Modification of flow and compressibility of corn starch using quasi-emulsion solvent diffusion method.

PubMed

Akhgari, Abbas; Sadeghi, Hasti; Dabbagh, Mohammad Ali

2014-08-01

The aim of this study was to improve flowability and compressibility characteristics of starch to use as a suitable excipient in direct compression tabletting. Quasi-emulsion solvent diffusion was used as a crystal modification method. Corn starch was dissolved in hydrochloric acid at 80°C and then ethanol as a non-solvent was added with lowering temperature until the formation of a precipitate of modified starch. Flow parameters, particle size and thermal behavior of the treated powders were compared with the native starch. Finally, the 1:1 mixture of naproxen and each excipient was tabletted, and hardness and friability of different tablets were evaluated. Larger and well shaped agglomerates were formed which showed different thermal behavior. Treated starch exhibited suitable flow properties and tablets made by the treated powder had relatively high hardness. It was found that recrystallization of corn starch by quasi emulsion solvent diffusion method could improve its flowability and compressibility characteristics.

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.

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.

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.

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.

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: physicochemical and technological characterisation.

PubMed

Marinich, J A; Ferrero, C; Jiménez-Castellanos, M R

2009-05-01

Nowadays, graft copolymers are being used as an interesting option when developing a direct compression excipient for controlled release matrix tablets. New graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS) were synthesised by free radical polymerization and alternatively dried in a vacuum oven (OD) or freeze-dried (FD). This paper evaluates the performance of these new macromolecules and discusses the effect of the carbohydrate nature and drying process on their physicochemical and technological properties. Grafting of EMA on the carbohydrate backbone was confirmed by IR and NMR spectroscopy, and the grafting yields revealed that graft copolymers present mainly a hydrophobic character. The graft copolymerization also leads to more amorphous materials with larger particle size and lower apparent density and water content than carbohydrates (MS, MHS). All the products show a lack of flow, except MHSEMA derivatives. MSEMA copolymers underwent much plastic flow and less elastic recovery than MHSEMA copolymers. Concerning the effect of drying method, FD derivatives were characterised by higher plastic deformation and less elasticity than OD derivatives. Tablets obtained from graft copolymers showed higher crushing strength and disintegration time than tablets obtained from raw starches. This behaviour suggests that these copolymers could be used as excipients in matrix tablets obtained by direct compression and with a potential use in controlled release.

[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.

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.

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.

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.

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.

Study of drug release and tablet characteristics of silicone adhesive matrix tablets.

PubMed

Tolia, Gaurav; Li, S Kevin

2012-11-01

Matrix tablets of a model drug acetaminophen (APAP) were prepared using a highly compressible low glass transition temperature (T(g)) polymer silicone pressure sensitive adhesive (PSA) at various binary mixtures of silicone PSA/APAP ratios. Matrix tablets of a rigid high T(g) matrix forming polymer ethyl cellulose (EC) were the reference for comparison. Drug release study was carried out using USP Apparatus 1 (basket), and the relationship between the release kinetic parameters of APAP and polymer/APAP ratio was determined to estimate the excipient percolation threshold. The critical points attributed to both silicone PSA and EC tablet percolation thresholds were found to be between 2.5% and 5% w/w. For silicone PSA tablets, satisfactory mechanical properties were obtained above the polymer percolation threshold; no cracking or chipping of the tablet was observed above this threshold. Rigid EC APAP tablets showed low tensile strength and high friability. These results suggest that silicone PSA could eliminate issues related to drug compressibility in the formulation of directly compressed oral controlled release tablets of poorly compressible drug powder such as APAP. No routinely used excipients such as binders, granulating agents, glidants, or lubricants were required for making an acceptable tablet matrix of APAP using silicone PSA. Copyright © 2012 Elsevier B.V. All rights reserved.

Mechanistic Insight into Caffeine-Oxalic Cocrystal Dissociation in Formulations: Role of Excipients.

PubMed

Duggirala, Naga Kiran; Vyas, Amber; Krzyzaniak, Joseph F; Arora, Kapildev K; Suryanarayanan, Raj

2017-11-06

Caffeine-oxalic acid cocrystal, widely reported to be stable under high humidity, dissociated in the presence of numerous pharmaceutical excipients. In cocrystal-excipient binary systems, the water mediated dissociation reaction occurred under pharmaceutically relevant storage conditions. Powder X-ray diffractometry was used to identify the dissociated products obtained as a consequence of coformer-excipient interaction. The proposed cocrystal dissociation mechanism involved water sorption, dissolution of cocrystal and excipient in the sorbed water, proton transfer from oxalic acid to the excipient, and formation of metal salts and caffeine hydrate. In compressed tablets with magnesium stearate, the cocrystal dissociation was readily discerned from the appearance of peaks attributable to caffeine hydrate and stearic acid. Neutral excipients provide an avenue to circumvent the risk of water mediated cocrystal dissociation.

Maltodextrin: a novel excipient used in sugar-based orally disintegrating tablets and phase transition process.

PubMed

Elnaggar, Yosra Shaaban R; El-Massik, Magda A; Abdallah, Ossama Y; Ebian, Abd Elazim R

2010-06-01

The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and standard processing equipment. The current investigation constitutes one attempt to fulfill this challenge. Maltodextrin, in the present work, was utilized as a novel excipient to prepare ODT of meclizine. Tablets were prepared by both direct compression and wet granulation techniques. The effect of maltodextrin concentrations on ODT characteristics--manifested as hardness and disintegration time--was studied. The effect of conditioning (40 degrees C and 75% relative humidity) as a post-compression treatment on ODT characteristics was also assessed. Furthermore, maltodextrin-pronounced hardening effect was investigated using differential scanning calorimetry (DSC) and X-ray analysis. Results revealed that in both techniques, rapid disintegration (30-40 s) would be achieved on the cost of tablet hardness (about 1 kg). Post-compression conditioning of tablets resulted in an increase in hardness (3 kg), while keeping rapid disintegration (30-40 s) according to guidance of the FDA for ODT. However, direct compression-conditioning technique exhibited drawbacks of long conditioning time and appearance of the so-called patch effect. These problems were, yet, absent in wet granulation-conditioning technique. DSC and X-ray analysis suggested involvement of glass-elastic deformation in maltodextrin hardening effect. High-performance liquid chromatography analysis of meclizine ODT suggested no degradation of the drug by the applied conditions of temperature and humidity. Overall results proposed that maltodextrin is a promising saccharide for production of ODT with accepted hardness-disintegration time compromise, utilizing standard processing equipment and phenomena of phase transition.

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.

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.

Investigation of drug-excipient compatibility using rheological and thermal tools

NASA Astrophysics Data System (ADS)

Trivedi, Maitri R.

HYPOTHESIS: We plan to investigate a different approach to evaluate drug-excipient physical compatibility using rheological and thermal tools as opposed to commonly used chemical techniques in pharmaceutical industry. This approach offers practical solutions to routinely associated problems arising with API's and commonly used hydrates forms of excipients. ABSTRACT: Drug-Excipient compatibility studies are an important aspect of pre-formulation and formulation development in pharmaceutical research and development. Various approaches have been used in pharmaceutical industry including use of thermal analysis and quantitative assessment of drug-excipient mixtures after keeping the samples under stress environment depending upon the type of formulation. In an attempt to provide better understanding of such compatibility aspect of excipients with different properties of API, various rheological and thermal studies were conducted on binary mixtures of excipients which exist in different hydrates. Dibasic Calcium Phosphate (DCP, anhydrous and dihydrate forms) and Lactose (Lac, anhydrous and monohydrate) were selected with cohesive API's (Acetaminophen and Aspirin). Binary mixtures of DCP and Lac were prepared by addition of 0% w/w to 50% w/w of the API into each powder blend. Rheological and thermal aspects were considered using different approaches such as powder rheometer, rotational shear cell and traditional rheometery approaches like angle of repose (AOR), hausner's ratio (HR) and cares index (CI). Thermal analysis was conducted using modulated differential scanning calorimetry (MDSC) and thermal effusivity. The data suggested that the powder rheometer showed distinctive understanding in the flowability behavior of binary mixtures with addition of increasing proportion of API's than traditional approaches. Thermal approaches revealed the potential interaction of water of crystallization DCP-D with the API (APAP) while such interactions were absent in DCP-A, while in case of Lac-M and Lac-A, interaction with water of crystallization were not present. Binary mixtures prepared with DCP-D were better flowable while blends with DCP-A were better in stability (physical), compressibility and permeability. Similarly binary mixtures prepared with Lac-M were better flowable and stable in physical compatibility as compared to Lac-A. Lac-A were better in compressibility and permeability. Second part of these research included understanding the powder behavior from wet granulation point of view. Wet granulation includes the formation of agglomerates with powders to form granules in order to have better flowability, content uniformity and compressibility of granular mass. End point determination of powders involving change in powder energies and compressibility, permeability along with thermal analyses were conducted. The effects of water of crystallization on end point determination was studied and based on which overall effects on drug-excipient compatibility using different hydrate forms of excipients were evaluated.

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.

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.

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.

PREPARATION AND CHARACTERIZATION OF ORALLY DISINTEGRATING LORATADINE TABLETS MANUFACTURED WITH CO-PROCESSED MIXTURES.

PubMed

Amelian, Aleksandra; Szekalska, Marta; Wilczewska, Agnieszka Zofia; Basa, Anna; Winnicka, Katarzyna

2016-01-01

The aim of this study was to develop orally disintegrated tablets (ODT) with loratadine using Parteck ODT and Ludiflash--new commercially available tableting excipients based on co-processed mannitol. ODT containing loratadine were prepared with 3% addition of various superdisintegrants (AcDiSol, Kollidon CL-F and Kollidon CL-SF) by direct compression method. Obtained tablets were characterized for friability, pore structure, and wetting and disintegration time measured by four independents methods. In order to identify possible interactions between loratadine and the excipients, differential scanning calorimetry was used. The results showed that all formulated ODT were characterized by appropriate mechanical properties (friability < 1%), the uniform content of the drug substance and pleasant mouth feeling. Disintegration time below 30 s was observed in formulations with crospovidones as disintegrant.

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

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

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

Hydrophilic excipients modulate the time lag of time-controlled disintegrating press-coated tablets.

