual instruments, reducing time and resource consumption, the method appears particularly attractive from an economic, ergonomic, and environmental viewpoint. The sample solution can be measured without dilution or other preparation procedures than the separation of the protein-free matrix by ultrafiltration, which might even be omitted for a constant matrix and excipient composition. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Method to study the effect of blend flowability on the homogeneity of acetaminophen.

PubMed

Llusá, Marcos; Pingali, Kalyana; Muzzio, Fernando J

2013-02-01

Excipient selection is key to product development because it affects their processability and physical properties, which ultimately affect the quality attributes of the pharmaceutical product. To study how the flowability of lubricated formulations affects acetaminophen (APAP) homogeneity. The formulations studied here contain one of two types of cellulose (Avicel 102 or Ceollus KG-802), one of three grades of Mallinckrodt APAP (fine, semi-fine, or micronized), lactose (Fast-Flo) and magnesium stearate. These components are mixed in a 300-liter bin blender. Blend flowability is assessed with the Gravitational Displacement Rheometer. APAP homogeneity is assessed with off-line NIR. Excluding blends dominated by segregation, there is a trend between APAP homogeneity and blend flow index. Blend flowability is affected by the type of microcrystalline cellulose and by the APAP grade. The preliminary results suggest that the methodology used in this paper is adequate to study of the effect of blend flow index on APAP homogeneity.

Applications of lipid based formulation technologies in the delivery of biotechnology-based therapeutics.

PubMed

du Plessis, Lissinda H; Marais, Etienne B; Mohammed, Faruq; Kotzé, Awie F

2014-01-01

In the last decades several new biotechnologically-based therapeutics have been developed due to progress in genetic engineering. A growing challenge facing pharmaceutical scientists is formulating these compounds into oral dosage forms with adequate bioavailability. An increasingly popular approach to formulate biotechnology-based therapeutics is the use of lipid based formulation technologies. This review highlights the importance of lipid based drug delivery systems in the formulation of oral biotechnology based therapeutics including peptides, proteins, DNA, siRNA and vaccines. The different production procedures used to achieve high encapsulation efficiencies of the bioactives are discussed, as well as the factors influencing the choice of excipient. Lipid based colloidal drug delivery systems including liposomes and solid lipid nanoparticles are reviewed with a focus on recent advances and updates. We further describe microemulsions and self-emulsifying drug delivery systems and recent findings on bioactive delivery. We conclude the review with a few examples on novel lipid based formulation technologies.

The influence of polymeric excipients on the process of pharmaceutical availability of therapeutic agents from a model drug form. Part I. In formulations with controlled disintegration and release time.

PubMed

Nachajski, Michal Jakub; Zgoda, Marian Mikołaj

2010-01-01

Pre-formulation research was conducted on the application of Ex. Echinaceae aq. siccum in the production of a quickly disintegrating suspension tablet, a lozenge with kariostatic sugar alcohols (mannitol, sorbitol), and, above all, a solid drug form with controlled release of therapeutic agents included in the extract. Morphological parameters of tablets obtained in the course of experiment were estimated and the profiles of the release (diffusion) ofhydrophilic therapeutic agents into model receptor fluids with varying values of osmolarity (0.1 mol HCl approximately 200 mOsm/l, hypotonic hydrating fluid approximately 143 mOsm/l, and compensatory paediatric fluid approximately 272 mOsm/l) were examined. The study focused on the technological problem of determining the effect of hydrogel Carbopol structure on the ordering of diffusion ofhydrophilic therapeutic agents from a model drug form (a tablet) into model fluids with variable osmolarity.

Design of sweet protein based sweeteners: hints from structure-function relationships.