PubMed

Lin, Shan-Yang; Li, Mei-Jane; Lin, Kung-Hsu

2004-08-16

An oral press-coated tablet was developed by means of direct compression to achieve the time-controlled disintegrating or rupturing function with a distinct predetermined lag time. This press-coated tablet containing sodium diclofenac in the inner core was formulated with an outer shell by different weight ratios of hydrophobic polymer of micronized ethylcellulose (EC) powder and hydrophilic excipients such as spray-dried lactose (SDL) or hydroxypropyl methylcellulose (HPMC). The effect of the formulation of an outer shell comprising both hydrophobic polymer and hydrophilic excipients on the time lag of drug release was investigated. The release profile of the press-coated tablet exhibited a time period without drug release (time lag) followed by a rapid and complete release phase, in which the outer shell ruptured or broke into 2 halves. The lag phase was markedly dependent on the weight ratios of EC/SDL or EC/HPMC in the outer shell. Different time lags of the press-coated tablets from 1.0 to 16.3 hours could be modulated by changing the type and amount of the excipients. A semilogarithmic plot of the time lag of the tablet against the weight ratios of EC/SDL or EC/HPMC in the outer shell demonstrated a good linear relationship, with r = 0.976 and r = 0.982, respectively. The predetermined time lag prior to the drug release from a press-coated tablet prepared by using a micronized EC as a retarding coating shell can be adequately scheduled with the addition of hydrophilic excipients according to the time or site requirements.

Release kinetics of papaverine hydrochloride from tablets with different excipients.

PubMed

Kasperek, Regina; Polski, Andrzej; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release.

Release Kinetics of Papaverine Hydrochloride from Tablets with Different Excipients

PubMed Central

Kasperek, Regina; Polski, Andrzej; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

Abstract The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release. PMID:25853076

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.

Effects of formulation variables and post-compression curing on drug release from a new sustained-release matrix material: polyvinylacetate-povidone.

PubMed

Shao, Z J; Farooqi, M I; Diaz, S; Krishna, A K; Muhammad, N A

2001-01-01

A new commercially available sustained-release matrix material, Kollidon SR, composed of polyvinylacetate and povidone, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound, diphenhydramine HCl. Kollidon SR was found to provide a sustained-release effect for the model compound, with certain formulation and processing variables playing an important role in controlling its release kinetics. Formulation variables affecting the release include the level of the polymeric material in the matrix, excipient level, as well as the nature of the excipients (water soluble vs. water insoluble). Increasing the ratio of a water-insoluble excipient, Emcompress, to Kollidon SR enhanced drug release. The incorporation of a water-soluble excipient, lactose, accelerated its release rate in a more pronounced manner. Stability studies conducted at 40 degrees C/75% RH revealed a slow-down in dissolution rate for the drug-Kollidon SR formulation, as a result of polyvinylacetate relaxation. Further studies demonstrated that a post-compression curing step effectively stabilized the release pattern of formulations containing > or = 47% Kollidon SR. The release mechanism of Kollidon-drug and drug-Kollidon-Emcompress formulations appears to be diffusion controlled, while that of the drug-Kollidon-lactose formulation appears to be controlled predominantly by diffusion along with erosion.

Optics-based compressibility parameter for pharmaceutical tablets obtained with the aid of the terahertz refractive index.

PubMed

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

2017-06-15

The objective of this study is to propose a novel optical compressibility parameter for porous pharmaceutical tablets. This parameter is defined with the aid of the effective refractive index of a tablet that is obtained from non-destructive and contactless terahertz (THz) time-delay transmission measurement. The optical compressibility parameter of two training sets of pharmaceutical tablets with a priori known porosity and mass fraction of a drug was investigated. Both pharmaceutical sets were compressed with one of the most commonly used excipients, namely microcrystalline cellulose (MCC) and drug Indomethacin. The optical compressibility clearly correlates with the skeletal bulk modulus determined by mercury porosimetry and the recently proposed terahertz lumped structural parameter calculated from terahertz measurements. This lumped structural parameter can be used to analyse the pattern of arrangement of excipient and drug particles in porous pharmaceutical tablets. Therefore, we propose that the optical compressibility can serve as a quality parameter of a pharmaceutical tablet corresponding with the skeletal bulk modulus of the porous tablet, which is related to structural arrangement of the powder particles in the tablet. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison studies on the percolation thresholds of binary mixture tablets containing excipients of plastic/brittle and plastic/plastic deformation properties.

PubMed

Amin, Mohd C I; Fell, John T

2004-01-01

Percolation theory has been used with great interest in understanding the design and characterization of dosage forms. In this study, work has been carried out to investigate the behavior of binary mixture tablets containing excipients of similar and different deformation properties. The binary mixture tablets were prepared by direct compression using lactose, polyvinyl chloride (PVC), Eudragit RS 100, and microcrystalline cellulose (MCC). The application of percolation theory on the relationships between compactibility, Pmax, or compression susceptibility (compressibility), gamma, and mixture compositions reveals the presence of percolation thresholds even for mixtures of similar deformation properties. The results showed that all mixture compositions exhibited at least one discreet change in the slope, which was referred to as the percolation threshold. The PVC/Eudragit RS100 mixture compositions showed significant percolation threshold at 80% (w/w) PVC loading. Two percolation thresholds were observed from a series of binary mixtures containing similar plastic deformation materials (PVC/MCC). The percolation thresholds were determined at 20% (w/w) and 80% (w/w) PVC loading. These are areas where one of the components percolates throughout the system and the properties of the tablets are expected to experience a sudden change. Experimental results, however, showed that total disruption of the tablet physical properties at the specified percolation thresholds can be observed for PVC/lactose mixtures at 20-30% (w/w) loading while only minor changes in the tablets' strength for PVC/MCC or PVC/Eudragit RS 100 mixtures were observed.

Development and evaluation of Pleurotus tuber-regium-cornstarch composite as a direct compression multifunctional excipient.

PubMed

Okoye, Ebere I; Onyekweli, Anthony O

2016-01-01

The aim was to develop a novel excipient from Pleurotus tuber-regium (PT)-cornstarch (CS) mixture and evaluate its multifunctional characteristics in tablet formulation. Composites were generated from dephytochemicalized PT and CS combined at 1:1 to 4:1 ratios and pregelatinized in a hot water bath at 65°C ± 2°C for 5 min. The paste was dried, pulverized, and screened through 150-μm sieve. PT-CS physical mixtures were prepared and their characteristics/functionalities in tableting chloroquine were compared to those of composites and microcrystalline cellulose (Avicel(®)). PT ash value was 0.40 ± 0.09% and heavy metal contents were below official limits. PT's differential scanning calorimetric (DSC) thermogram depicted broad melting peak at 329.5°C; this peak was attenuated by the presence of CS. Fourier transform infrared (FTIR) spectra predicted compatibility between PT and CS. Composites consolidated better and also flowed better than physical mixtures and Avicel(®). Increasing PT content enhanced the excipients' swellabilities, and composites possessed significantly (P < 0.05) better swelling indices than Avicel(®). The composites underwent fragmentation before plastic deformation with yield pressures significantly (P < 0.05) higher than those of the physical mixtures, which exhibited only plastic deformation. The mechanical properties of chloroquine tablets were acceptable, with the 1:4 (PT:CS) imparting the best properties. Mean disintegration times for the commercial comparator and Avicel(®) -containing tablets were significantly higher (P < 0.05) than those of composites. Drug release from tablets formulated with composites were similar to the commercial comparator, but significantly higher (P < 0.05) than those of Avicel(®). The novel composites are excellent multifunctional excipients, the best (PT:CS 1:4) one showcasing potentially better mechanical functionality than Avicel(®), a popular multifunctional excipient.

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.

Drug release and swelling kinetics of directly compressed glipizide sustained-release matrices: establishment of level A IVIVC.

PubMed

Sankalia, Jolly M; Sankalia, Mayur G; Mashru, Rajashree C

2008-07-02

The purpose of this study was to examine a level A in vitro-in vivo correlation (IVIVC) for glipizide hydrophilic sustained-release matrices, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, and lactose on in vitro release profiles was studied and fitted to various release kinetics models. Water uptake kinetics with scanning electron microscopy (SEM) was carried out to support the drug release mechanism. An IVIVC was established by comparing the pharmacokinetic parameters of optimized (M-24) and marketed (Glytop-2.5 SR) formulations after single oral dose studies on white albino rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed the glipizide release within the predetermined constraints at all time points with Korsmeyer-Peppas' and zero-order release mechanism, respectively. Kopcha model revealed that the xanthan gum is the major excipient responsible for the diffusional release profile and was further supported by SEM and swelling studies. A significant level A IVIVC with acceptable limits of prediction errors (below 15%) enables the prediction of in vivo performance from their in vitro release profile. It was concluded that proper selection of rate-controlling polymers with release rate modifier excipients will determine overall release profile, duration and mechanism from directly compressed matrices.

Enhanced dissolution of sildenafil citrate as dry foam tablets.

PubMed

Sawatdee, Somchai; Atipairin, Apichart; Sae Yoon, Attawadee; Srichana, Teerapol; Changsan, Narumon

2017-01-30

Dry foam formulation technology is alternative approach to enhance dissolution of the drug. Sildenafil citrate was suspended in sodium dodecyl sulfate solution and adding a mixture of maltodextrin and mannitol as diluent to form a paste. Sildenafil citrate paste was passed through a nozzle spray bottle to obtain smooth foam. The homogeneous foam was dried in a vacuum oven and sieved to obtain dry foam granules. The granules were mixed with croscarmellose sodium, magnesium stearate and compressed into tablet. All formulations were evaluated for their physicochemical properties and dissolution profiles. All the tested excipients were compatible with sildenafil citrate by both differential scanning calorimetry (DSC) and infrared (IR) analysis. There are no X-ray diffraction (XRD) peaks representing crystals of sildenafil citrate observed form dry foam formulations. The hardness of tablets was about 5 kg, friability test <1% with a disintegration time <5 min. The sildenafil citrate dry foam tablet had higher dissolution rate in 0.1 N HCl in comparison with commercial sildenafil citrate tablet, sildenafil citrate prepared by direct compression and wet granulation method. Sildenafil citrate dry foam tablet with the high-level composition of surfactant, water and diluent showed enhanced dissolution rate than that of the lower-level composition of these excipients. This formulation was stable under accelerated conditions for at least 6 months.

Evaluation and Comparison of Three Types of Spray Dried Coprocessed Excipient Avicel® for Direct Compression

PubMed Central

Solný, Tomaš

2018-01-01

As coprocessed excipients (CPE) gain a lot of focus recently, this article compares three commercially available CPE of Avicel brand, namely, CE 15, DG, and HFE 102. Comparison is based on measured physical properties of coprocessed mixtures, respectively, flow properties, pycnometric density, mean particle size, specific surface area, moisture content, hygroscopicity, solubility, pH leaching, electrostatic charge, SEM images, and DSC. Tablets were made employing three pressure sets. Viscoelastic properties and ejection force were assessed during compression, as well as pycnometric density, mass uniformity, height, tensile strength, friability, disintegration, and wetting times. Avicel CE 15 is of mid-range flow properties, contains mid-size and nonspherical particles, and has high hygroscopicity, growing negative charge, best lubricity, lowest tensile strength, and mid-long disintegration times. Avicel DG possesses the worst flow properties, small asymmetrical particles, lowest hygroscopicity, stable charge, intermediate lubricity, and tensile strength and exhibits fast disintegration of tablets. Finally, Avicel HFE 102 has the best flow properties, large symmetrical particles, and middle hygroscopicity and its charge fluctuates throughout blending. It also exhibits inferior lubricity, the highest tensile strength, and slow disintegration of tablets. Generally, it is impossible to select the best CPE, as their different properties fit versatile needs of countless manufacturers and final products. PMID:29850496

Compression parameters of hexagonal boron nitride on direct compression mixture of microcrystalline cellulose and modified starch.

PubMed

Halaçoğlu, Mekin Doğa; Uğurlu, Timuçin

2015-01-01

The objective of this study was to investigate the effects of conventional lubricants including a new candidate lubricant "hexagonal boron nitride (HBN)" on direct compression powders. Lubricants such as magnesium stearate (MGST), glyceryl behenate, stearic acid, talc and polyethylene glycol6000 were studied and tablets were manufactured on a single station instrumented tablet press. This study comprised the continuation of our previous one, so mixture of microcrystalline cellulose and modified starch was used as a master formula to evaluate effects of lubricants on pharmaceutical excipients that undergo complete plastic deformation without any fragmentation under compression pressure. Bulk and tapped densities, and Carr's index parameters were calculated for powders. Tensile strength, cohesion index, lower punch ejection force and lubricant effectiveness values were investigated for tablets. The deformation mechanisms of tablets were studied during compression from the Heckel plots with or without lubricant. MGST was found to be the most effective lubricant and HBN was found very close to it. HBN did not show a significant negative effect on the crushing strength and disintegration time of the tablets when we compared with MGST. Based on the Heckel plots at the level of 1%, formulation prepared with HBN showed the most pronounced plastic character.

Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression.

PubMed

Ofori-Kwakye, Kwabena; Mfoafo, Kwadwo Amanor; Kipo, Samuel Lugrie; Kuntworbe, Noble; Boakye-Gyasi, Mariam El

2016-01-01

The study was aimed at developing extended release matrix tablets of poorly water-soluble diclofenac sodium and highly water-soluble metformin hydrochloride by direct compression using cashew gum, xanthan gum and hydroxypropylmethylcellulose (HPMC) as release retardants. The suitability of light grade cashew gum as a direct compression excipient was studied using the SeDeM Diagram Expert System. Thirteen tablet formulations of diclofenac sodium (∼100 mg) and metformin hydrochloride (∼200 mg) were prepared with varying amounts of cashew gum, xanthan gum and HPMC by direct compression. The flow properties of blended powders and the uniformity of weight, crushing strength, friability, swelling index and drug content of compressed tablets were determined. In vitro drug release studies of the matrix tablets were conducted in phosphate buffer (diclofenac: pH 7.4; metformin: pH 6.8) and the kinetics of drug release was determined by fitting the release data to five kinetic models. Cashew gum was found to be suitable for direct compression, having a good compressibility index (ICG) value of 5.173. The diclofenac and metformin matrix tablets produced generally possessed fairly good physical properties. Tablet swelling and drug release in aqueous medium were dependent on the type and amount of release retarding polymer and the solubility of drug used. Extended release of diclofenac (∼24 h) and metformin (∼8-12 h) from the matrix tablets in aqueous medium was achieved using various blends of the polymers. Drug release from diclofenac tablets fitted zero order, first order or Higuchi model while release from metformin tablets followed Higuchi or Hixson-Crowell model. The mechanism of release of the two drugs was mostly through Fickian diffusion and anomalous non-Fickian diffusion. The study has demonstrated the potential of blended hydrophilic polymers in the design and optimization of extended release matrix tablets for soluble and poorly soluble drugs by direct compression.

Spray-dried chitosan as a direct compression tableting excipient.

PubMed

Chinta, Dakshinamurthy Devanga; Graves, Richard A; Pamujula, Sarala; Praetorius, Natalie; Bostanian, Levon A; Mandal, Tarun K

2009-01-01

The objective of this study was to prepare and evaluate a novel spray-dried tableting excipient using a mixture of chitosan and lactose. Three different grades of chitosan (low-, medium-, and high-molecular-weight) were used for this study. Propranolol hydrochloride was used as a model drug. A specific amount of chitosan (1, 1.9, and 2.5 g, respectively) was dissolved in 50 mL of an aqueous solution of citric acid (1%) and later mixed with 50 mL of an aqueous solution containing lactose (20, 19.1, and 18.5 g, respectively) and propanolol (2.2 g). The resultant solution was sprayed through a laboratory spray drier at 1.4 mL/min. The granules were evaluated for bulk density, tap density, Carr index, particle size distribution, surface morphology, thermal properties, and tableting properties. Bulk density of the granules decreased from 0.16 to 0.13 g/mL when the granules were prepared using medium- or high-molecular-weight chitosan compared with the low-molecular-weight chitosan. The relative proportion of chitosan also showed a significant effect on the bulk density. The granules prepared with 1 g of low-molecular-weight chitosan showed the minimum Carr index (11.1%) indicating the best flow properties among all five formulations. All three granules prepared with 1 g chitosan, irrespective of their molecular weight, showed excellent flow properties. Floating tablets prepared by direct compression of these granules with sodium bicarbonate showed 50% drug release between 30 and 35 min. In conclusion, the spray-dried granules prepared with chitosan and lactose showed excellent flow properties and were suitable for tableting.

Roller compaction of different pseudopolymorphic forms of theophylline: Effect on compressibility and tablet properties.

PubMed

Hadzović, Ervina; Betz, Gabriele; Hadzidedić, Seherzada; El-Arini, Silvia Kocova; Leuenberger, Hans

2010-08-30

The effect of roller compaction on disintegration time, dissolution rate and compressibility of tablets prepared from theophylline anhydrate powder, theophylline anhydrate fine powder and theophylline monohydrate was studied. In addition, the influence of adding microcrystalline cellulose, a commonly used excipient, in mixtures with these materials was investigated. Theophylline anhydrate powder was used as a model drug to investigate the influence of different compaction pressures on the tablet properties. Tablets with same porosity were prepared by direct compaction and by roller compaction/re-compaction. Compressibility was characterized by Heckel and modified Heckel equations. Due to the property of polymorphic materials to change their form during milling and compression, X-ray diffraction analysis of theophylline anhydrate powder, theophylline anhydrate fine powder and theophylline monohydrate powders and granules was carried out. After roller compaction the disintegration time and the dissolution rate of the tablets were significantly improved. Compressibility of theophylline anhydrate powder and theophylline anhydrate fine powder was decreased, while theophylline monohydrate showed higher compressibility after roller compaction. Microcrystalline cellulose affected compressibility of theophylline anhydrate powder, theophylline anhydrate fine powder and theophylline monohydrate whereby the binary mixtures showed higher compressibility than the individual materials. X-ray diffraction analyses confirmed that there were no polymorphic/pseudopolymorphic changes after roller compaction. Copyright 2010 Elsevier B.V. All rights reserved.

[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.

Orodispersible tablets containing taste-masked solid lipid pellets with metformin hydrochloride: Influence of process parameters on tablet properties.

PubMed

Petrovick, Gustavo Freire; Kleinebudde, Peter; Breitkreutz, Jörg

2018-01-01

Compaction of multiparticulates into tablets, particularly into orodispersible tablets (ODTs), is challenging. The compression of pellets, made by solid lipid extrusion/spheronization processes, presents peculiar difficulties since solid lipids usually soften or melt at relatively low temperature ranges and due to applied mechanical forces. Until now, there are no reports in literature about the development of ODTs based on solid lipid pellets. To investigate the feasibility of producing such tablets, a design of experiment (DoE) approach was performed to elucidate the influence of compression force and amount of two co-processed excipients (Ludiflash ® and Parteck ® ODT) on properties of the tablets (friability, tensile strength, and disintegration time). ODTs (15 mm, flat-faced) with solid lipid pellets (250-1000 µm in diameter) containing 500 mg of metformin HCl, presenting immediate drug release profile and taste-masked properties, were targeted. During compression, a strong lamination of the tablets containing Parteck ® ODT was observed. This phenomenon was prominently observed when high compression forces (≥5 kN) and high excipient amounts (≥40%; w/w) were used. On the other hand, the DoE focused on tablets with Ludiflash ® showed better results regarding the production of ODTs. A positive influence of the compression force on the tensile strength and disintegration time of the tablets, regarding specifications of the Ph. Eur., was observed. The increase in the amount of this excipient resulted in fast disintegrating tablets, however, a negative influence on the tensile strength was noticed. After optimization of the parameters and formulation, based on the DoE results and considering the Ph. Eur. specifications for tablets, ODTs based on lipid pellets containing metformin HCl presenting immediate release profile (85% drug release in less than 30 min) and taste-masked properties (determined by an electronic tongue) were successfully obtained. Copyright © 2017 Elsevier B.V. All rights reserved.

Dissolution enhancement of chlorzoxazone using cogrinding technique

PubMed Central

Raval, Mihir K.; Patel, Jaydeep M.; Parikh, Rajesh K.; Sheth, Navin R.

2015-01-01

Purpose: The aim of the present work was to improve rate of dissolution and processing parameters of BCS class II drug, chlorzoxazone using cogrinding technique in the presence of different excipients as a carrier. Materials and Methods: The drug was coground with various carriers like polyethylene glycol (PEG 4000), hydroxypropyl methylcellulose (HPMC) E50LV, polyvinylpyrrolidone (PVP)K30, Kaolin and Neusilin US2 using ball mill, where only PEG 4000 improved dissolution rate of drug by bringing amorphization in 1:3 ratio. The coground mixture after 3 and 6 h was evaluated for various analytical, physicochemical and mechanical parameters. Results: The analysis showed conversion of Chlorzoxazone from its crystalline to amorphization form upon grinding with PEG 4000. Coground mixture as well as its directly compressed tablet showed 2.5-fold increment in the dissolution rate compared with pure drug. Directly compressible tablets prepared from pure drug required a large quantity of microcrystalline cellulose (MCC) during compression. The coground mixture and formulation was found stable in nature even after storage (40°C/75% relative humidity). Conclusions: Cogrinding can be successfully utilized to improve the rate of dissolution of poorly water soluble drugs and hence bioavailability. PMID:26682195

Preliminary studies of the development of a direct compression cellulose excipient from bagasse.