PubMed

Rega, Michele Fortunato; Di Monaco, Rossella; Leone, Serena; Donnarumma, Federica; Spadaccini, Roberta; Cavella, Silvana; Picone, Delia

2015-04-15

Sweet proteins represent a class of natural molecules, which are extremely interesting regarding their potential use as safe low-calories sweeteners for individuals who need to control sugar intake, such as obese or diabetic subjects. Punctual mutations of amino acid residues of MNEI, a single chain derivative of the natural sweet protein monellin, allow the modulation of its taste. In this study we present a structural and functional comparison between MNEI and a sweeter mutant Y65R, containing an extra positive charge on the protein surface, in conditions mimicking those of typical beverages. Y65R exhibits superior sweetness in all the experimental conditions tested, has a better solubility at mild acidic pH and preserves a significant thermal stability in a wide range of pH conditions, although slightly lower than MNEI. Our findings confirm the advantages of structure-guided protein engineering to design improved low-calorie sweeteners and excipients for food and pharmaceutical preparations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Suppressed Release of Clarithromycin from Tablets by Crystalline Phase Transition of Metastable Polymorph Form I.

PubMed

Fujiki, Sadahiro; Watanabe, Narumi; Iwao, Yasunori; Noguchi, Shuji; Mizoguchi, Midori; Iwamura, Takeru; Itai, Shigeru

2015-08-01

The pharmaceutical properties of clarithromycin (CAM) tablets containing the metastable form I of crystalline CAM were investigated. Although the dissolution rate of form I was higher than that of stable form II, the release of CAM from form I tablet was delayed. Disintegration test and liquid penetration test showed that the disintegration of the tablet delayed because of the slow penetration of an external solution into form I tablet. Investigation by scanning electron microscopy revealed that the surface of form I tablet was covered with fine needle-shaped crystals following an exposure to the external solution. These crystals were identified as form IV crystals by powder X-ray diffraction. The phenomenon that CAM releases from tablet was inhibited by fine crystals spontaneously formed on the tablet surface could be applied to the design of sustained-release formulation systems with high CAM contents by minimizing the amount of functional excipients. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Exploring the Halal Status of Cardiovascular, Endocrine, and Respiratory Group of Medications

PubMed Central

Sarriff, Azmi; Abdul razzaq, Hadeer Akram

2013-01-01

Muslim consumers have special needs in medical treatment that differ from non-Muslim consumers. In particular, there is a growing demand among Muslim consumers for Halal medications. This descriptive exploratory study aims to determine the Halal status of selected cardiovascular, endocrine, and respiratory medications stored in an out-patient pharmacy in a Malaysian governmental hospital. Sources of active ingredients and excipients for each product were assessed for Halal status based on available information obtained from product leaflets, the Medical Information Management System (MIMS) website, or manufacturers. Halal status was based on the products’ sources and categorized into Halal, Mushbooh, or Haram. The proportions of Halal, Mushbooh, and Haram products were at 19.1%, 57.1%, and 23.8%, respectively. The percentage of active ingredients for cardiovascular/endocrine products that were assessed as Haram was 5.3%; for respiratory medications, it was only 1.1%. For excipients, 1.7% and 4.8% fall under the category of Haram for cardiovascular/endocrine products and respiratory products, respectively. Ethanol and magnesium stearate were found to be the common substances that were categorized as Haram and Mushbooh. PMID:23785257

Co-Processed Chitin-Mannitol as a New Excipient for Oro-Dispersible Tablets

PubMed Central

Daraghmeh, Nidal; Chowdhry, Babur Z.; Leharne, Stephen A.; Al Omari, Mahmoud M. H.; Badwan, Adnan A.

2015-01-01

This study describes the preparation, characterization and performance of a novel excipient for use in oro-dispersible tablets (ODT). The excipient (Cop–CM) consists of chitin and mannitol. The excipient with optimal physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w) and produced by roll compaction (RC). Differential scanning calorimetry (DSC), Fourier transform-Infrared (FT-IR), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) techniques were used to characterize Cop–CM, in addition to characterization of its powder and ODT dosage form. The effect of particle size distribution of Cop–CM was investigated and found to have no significant influence on the overall tablet physical properties. The compressibility parameter (a) for Cop–CM was calculated from a Kawakita plot and found to be higher (0.661) than that of mannitol (0.576) due to the presence of the highly compressible chitin (0.818). Montelukast sodium and domperidone ODTs produced, using Cop–CM, displayed excellent physicochemical properties. The exceptional binding, fast wetting and superdisintegration properties of Cop–CM, in comparison with commercially available co-processed ODT excipients, results in a unique multifunctional base which can successfully be used in the formulation of oro-dispersible and fast immediate release tablets. PMID:25830680

Whisker growth of l-menthol in coexistence with various excipients.