PubMed

Padmadisastra, Y; Gonda, I

1989-06-01

Bagasse is an unused by-product in cane sugar manufacture. Bagasse from sugar cane manually harvested in Indonesia was transformed to pulp by mechanical means and repeated autoclaving in 1.4% NaOH. It was then subjected to cycles of bleaching with hypochlorite and acid hydrolysis with 2.5 M HCl to produce 'microcrystalline' cellulose (MCC). Extraction of waxes by petroleum ether was necessary in order to improve the disintegration properties of tablets made from this material, DICEB III. When the bagasse-derived cellulose was reconstituted by recombining different proportions of selected sieve cuts to have a similar sieve size distribution as the commercially available MCC, Avicel PH102, it was found that the latter and DICEB III also had similar crystallinity as measured by X-ray powder diffraction (degree of crystallinity 2.8 +/- 0.2). The crystallinity and flow index were also relatively insensitive to most of the changes in the manufacturing procedure, indicating that the production process was quite robust. Directly compressed tablets were made containing 50 mg of caffeine and 500 mg of either Avicel PH102 or DICEB III to approximately the same hardness (11.6 +/- 1.1 and 13.7 +/- 0.5 kPa, respectively). They displayed similar satisfactory disintegration and dissolution behavior. However, DICEB III required greater compaction pressures than Avicel PH102, perhaps because the former was not spray dried to give spherical agglomerates of particles of uniform size as the commercial product. Rather, DICEB III consisted mainly of single irregular particles. Further work is required to improve the new excipient and to explore if the bagasse from mechanically harvested sugar cane (often contaminated by soil) could also be used for production of MCC.

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

Downstream processing of a ternary amorphous solid dispersion: The impacts of spray drying and hot melt extrusion on powder flow, compression and dissolution.

PubMed

Davis, Mark T; Potter, Catherine B; Walker, Gavin M

2018-06-10

Downstream processing aspects of a stable form of amorphous itraconazole exhibiting enhanced dissolution properties were studied. Preparation of this ternary amorphous solid dispersion by either spray drying or hot melt extrusion led to significantly different powder processing properties. Particle size and morphology was analysed using scanning electron microscopy. Flow, compression, blending and dissolution were studied using rheometry, compaction simulation and a dissolution kit. The spray dried material exhibited poorer flow and reduced sensitivity to aeration relative to the milled extrudate. Good agreement was observed between differing forms of flow measurement, such as Flow Function, Relative flow function, Flow rate index, Aeration rate, the Hausner ratio and the Carr index. The stability index indicated that both powders were stable with respect to agglomeration, de-agglomeration and attrition. Tablet ability and compressibility studies showed that spray dried material could be compressed into stronger compacts than extruded material. Blending of the powders with low moisture, freely-flowing excipients was shown to influence both flow and compression. Porosity studies revealed that blending could influence the mechanism of densification in extrudate and blended extrudate formulations. Following blending, the powders were compressed into four 500 mg tablets, each containing a 100 mg dose of amorphous itraconazole. Dissolution studies revealed that the spray dried material released drug faster and more completely and that blending excipients could further influence the dissolution rate. Copyright © 2018 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.

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.

A systematic and mechanistic evaluation of aspartic acid as filler for directly compressed tablets containing trimethoprim and trimethoprim aspartate.

PubMed

ElShaer, Amr; Hanson, Peter; Mohammed, Afzal R

2013-04-01

The generally accepted paradigm of 'inert' and 'mono functional' excipient in dosage form has been recently challenged with the development of individual excipients capable of exhibiting multiple functions (e.g. binder-disintegrants, surfactant which affect P-gp function). The proposed study has been designed within the realm of multifunctionality and is the first and novel investigation towards evaluation of aspartic acid as a filler and disintegration enhancing agent for the delivery of biopharmaceutical class IV model drug trimethoprim. The study investigated powder characteristics using angle of repose, laser diffractometry and scanning electron microscopy (SEM). The prepared tablets were characterised using Heckel analysis, disintegration time and tensile strength measurements. Although Heckel analysis revealed that both TMP and TMP aspartate salt have high elasticity, the salt form produced a stronger compact which was attributed to the formation of agglomerates. Aspartic acid was found to have high plasticity, but its incorporation into the formulations was found to have a negative impact on the compaction properties of TMP and its salt. Surface morphology investigations showed that mechanical interlocking plays a vital role in binding TMP crystals together during compaction, while the small particle size of TMP aspartate agglomerates was found to have significant impact on the tensile strength of the tablets. The study concluded that aspartic acid can be employed as filler and disintegrant and that compactability within tablets was independent of the surface charge of the excipients. Copyright © 2012 Elsevier B.V. All rights reserved.

Formulation Development of Spherical Crystal Agglomerates of Itraconazole for Preparation of Directly Compressible Tablets with Enhanced Bioavailability.

PubMed

Fadke, Janki; Desai, Jagruti; Thakkar, Hetal

2015-12-01

The objective of the present work was to formulate tablet dosage form of itraconazole with enhanced bioavailability. Spherical crystal agglomerates (SCA) of itraconazole prepared by quasi emulsification solvent diffusion method using Soluplus and polyethylene glycol 4000 (PEG 4000) showed increased solubility (540 μg/ml) in 0.1 N hydrochloric acid as compared to pure drug (12 μg/ml). A Fourier transform infrared (FTIR) study indicated compatibility of drug with the excipients. The developed SCA were spherical with smooth surface having an average size of 412 μm. The significantly improved micromeritic properties compared to the plain drug suggested its suitability for direct compression. The antifungal activity of itraconazole was retained in the SCA form as evidenced from the results of the disc diffusion method. The optimized SCA formulation could be easily compressed into tablet with desirable characteristics of hardness (5 kg/cm(2)) and disintegration time (6.3 min). The in vitro dissolution studies showed significant difference in the dissolution profiles of pure drug (21%) and SCA formulation (85%) which was even greater than that of marketed preparation (75%). In vivo pharmacokinetic showed significant enhancement in C max and AUC0-t with relative bioavailability of 225%. The SCA formulation seems to be promising for enhancement of oral bioavailability of itraconazole.

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.

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.

Isolation, characterization and investigation of Cordia dichotoma fruit polysaccharide as a herbal excipient.

PubMed

Pawar, Harshal Ashok; Jadhav, Pravin

2015-01-01

The objective of the present research work was to isolate, purify and characterize Cordia dichotoma gum and investigate its disintegration property in oral tablets. The isolated gum was tested for physicochemical characteristics such as solubility, pH (1% w/w in water), swelling index, loss on drying, ash value, bulk and tapped density, Carr's index, Hausner's ratio and angle of repose. The Orodispersible tablets of valsartan were prepared by direct compression method and evaluated for average weight (mg), drug content (%), thickness (mm), hardness (kg/cm(2)), friability (%), wetting time (sec), water absorption ratio (%) and disintegration time (sec). FTIR studies revealed that there was no interaction between drug, gum and other excipients used in the study. The F4 batch with disintegration time 26.34 ± 0.78 s and in vitro release 99.64 ± 0.43% was selected as optimized formulation. This formulation was compared with conventional marketed formulation and was found superior. Batch F4 was subjected to stability studies for three months and was tested for its disintegration time, drug contents and dissolution behaviour. Batch F4 was found stable for three months at accelerated temperature. Copyright © 2014 Elsevier B.V. All rights reserved.

Impact of excipient interactions on solid dosage form stability.

PubMed

Narang, Ajit S; Desai, Divyakant; Badawy, Sherif

2012-10-01

Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.

Chitinosans as tableting excipients for modified release delivery systems.

PubMed

Rege, P R; Shukla, D J; Block, L H

1999-04-20

The term 'chitinosans' embraces the spectrum of acetylated poly(N-glucosamines) ranging from chitin to chitosan. Chitinosans (I), at acidic pH, have protonated amines which can interact with oppositely charged drug ions and, thereby, modify drug release from drug delivery systems. Tablets were compressed from a physical mixture containing salicylic acid (II) as the model drug, I, and magnesium stearate. Five commercial I compounds, varying in degree of deacetylation and molecular weight, were selected. Tablets were compressed at 5000, 10 000, and 15 000 psig using a Carver and a single punch tablet press. The differential scanning calorimetry thermograms provided evidence of I-II interaction in the powder blend. Analysis of variance (ANOVA) indicated that the compression pressure did not significantly affect the crushing strength (CS) or the release profile of II from the I-matrix tablets (P?0.05). Furthermore, the ANOVA also indicated that the tablet press used during manufacture did not affect the above properties (P?0.05); however, the chitinosans significantly affected the CS as well as the release profile of II from I-matrix tablets (P<0.05). This study provides further evidence for the use of commercial I compounds as excipients for use in modified release drug delivery systems. Copyright.

Eudragit E as excipient for production of granules and tablets from Phyllanthus niruri L spray-dried extract.

PubMed

Pereira de Souza, Tatiane; Martínez-Pacheco, Ramón; Gómez-Amoza, José Luiz; Petrovick, Pedro Ros

2007-04-27

The aim of this study was to investigate the feasibility of using Eudragit E as a granulating agent for a spray-dried extract from Phyllanthus niruri to obtain tablets containing a high dose of this product. The granules were developed by wet granulation and contained 2.5%, 5.0%, and 10.0% Eudragit E in the final product concentration. The tablets were produced on a single-punch tablet press by direct compression of granules using 0.5% magnesium stearate as a lubricant. The tablets were elaborated following a 2 x 3 factorial design, where Eudragit E concentration and compression force were the independent variables, and tensile strength and the extract release of the tablets were the dependent variables. All granules showed better technological properties than the spray-dried extract, including less moisture sorption. The characteristics of the granules were directly dependent on the proportion of Eudragit E in the formulation. In general, all tablets showed high mechanical resistance with less than 1% friability, less moisture sorption, and a slower extract release profile. The Eudragit E concentration and compression force of the tablets significantly influenced both dependent variables studied. In conclusion, Eudragit E was efficient as a granulating agent for the spray-dried extract, but additional studies are needed to further optimize the formulations in order to achieve less water sorption and improve the release of the extract from the tablets.

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.

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.

Ultrasound transmission measurements for tensile strength evaluation of tablets.

PubMed

Simonaho, Simo-Pekka; Takala, T Aleksi; Kuosmanen, Marko; Ketolainen, Jarkko

2011-05-16

Ultrasound transmission measurements were performed to evaluate the tensile strength of tablets. Tablets consisting of one ingredient were compressed from dibasic calcium phosphate dehydrate, two grades of microcrystalline cellulose and two grades of lactose monohydrate powders. From each powder, tablets with five different tensile strengths were directly compressed. Ultrasound transmission measurements were conducted on every tablet at frequencies of 2.25 MHz, 5 MHz and 10 MHz and the speed of sound was calculated from the acquired waveforms. The tensile strength of the tablets was determined using a diametrical mechanical testing machine and compared to the calculated speed of sound values. It was found that the speed of sound increased with the tensile strength for the tested excipients. There was a good correlation between the speed of sound and tensile strength. Moreover, based on the statistical tests, the groups with different tensile strengths can be differentiated from each other by measuring the speed of sound. Thus, the ultrasound transmission measurement technique is a potentially useful method for non-destructive and fast evaluation of the tensile strength of tablets. Copyright © 2011 Elsevier B.V. All rights reserved.

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

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.

A Holistic Multi Evidence Approach to Study the Fragmentation Behaviour of Crystalline Mannitol

PubMed Central

Koner, Jasdip S.; Rajabi-Siahboomi, Ali; Bowen, James; Perrie, Yvonne; Kirby, Daniel; Mohammed, Afzal R.

2015-01-01

Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties. PMID:26553127

A Holistic Multi Evidence Approach to Study the Fragmentation Behaviour of Crystalline Mannitol

NASA Astrophysics Data System (ADS)

Koner, Jasdip S.; Rajabi-Siahboomi, Ali; Bowen, James; Perrie, Yvonne; Kirby, Daniel; Mohammed, Afzal R.

2015-11-01

Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties.

Development of Orodispersible Tablets of Candesartan Cilexetil-β-cyclodextrin Complex

PubMed Central

Sravya, Maddukuri; Deveswaran, Rajamanickam; Bharath, Srinivasan; Basavaraj, Basappa Veerbadraiah; Madhavan, Varadharajan

2013-01-01

The aim of this study was to investigate the use of inclusion complexation technique employing β-cyclodextrin in improving the dissolution profile of candesartan cilexetil, a BCS class-II drug, and to formulate the inclusion complex into orodispersible tablets. The inclusion complexes were formed by physical mixing, kneading, coevaporation, and lyophilisation methods. Inclusion complexes were characterized by FTIR, DSC, XRD, NMR, and mass spectral studies. Inclusion complexes prepared using kneading, and lyophilisation techniques in the molar ratio 1 : 5 with β-cyclodextrin were used for formulating orodispersible tablets by direct compression with different superdisintegrants like croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose in varying concentrations. The directly compressible powder was evaluated for precompression parameters, and the prepared orodispersible tablets were evaluated for postcompression parameters. Drug-excipient compatibility studies showed no interaction, and characterization proved the formation of inclusion complex. In vitro disintegration time was found to be within 3 minutes, and all the formulations showed complete drug release of 100% within 20 minutes. The optimized formulation was found to be stable after 6 months and showed no significant change in drug content. This work proved β-cyclodextrins to be effective solubilizing agent in improving the solubility of poorly water soluble drugs. PMID:26555987

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.

[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 Effect of Formulation Excipients and Thermal Treatment on the Release Properties of Lisinopril Spheres and Tablets.

PubMed

Amador Ríos, Zoriely; Ghaly, Evone Shehata

2015-01-01

Multiparticulate systems are used in the development of controlled release systems. The objective of this study was to determine the effect of the wax level, the type of excipient, and the exposure of the tablets to thermal treatment on drug release. Spheres from multiparticulate system with different wax levels and excipients were developed using the drug Lisinopril and compressed into tablets; these tablets were analyzed to determine the drug release. All tablets contained constant level of Lisinopril (10% w/w) and Compritol (30% and 50% w/w). Also, as a diluent, all of them contained 30% w/w Avicel and 30% w/w dibasic calcium phosphate or lactose, or 60% Avicel. Tablets compacted from spheres prepared by extruder/marumerizer and using 30% w/w lipid and 60% Avicel released 84% of drug at six hours of dissolution testing, while tablets of the same composition but prepared using 30% dibasic calcium phosphate and 30% Avicel released 101%. When the tablets were thermally treated, the drug release reduced. As the percent of lipid increased in the formulation, the drug release decreased. Compaction of tablets prepared from spheres with wax has potential for controlling the drug release.

Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs.

PubMed

Serajuddin, A T

1999-10-01

Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations were difficult to scale up for the manufacture of dosage forms. The situation has, however, been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts. Solid plugs are formed inside the capsules when the melts are cooled to room temperature. Because of surface activity of carriers used, complete dissolution of drug from such solid dispersions can be obtained without the need for pulverization, sieving, mixing with excipients, etc. Equipment is available for large-scale manufacturing of such capsules. Some practical limitations of dosage form development might be the inadequate solubility of drugs in carriers and the instability of drugs and carriers at elevated temperatures necessary to manufacture capsules.

New insights on poly(vinyl acetate)-based coated floating tablets: characterisation of hydration and CO2 generation by benchtop MRI and its relation to drug release and floating strength.

PubMed

Strübing, Sandra; Abboud, Tâmara; Contri, Renata Vidor; Metz, Hendrik; Mäder, Karsten

2008-06-01

The purpose of this study was to investigate the mechanism of floating and drug release behaviour of poly(vinyl acetate)-based floating tablets with membrane controlled drug delivery. Propranolol HCl containing tablets with Kollidon SR as an excipient for direct compression and different Kollicoat SR 30 D/Kollicoat IR coats varying from 10 to 20mg polymer/cm2 were investigated regarding drug release in 0.1N HCl. Furthermore, the onset of floating, the floating duration and the floating strength of the device were determined. In addition, benchtop MRI studies of selected samples were performed. Coated tablets with 10mg polymer/cm2 SR/IR, 8.5:1.5 coat exhibited the shortest lag times prior to drug release and floating onset, the fastest increase in and highest maximum values of floating strength. The drug release was delayed efficiently within a time interval of 24 h by showing linear drug release characteristics. Poly(vinyl acetate) proved to be an appropriate excipient to ensure safe and reliable drug release. Floating strength measurements offered the possibility to quantify the floating ability of the developed systems and thus to compare different formulations more efficiently. Benchtop MRI studies allowed a deeper insight into drug release and floating mechanisms noninvasively and continuously.

Evaluation of several microcrystalline celluloses obtained from agricultural by-products

PubMed Central

Rojas, John; Lopez, Alvin; Guisao, Santiago; Ortiz, Carlos

2011-01-01

Microcrystalline cellulose (MCCI) has been widely used as an excipient for direct compression due to its good flowability, compressibility, and compactibility. In this study, MCCI was obtained from agricultural by-products, such as corn cob, sugar cane bagasse, rice husk, and cotton by pursuing acid hydrolysis, neutralization, clarification, and drying steps. Further, infrared spectroscopy (IR), X-ray diffraction (XRD), optical microscopy, degree of polymerization (DP), and powder and tableting properties were evaluated and compared to those of Avicel PH101, Avicel PH102, and Avicel PH200. Except for the commercial products, all materials showed a DP from 55 to 97. Particles of commercial products and corn cob had an irregular shape, whereas bagasse particles were elongated and thick. Rice and cotton particles exhibited a flake-like and fiber-like shape, respectively. MCCI as obtained from rice husk and cotton was the most densified material, while that produced from corn cob and bagasse was bulky, porous, and more compressible. All products had a moisture content of less than 10% and yields from 7.4% to 60.4%. MCCI as obtained from bagasse was the most porous and compressible material among all materials. This product also showed the best tableting properties along with Avicel products. Likewise, all MCCI products obtained from the above-mentioned sources showed a more rapid disintegration time than that of Avicel products. These materials can be used as a potential source of MCCI in the production of solid dosage forms. PMID:22171310

A Robust Static Headspace GC-FID Method to Detect and Quantify Formaldehyde Impurity in Pharmaceutical Excipients

PubMed Central

Al-Khayat, Mohammad Ammar; Karabet, Francois; Al-Mardini, Mohammad Amer

2018-01-01

Formaldehyde is a highly reactive impurity that can be found in many pharmaceutical excipients. Trace levels of this impurity may affect drug product stability, safety, efficacy, and performance. A static headspace gas chromatographic method was developed and validated to determine formaldehyde in pharmaceutical excipients after an effective derivatization procedure using acidified ethanol. Diethoxymethane, the derivative of formaldehyde, was then directly analyzed by GC-FID. Despite the simplicity of the developed method, however, it is characterized by its specificity, accuracy, and precision. The limits of detection and quantification of formaldehyde in the samples were of 2.44 and 8.12 µg/g, respectively. This method is characterized by using simple and economic GC-FID technique instead of MS detection, and it is successfully used to analyze formaldehyde in commonly used pharmaceutical excipients. PMID:29686930

A material-sparing method for assessment of powder deformation characteristics using data collected during a single compression-decompression cycle.

PubMed

Katz, Jeffrey M; Roopwani, Rahul; Buckner, Ira S

2013-10-01

Compressibility profiles, or functions of solid fraction versus applied pressure, are used to provide insight into the fundamental mechanical behavior of powders during compaction. These functions, collected during compression (in-die) or post ejection (out-of-die), indicate the amount of pressure that a given powder formulation requires to be compressed to a given density or thickness. To take advantage of the benefits offered by both methods, the data collected in-die during a single compression-decompression cycle will be used to generate the equivalent of a complete out-of-die compressibility profile that has been corrected for both elastic and viscoelastic recovery of the powder. This method has been found to be both a precise and accurate means of evaluating out-of-die compressibility for four common tableting excipients. Using this method, a comprehensive characterization of powder compaction behavior, specifically in relation to plastic/brittle, elastic and viscoelastic deformation, can be obtained. Not only is the method computationally simple, but it is also material-sparing. The ability to characterize powder compressibility using this approach can improve productivity and streamline tablet development studies. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

High-amylose sodium carboxymethyl starch matrices for oral, sustained drug-release: formulation aspects and in vitro drug-release evaluation.