PubMed

Yuasa, H; Ooi, M; Takashima, Y; Kanaya, Y

2000-08-10

The purpose of the present study was to clarify the mechanism for l-menthol whisker growth. l-Menthol was mixed with an excipient, and the interaction was examined by IR measurement, thermal analysis and powder X-ray diffraction. Then we examined the involvement of the capillary condensation using the pore size distribution measurement. By mixing l-menthol with an excipient with whisker growth, the hydroxyl group stretching band of l-menthol was shifted to the higher wavenumber in the IR spectrum, the melting point and heat of fusion of l-menthol became lower in the thermal analysis, and the diffraction intensity of l-menthol became lower in the powder X-ray diffraction. The excipients with whisker growth showed the tendency to have the meso-pore involved in the capillary condensation in the pore size distribution measurement. From the above results, the whisker growth mechanism is considered as follows. When l-menthol was mixed with an excipient with whisker growth, the crystallinity of l-menthol was lowered and the vapor pressure was increased by the interaction mainly consisting of the hydrogen bond. The generated l-menthol vapor entered meso-pore, the saturated vapor pressure was lowered by the capillary condensation, and the nucleation occurred. The vapor was further supplied, generating the growth of whisker.

Dramatic enhancement of enzymatic activity in organic solvents by lyoprotectants

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

Dabulis, K.; Klibanov, A.M.

1993-03-05

When seven different hydrolytic enzymes (four proteases and three lipases) were lyophilized from aqueous solution containing a ligand, N-Ac-L-Phe-NH[sub 2], their catalytic activity in anhydrous solvents was far greater (one to two orders of magnitude) than that of the enzymes lyophilized without the ligand. This ligand-induced activation was expressed regardless of whether the substrate employed in organic solvents structurally resembled the ligand. Furthermore, nonligand lyoprotectants [sorbitol, other sugars, and poly(ethylene glycol)] also dramatically enhanced enzymatic activity in anhydrous solvents when present in enzyme aqueous solution prior to lyophilization. The effects of the ligand and of the lyoprotectants were nonadditive, suggestingmore » the same mechanism of action. Excipient-activated and nonactivated enzymes exhibited identical activities in water. Also, addition of the excipients directly to suspensions of nonactivated enzymes in organic solvents had no appreciable effect on catalytic activity. These observations indicate that the mechanism of the excipient-induced activation is based on the ability of the excipients to alleviate reversible denaturation of enzymes upon lyophilization. Activity enhancement induced by the excipients is displayed even after their removal by washing enzymes with anhydrous solvents. Subtilisin Carlsberg, lyophilized with sorbitol, was found to be a much more efficient practical catalyst than its regular' counterpart.« less

Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers

PubMed Central

Jämstorp, Erik; Yarra, Tejaswi; Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne; Strømme, Maria

2012-01-01

Improving acid resistance, while maintaining the excellent mechanical stability is crucial in the development of a sustained and safe oral geopolymer dosage form for highly potent opioids. In the present work, commercially available Methacrylic acid–ethyl acrylate copolymer, Polyethylene-glycol (PEG) and Alginate polymer excipients were included in dissolved or powder form in geopolymer pellets to improve the release properties of Zolpidem, herein acting as a model drug for the highly potent opioid Fentanyl. Scanning electron microscopy, compression strength tests and drug release experiments, in gastric pH 1 and intestinal pH 6.8 conditions, were performed. The polymer excipients, with an exception for PEG, reduced the drug release rate in pH 1 due to their ability to keep the pellets in shape, in combination with the introduction of an insoluble excipient, and thereby maintain a barrier towards drug diffusion and release. Neither geopolymer compression strength nor the release in pH 6.8 was considerably impaired by the incorporation of the polymer excipients. The geopolymer/polymer composites combine high mechanical strength and good release properties under both gastric and intestinal pH conditions, and are therefore promising oral dosage forms for sustained release of highly potent opioids. PMID:25755991