PubMed

Brouillet, F; Bataille, B; Cartilier, L

2008-05-22

High-amylose sodium carboxymethyl starch (HASCA), produced by spray-drying (SD), was previously shown to have interesting properties as a promising pharmaceutical sustained drug-release tablet excipient for direct compression, including ease of manufacture and high crushing strength. This study describes the effects of some important formulation parameters, such as compression force (CF), tablet weight (TW), drug-loading and electrolyte particle size, on acetaminophen-release performances from sustained drug-release matrix tablets based on HASCA. An interesting linear relationship between TW and release time was observed for a typical formulation of the system consisting of 40% (w/w) acetaminophen as model drug and 27.5% NaCl as model electrolyte dry-mixed with HASCA. Application of the Peppas and Sahlin model gave a better understanding of the mechanisms involved in drug-release from the HASCA matrix system, which is mainly controlled by surface gel layer formation. Indeed, augmenting TW increased the contribution of the diffusion mechanism. CFs ranging from 1 to 2.5 tonnes/cm(2) had no significant influence on the release properties of tablets weighing 400 or 600 mg. NaCl particle size did not affect the acetaminophen-release profile. Finally, these results prove that the new SD process developed for HASCA manufacture is suitable for obtaining similar-quality HASCA in terms of release and compression performances.

Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.

PubMed

Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N

2015-06-01

Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.

Isolation, characterization and investigation of Plantago ovata husk polysaccharide as superdisintegrant.

PubMed

Pawar, Harshal; Varkhade, Chhaya

2014-08-01

Psyllium husk (Plantago ovata, Family: Plantaginaceae) contains a high proportion of hemicellulose, composed of a xylan backbone linked with arabinose, rhamnose, and galacturonic acid units (arabinoxylans). Polysaccharide was isolated from Psyllium husk using solvent precipitation method. The isolated polysaccharide was evaluated for various physicochemical parameters. The rheological behavior of polysaccharide (1% w/v in water) was studied using Brookfield viscometer. Polysaccharide derived from the husk of P. ovata was investigated as superdisintegrant in the fast dissolving tablets. Valsartan, an antihypertensive drug, was selected as a model drug. The tablets of Valsartan were prepared separately using different concentrations (1, 2.5, 5, 7.5% w/w) of isolated Plantago ovata (P. ovata) husk polysaccharide (Natural) and crospovidone as a synthetic superdisintegrant by direct compression method. The prepared tablets were evaluated for various pre-compression and post-compression parameters. The drug excipient interactions were characterized by FTIR studies. The formulation F4 containing7.5% polysaccharide showed rapid wetting time and disintegration time as compared to formulation prepared using synthetic superdisintegrant at the same concentration level. Hence batch F4 was considered as optimized formulation. The stability studies were performed on formulation F4. The disintegration time and in vitro drug release of the optimized formulation was compared with the marketed formulation (Conventional tablets). Copyright © 2014 Elsevier B.V. All rights reserved.

Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant.

PubMed

Leane, Michael M; Sinclair, Wayne; Qian, Feng; Haddadin, Raja; Brown, Alan; Tobyn, Mike; Dennis, Andrew B

2013-01-01

Amorphous forms of poorly soluble drugs are more frequently being incorporated into solid dispersions for administration and extensive research has led to a reasonable understanding of how these dispersions, although still kinetically unstable, improve stability relative to the pure amorphous form. There remains however a paucity of literature describing the effects on such solid dispersions of subsequent processing into solid dosage forms such as tablets. This paper addresses this area by looking at the effects of the addition of common excipients and different manufacturing routes on the stability of a spray-dried dispersion (SDD) of the cannabinoid CB-1 antagonist, ibipinabant. A marked difference in physical stability of tablets was seen with the different fillers with microcrystalline cellulose (MCC) giving the best stability profile. It was found that minimising the number of compression steps led to improved formulation stability with a direct compression process giving the best results. Increased levels of crystallinity were seen in coated tablets most likely due to the exposure of the amorphous matrix to moisture and heat during the coating process. DSIMS analysis of the SDD particles indicated increased levels of polymer on the surface.

Application of instrumental evaluation of color for the pre-formulation and formulation of rabeprazole.

PubMed

Rhee, Yun-Seok; Park, Chun-Woong; Shin, Yoon-Sub; Kam, Sung-Hoon; Lee, Kyu-Hyun; Park, Eun-Seok

2008-02-28

The aims of this study were to fast screen the compatibility of rabeprazole and excipients using a spectrocolorimeter and to examine the relationship between the color change value and drug contents/drug degradation products in solid dosage forms. The color change values of rabeprazole-excipient mixtures were measured using a spectrocolorimeter, with six tablet formulations compressed using a single-punch instrumental tablet press. The rabeprazole and degradation products contents in the tablets were analyzed using an HPLC method, with the color change values of the tablets measured using spectrocolorimetery for 4 weeks. These experiments indicated that the instrumental evaluation of color was a speedy, simple and useful tool in the determination of the interaction between the drug and excipients, as well as in the formulation of solid dosage forms. The relationships of the % reduced drug contents versus the color change value, and those of the % drug degradation products versus the color change value were exponentially increased in formulations containing zinc stearate. On stress testing, the color change value of rabeprazole was inconsistent with previous reports, as the degradation of rabeprazole can be greatly influenced by humidity as well as temperature. Consequently, these results highlight the potential of color formation in the application of pre-formulation and formulation of drugs.

Impacts of compression on crystallization behavior of freeze-dried amorphous sucrose.

PubMed

Imamura, Koreyoshi; Nomura, Mayo; Tanaka, Kazuhiro; Kataoka, Nobuhide; Oshitani, Jun; Imanaka, Hiroyuki; Nakanishi, Kazuhiro

2010-03-01

An amorphous matrix comprised of sugar molecules is used as excipient and stabilizing agent for labile ingredients in the pharmaceutical industry. The amorphous sugar matrix is often compressed into a tablet form to reduce the volume and improve handling. Herein, the effect of compression on the crystallization behavior of an amorphous sucrose matrix was investigated. Amorphous sucrose samples were prepared by freeze-drying and compressed under different conditions, followed by analyses by differential scanning calorimetry, isothermal crystallization tests, X-ray powder diffractometry, Fourier transform infrared spectroscopy (FTIR), and gas pycnometry. The compressed sample had a lower crystallization temperature and a shorter induction period for isothermal crystallization, indicating that compression facilitates the formation of the critical nucleus of a sucrose crystal. Based on FTIR and molecular dynamics simulation results, the conformational distortion of sucrose molecules due to the compression appears to contribute to the increase in the free energy of the system, which leads to the facilitation of critical nucleus formation. An isothermal crystallization test indicated an increase in the growth rate of sucrose crystals by the compression. This can be attributed to the transformation of the microstructure from porous to nonporous, as the result of compression. 2009 Wiley-Liss, Inc. and the American Pharmacists Association

Development and in vitro evaluation of carboxymethyl chitosan based drug delivery system for the controlled release of propranolol hydrochloride

NASA Astrophysics Data System (ADS)

Hernawan; Nur Hayati, Septi; Nisa, Khoirun; Wheni Indrianingsih, Anastasia; Darsih, Cici; Kismurtono, Muhammad

2017-12-01

Propranolol hydrochloride is a nonselective β-adrenergic drug and has been used as angina pectoris, antihypertensive, and that of many other cardiovascular disorders. It has a relatively short plasma half-life and duration of action are considered too short in certain circumstances. Thus, it’s fascinating to elongate the action. The tablet formula was based on extended-release by a propranolol hydrochloride based carboxymethyl chitosan matrix. Here we used direct compression technique with internal wet granulation to prepare the tablets. The tablets were evaluated for physical properties (hardness, weight variation test, friability) and in vitro release studies. There was no interaction observed between propranolol hydrochloride and excipients. Dissolution profiles of each formulation were followed zero order model. In conclusion, these results strongly suggest that in appropriate proportions carboxymethyl chitosan with internal granulation is suitable for formulating propranolol hydrochloride controlled release.

Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator.

PubMed

Alsulays, Bader B; Fayed, Mohamed H; Alalaiwe, Ahmed; Alshahrani, Saad M; Alshetaili, Abdullah S; Alshehri, Sultan M; Alanazi, Fars K

2018-05-16

The objective of this study was to examine the influence of drug amount and mixing time on the homogeneity and content uniformity of a low-dose drug formulation during the dry mixing step using a new gentle-wing high-shear mixer. Moreover, the study investigated the influence of drug incorporation mode on the content uniformity of tablets manufactured by different methods. Albuterol sulfate was selected as a model drug and was blended with the other excipients at two different levels, 1% w/w and 5% w/w at impeller speed of 300 rpm and chopper speed of 3000 rpm for 30 min. Utilizing a 1 ml unit side-sampling thief probe, triplicate samples were taken from nine different positions in the mixer bowl at selected time points. Two methods were used for manufacturing of tablets, direct compression and wet granulation. The produced tablets were sampled at the beginning, middle, and end of the compression cycle. An analysis of variance analysis indicated the significant effect (p < .05) of drug amount on the content uniformity of the powder blend and the corresponding tablets. For 1% w/w and 5% w/w formulations, incorporation of the drug in the granulating fluid provided tablets with excellent content uniformity and very low relative standard deviation (∼0.61%) during the whole tableting cycle compared to direct compression and granulation method with dry incorporation mode of the drug. Overall, gentle-wing mixer is a good candidate for mixing of low-dose cohesive drug and provides tablets with acceptable content uniformity with no need for pre-blending step.

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.

Sustained release of diltiazem HCl tableted after co-spray drying and physical mixing with PVAc and PVP.

PubMed

Al-Zoubi, Nizar; Al-Obaidi, Ghada; Tashtoush, Bassam; Malamataris, Stavros

2016-01-01

In this work, aqueous diltiazem HCl and polyvinyl-pyrrolidone (PVP) solutions were mixed with Kollicoat SR 30D and spray dried to microparticles of different drug:excipient ratio and PVP content. Co-spray dried products and physical mixtures of drug, Kollidon SR and PVP were tableted. Spray drying process, co-spray dried products and compressibility/compactability of co-spray dried and physical mixtures, as well as drug release and water uptake of matrix-tablets was evaluated. Simple power equation fitted drug release and water uptake (R(2) > 0.909 and 0.938, respectively) and correlations between them were examined. Co-spray dried products with PVP content lower than in physical mixtures result in slower release, while at equal PVP content (19 and 29% w/w of excipient) in similar release (f2 > 50). Increase of PVP content increases release rate and co-spray drying might be an alternative, when physical mixing is inadequate. Co-spray dried products show better compressibility/compatibility but higher stickiness to the die-wall compared to physical mixtures. SEM observations and comparison of release and swelling showed that distribution of tableted component affects only the swelling, while PVP content for both co-spray dried and physical mixes is major reason for release alterations and an aid for drug release control.

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.

Development of gastro-resistant tablets for the protection and intestinal delivery of Lactobacillus fermentum CECT 5716.

PubMed

Villena, María José Martín; Lara-Villoslada, Ferderico; Martínez, María Adolfina Ruiz; Hernández, María Encarnación Morales

2015-06-20

Different studies have attributed health benefits to Lactobacillus fermentum CECT 5716. However, the main problem associated with probiotics, is their low resistance to environmental and technological factors. Actually, probiotics are marketed as capsules or sachets, but few probiotic tablets exist. The aim of this study was to design tablets made out of functional polymers (formula 1: methocel K-15-sodium alginate; formula 2: Eudragit(®) L-100-sodium alginate; formula 3: cellulose acetate phthalate) that improve the stability and survival of probiotics. Rigid tablets were produced through direct compression with a bacterial content of 10(9)CFU/tablet (9logCFU). Tablets were shown to improve the survival of cells when exposed to an acidic medium as compared to free cells. Eudragit(®) L-100-sodium alginate was found to be the most suitable excipient for the protection of probiotic within gastric conditions, resulting in the survival of 10(9)CFU (9logCFU) after 2h of incubation. Finally, these tablets were found to be stable over 6 months when stored at 4°C. No significant differences were reported between the number of cells at time cero and after 6 months of storage at 4°C (p>0.05). In conclusion, direct compression using Eudragit(®) L-100-sodium alginate seems to be a suitable to produce probiotics tablets and could confer protection during passage trough stomach and storage. Copyright © 2015 Elsevier B.V. All rights reserved.

A comparison between two powder compaction parameters of plasticity: the effective medium A parameter and the Heckel 1/K parameter.

PubMed

Mahmoodi, Foad; Klevan, Ingvild; Nordström, Josefina; Alderborn, Göran; Frenning, Göran

2013-09-10

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data. Copyright © 2013 Elsevier B.V. All rights reserved.

Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations.

PubMed

Chakravarty, Paroma; Kothari, Sanjeev; Deese, Alan; Lubach, Joseph W

2015-07-06

The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 °C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ∼70% RH (25 °C). Our results highlight the outcome of inadvertent drug-excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development.

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

Torsemide Fast Dissolving Tablets: Development, Optimization Using Box-Bhenken Design and Response Surface Methodology, In Vitro Characterization, and Pharmacokinetic Assessment.

PubMed

El-Shenawy, Ahmed A; Ahmed, Mahmoud M; Mansour, Heba F; Abd El Rasoul, Saleh

2017-08-01

The present study planed to develop new fast dissolving tablets (FDTs) of torsemide. Solid dispersions (SDs) of torsemide and sorbitol (3:1) or polyvinylpyrrolidone (PVP) k25 were prepared. The prepared SDs were evaluated for in-vitro dissolution. Fourier transform infrared spectroscopy and differential scanning calorimetry for SDs revealed no drug/excipient interactions and transformation of torsemide to the amorphous form. Torsemide/sorbitol SD was selected for formulation of torsemide FDTs by direct compression method. Box-Bhenken factorial design was employed to design 15 formulations using croscarmellose sodium and crospovidone at different concentrations. The response surface methodology was used to analyze the effect of changing these concentrations (independent variables) on disintegration time (Y 1 ), percentage friability (Y 2 ), and amount torsemide released at 10 min. The physical mixtures of torsemide and the used excipients were evaluated for angle of repose, Hausner's ratio, and Carr's index. The prepared FDTs tablets were evaluated for wetting and disintegration time, weight variation, drug content, percentage friability, thickness, hardness, and in vitro release. Based on the in-vitro results and factorial design characterization, F10 and F7 were selected for bioavailability studies following administration to Albino New Zealand rabbits. They showed significantly higher C max and (AUC 0-12 ) and shorter T max than those obtained after administration of the corresponding ordinary commercial Torseretic ® tablets. Stability study was conducted for F10 that showed good stability upon storage at 30°C/75% RH and 40°C/75% RH for 3 months.

Improving Powder Tableting Performance through Materials Engineering

NASA Astrophysics Data System (ADS)

Osei-Yeboah, Frederick

Adequate mechanical strength is a critical requirement to the successful development of a tablet product. Before tablet compression, powders are often engineered by various processes including wet granulation and surface coating, which may improve or adversely affect the powder tableting performance. Such effects, commonly, result from a change in either particle mechanical properties or particulate (size, shape) properties. In this work, tableting performance is interpreted based on the qualitative bonding-area and bonding-strength (BABS) model. The tabletability of the microcrystalline cellulose (MCC) granules deteriorates rapidly with increasing amount of granulating water and eventually leads to over-granulation at high water level. Granule surface smoothing, size enlargement, granule densification and shape rounding are the dominant factors leading to the tabletability reduction of plastic MCC. Incorporation of increasing amounts of brittle excipients, such as lactose or dibasic calcium phosphate reduces the rate of tabletability reduction by promoting more granule fragmentation, introducing more surface area available for bonding. When a sufficient amount of brittle excipients is used, the over-granulation phenomenon can be eliminated. Surface coating of incompressible MCC pellets with highly bonding polymer leads to sufficient surface deformation and adhesion to enable direct compression of the pellets into tablets of adequate mechanical strength. This improvement is enhanced by the presence of moisture, which plasticizes the polymer to allow the development of a larger bonding area between coated pellets. The relationship between mechanical properties and tableting behavior is systematically investigated in polymeric composites using celecoxib-polyvinylpyrrolidone vinyl acetate solid dispersions. Mechanical properties such as indentation hardness of the solid dispersions were measured using nanoindentation. Incorporation of celecoxib up to 60% by weight hardens the polymers, which reduces bonding area but increases bonding strength. On the other hand, moisture softens the solid dispersions and facilitates deformation under pressure to improve tablet mechanical strength. In summary, insights into the deteriorated tabletability of wet granulated powders have been developed and strategies for improving tabletability have been demonstrated. Also, the relationship between particle mechanical properties and tableting performance has been examined using solid dispersions. The BABS model has been further developed to enable its widespread application in interpreting complex tableting behavior.

The Impact of Amorphisation and Spheronization Techniques on the Improved in Vitro & in Vivo Performance of Glimepiride Tablets

PubMed Central

Makar, Rana Refaat; Latif, Randa; Hosni, Ehab Ahmed; El Gazayerly, Omaima Naim

2017-01-01

Purpose: Triple solid dispersion adsorbates (TSDads) and spherical agglomerates (SA) present new techniques that extensively enhance dissolution of poorly soluble drugs. The aim of the present study is to hasten the onset of hypoglycemic effect of glimepiride through enhancing its rate of release from tablet formulation prepared from either technique. Methods: Drug release from TSDads or SA tablets with different added excipients was explored. Scanning electron microscopy (SEM) and effect of compression on dissolution were illustrated. Pharmacodynamic evaluation was performed on optimized tablets. Results: TSDads & SA tablets with Cross Povidone showed least disintegration times of 1.48 and 0.5 min. respectively. Kinetics of drug release recorded least half-lives (54.13 and 59.83min for both techniques respectively). Cross section in tablets displayed an organized interconnected matrix under SEM, accounting for the rapid access of dissolution media to the tablet core. Components of tablets filled into capsules showed a similar release profile to that of tablets after compression as indicated by similarity factor. The onset time of maximum reduction in blood glucose in male albino rabbits was hastened to 2h instead of 3h for commercial tablets. Conclusion: After optimization of tablet excipients that interacted differently with respect to their effect on drug release, we could conclude that both amorphisation and spheronization were equally successful in promoting in vitro dissolution enhancement as well as providing a more rapid onset time for drug action in vivo. PMID:29399545

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.

Synthesis, characterization of thiolated karaya gum and evaluation of effect of pH on its mucoadhesive and sustained release properties.

PubMed

Bahulkar, Swati S; Munot, Neha M; Surwase, Sachin S

2015-10-05

Present study aims at synthesis and characterization of thiolated gum karaya by reacting karaya gum with 80% thioglycolic acid resulting in esterification and immobilization of thiol groups on polymeric backbone. Immobilized thiol groups were found to be 5.026 mM/g determined by Ellman's method. It was characterized by FTIR, DSC and XRD. Directly compressible tablets prepared using thiolated gum displayed more disintegration time, swelling and mucoadhesion with increase in pH of medium simulating gastric and intestinal environment than plain gum. Controlled drug release for more than 24h by Fickian diffusion following Korsemeyer-Peppas model was observed with Metoprolol Succinate as a model drug as compared to plain gum which released more than 90% of the drug within 2h. Synthesized thiomer showed no cytotoxicity determined using HepG2 cell line. According to these results, thiolated gum karaya seems to be promising excipient for the development of mucoadhesive drug delivery systems. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hydroxyethyl Pachyman as a novel excipient for sustained-release matrix tablets.

PubMed

Zhou, Xiaoju; Wang, Pengyu; Wang, Jiong; Liu, Zhi; Hong, Xuechuan; Xiao, Yuling; Liu, Peng; Hu, Xianming

2016-12-10

This paper addressed the application of hydroxyethyl pachyman (HEP) as a novel matrix for sustained - release tablets, using diclofenac sodium (DS) as a model drug. The studies showed the HEP tablets prepared by wet granulation had much slower drug release as compared to those prepared by direct compression. Meanwhile, increasing the percentage of HEP in the formulations caused a decrease in drug release rates. Moreover, DS release from the HEP tablets was much higher at high pH (6.8) than that at low pH (1.2). Morphology studies proved the HEP tablet formed a continuous gel layer with porous inner structure in the dissolution media. Analysis of DS release profiles revealed that diffusion and matrix erosion occurred in simulated intestinal fluid(SIF, pH=6.8) for all the tablets. The experimental results predict HEP has a potential as a hydrophilic matrix in tablets to prolong drug release. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Use of the direct compression aid Ludiflash(®) for the preparation of pellets via wet extrusion/spheronization.

PubMed

Roblegg, Eva; Schrank, Simone; Griesbacher, Martin; Radl, Stefan; Zimmer, Andreas; Khinast, Johannes

2011-10-01

Conventional solid oral dosage forms are unsuitable for children due to problems associated with swallowing and unpleasant taste. Additionally, the limit of tablets lays in the patient adapted dosing. Therefore, the suitability of Ludiflash(®), a direct compression aid for orally disintegrating tablets, was investigated for the preparation of individually dosable pellets. Micropellets consisting of Ludiflash(®) and small amounts of microcrystalline cellulose were prepared via the wet extrusion/spheronization technique. Paracetamol and ibuprofen were applied as model drugs. The obtained pellets were characterized with respect to drug release and disintegration characteristics, mechanical properties, as well as size and shape. Drug loading was possible up to 30% for ibuprofen and even up to 50% for paracetamol. Higher ibuprofen loadings resulted in considerably slowed drug release and higher paracetamol contents yielded in non-spherical pellets. In vitro release studies revealed that more than 80% of the drug was released within 30 and 60 min for paracetamol and ibuprofen, respectively. Drug release rates were highly influenced by the pellet disintegration behavior. Investigations of the release mechanism using the Korsemeyer-Peppas approach suggested Super Case II drug transport for all paracetamol formulations and anomalous drug transport for most ibuprofen formulations. All pellets exhibited a low porosity and friability, as well as a sufficiently high tensile strength, which was significantly influenced by the type of model drug. Ludiflash(®) can be applied as main excipient for the preparation of individually dosable pellets combining fast drug release and a high mechanical stability.

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

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

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.

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.

Orodispersible films and tablets with prednisolone microparticles.

PubMed

Brniak, Witold; Maślak, Ewelina; Jachowicz, Renata

2015-07-30

Orodispersible tablets (ODTs) and orodispersible films (ODFs) are solid oral dosage forms disintegrating or dissolving rapidly when placed in the mouth. One of the main issues related to their preparation is an efficient taste masking of a bitter drug substance. Therefore, the aim of this study was to prepare and evaluate the microparticles intended to mask a bitter taste of the prednisolone and use them in further preparation of two orodispersible dosage forms. Microparticles based on the Eudragit E PO or E 100 as a taste-masking agent were prepared with spray-drying technique. Tablets containing microparticles, co-processed ODT excipient Pharmaburst, and lubricant were directly compressed with single-punch tablet press. Orodispersible films were prepared by casting polymeric solutions of hydroxypropyl methylcellulose containing uniformly dispersed microparticles. Physicochemical properties of microparticles were evaluated, as well as mechanical properties analysis, disintegration time measurements and dissolution tests were performed for prepared dosage forms. Both formulations showed good mechanical resistance while maintaining excellent disintegration properties. The dissolution studies showed good masking properties of microparticles with Eudragit E 100. The amount of prednisolone released during the first minute in phosphate buffer 6.8 was around 0.1%. After incorporation into the orodispersible forms, the amount of released prednisolone increased significantly. It was probably the effect of faster microparticles wetting in orodispersible forms and their partial destruction by compression force during tableting process. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

SOME PROTECTION METHODS FOR CUTANEOUS IRRADIATION WITH FAST ELECTRONS (in Italian)

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

Trucchi, O.

1962-09-01

The influence exerted by some substances, particularly by fatty substances and cortisone derivatives, on the skin reaction to fast electrons is examined. The means employed were applied on the skin immediately before the irradiation; their effectiveness varies in relation with the dose fractionation; this decreases in general the capacity of the various substances tested of modifying the skin reaction. The changes induced by these means are both quantitative and relative to the course (anticipation of the appearance of the erythema); they may occur uniformly in all phases of the reaction or only in one (a change of the first phasemore » of the erythema is usually observed). The quality of the excipient, the action of which is often responsible for the aggravation of the skin reaction, is to be taken into account in the evaluation of the typical effect of the medications. Within the limits of the doses employed (1000 rad in only a sitting, 5000 rad in case of fractionation) the influence of fatty substances on the skin reactions due to irradiation with quick electrons proved not to be marked but only scarcely appreciable. The mineral fats may increase the reaction due to quick electrons in some cases: they do not have, however, either a protective or therapeutic effect during the acute phase of the reaction. The cortisone derivatives are uneffective when they are directly and exclusively applied on the irradiated skin, while they are successfully used by general route, especially in the reactions of the mucous membranes produced by quick electrons; in any way, the topical use of cortisone derivatives with excipients deprived from mineral fats proved to be preferable. Among the physical means employed, the compression gave the best results, in the cases where it could be applied. (auth)« less

[Determination of contact angle of pharmaceutical excipients and regulating effect of surfactants on their wettability].

PubMed

Hua, Dong-dong; Li, He-ran; Yang, Bai-xue; Song, Li-na; Liu, Tiao-tiao; Cong, Yu-tang; Li, San-ming

2015-10-01

To study the effects of surfactants on wettability of excipients, the contact angles of six types of surfactants on the surface of two common excipients and mixture of three surfactants with excipients were measured using hypsometry method. The results demonstrated that contact angle of water on the surface of excipients was associated with hydrophilcity of excipients. Contact angle was lowered with increase in hydrophilic groups of excipient molecules. The sequence of contact angle from small to large was starch < sodium benzoate < polyvinylpyrrolidone < sodium carboxymethylcellulose < sodium alginate < chitosan < hydroxypropyl methyl cellulose

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.

The Effects of Pharmaceutical Excipients on Gastrointestinal Tract Metabolic Enzymes and Transporters-an Update.

PubMed

Zhang, Wenpeng; Li, Yanyan; Zou, Peng; Wu, Man; Zhang, Zhenqing; Zhang, Tao

2016-07-01

Accumulating evidence from the last decade has shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on metabolic enzymes and/or drug transporters. Hence, the absorption, distribution, metabolism, and elimination (ADME) of active pharmaceutical ingredients (APIs) may be altered due to the modulation of their metabolism and transport by excipients. The impact of excipients is a potential concern for Biopharmaceutics Classification System (BCS)-based biowaivers, particularly as the BCS-based biowaivers have been extended to class 3 drugs in certain dosage forms. The presence of different excipients or varying amounts of excipients between formulations may result in bio-inequivalence. The excipient impact may lead to significant variations in clinical outcomes as well. The aim of this paper is to review the recent findings of excipient effects on gastrointestinal (GI) absorption, focusing on their interactions with the metabolic enzymes and transporters in the GI tract. A wide range of commonly used excipients such as binders, diluents, fillers, solvents, and surfactants are discussed here. We summarized the reported effects of those excipients on GI tract phase I and phase II enzymes, uptake and efflux transporters, and relevant clinical significance. This information can enhance our understanding of excipient influence on drug absorption and is useful in designing pharmacokinetic studies and evaluating the resultant data.

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.

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.

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets.

PubMed

Eddington, N D; Ashraf, M; Augsburger, L L; Leslie, J L; Fossler, M J; Lesko, L J; Shah, V P; Rekhi, G S

1998-11-01

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.

Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations.

PubMed

Korang-Yeboah, Maxwell; Rahman, Ziyaur; Shah, Dhaval; Mohammad, Adil; Wu, Suyang; Siddiqui, Akhtar; Khan, Mansoor A

2016-02-29

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution. Published by Elsevier B.V.

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.

Characterization of Protein-Excipient Microheterogeneity in Biopharmaceutical Solid-State Formulations by Confocal Fluorescence Microscopy.

PubMed

Koshari, Stijn H S; Ross, Jean L; Nayak, Purnendu K; Zarraga, Isidro E; Rajagopal, Karthikan; Wagner, Norman J; Lenhoff, Abraham M

2017-02-06

Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three-dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis. While industrially relevant lyophilization procedures of a model IgG1 mAb generally lead to uniform protein-excipient distribution, the method shows that specific spray-drying conditions lead to distinct protein-excipient segregation. Therefore, this method can enable more definitive optimization of formulation conditions than has previously been possible.

Comparison of microcrystalline characterization results from oil palm midrib alpha cellulose using different delignization method

NASA Astrophysics Data System (ADS)

Yuliasmi, S.; Pardede, T. R.; Nerdy; Syahputra, H.

2017-03-01

Oil palm midrib is one of the waste generated by palm plants containing 34.89% cellulose. Cellulose has the potential to produce microcrystalline cellulose can be used as an excipient in tablet formulations by direct compression. Microcrystalline cellulose is the result of a controlled hydrolysis of alpha cellulose, so the alpha cellulose extraction process of oil palm midrib greatly affect the quality of the resulting microcrystalline cellulose. The purpose of this study was to compare the microcrystalline cellulose produced from alpha cellulose extracted from oil palm midrib by two different methods. Fisrt delignization method uses sodium hydroxide. Second method uses a mixture of nitric acid and sodium nitrite, and continued with sodium hydroxide and sodium sulfite. Microcrystalline cellulose obtained by both method was characterized separately, including organoleptic test, color reagents test, dissolution test, pH test and determination of functional groups by FTIR. The results was compared with microcrystalline cellulose which has been available on the market. The characterization results showed that microcrystalline cellulose obtained by first method has the most similar characteristics to the microcrystalline cellulose available in the market.

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.

Dissolution enhancement of tadalafil by liquisolid technique.

PubMed

Lu, Mei; Xing, Haonan; Yang, Tianzhi; Yu, Jiankun; Yang, Zhen; Sun, Yanping; Ding, Pingtian

2017-02-01

This study aimed to enhance the dissolution of tadalafil, a poorly water-soluble drug by applying liquisolid technique. The effects of two critical formulation variables, namely drug concentration (17.5% and 35%, w/w) and excipients ratio (10, 15 and 20) on dissolution rates were investigated. Pre-compression tests, including particle size distribution, flowability determination, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and scanning electron microscopy (SEM), were carried out to investigate the mechanism of dissolution enhancement. Tadalafil liquisolid tablets were prepared and their quality control tests, dissolution study, contact angle measurement, Raman mapping, and storage stability test were performed. The results suggested that all the liquisolid tablets exhibited significantly higher dissolution rates than the conventional tablets and pure tadalafil. FT-IR spectrum reflected no drug-excipient interactions. DSC and XRD studies indicated reduction in crystallinity of tadalafil, which was further confirmed by SEM and Raman mapping outcomes. The contact angle measurement demonstrated obvious increase in wetting property. Taken together, the reduction of particle size and crystallinity, and the improvement of wettability were the main mechanisms for the enhanced dissolution rate. No significant changes were observed in drug crystallinity and dissolution behavior after storage based on XRD, SEM and dissolution results.

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.

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.

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.

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

[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.

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.

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.

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.

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.

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.

Lean production of taste improved lipidic sodium benzoate formulations.

PubMed

Eckert, C; Pein, M; Breitkreutz, J

2014-10-01

Sodium benzoate is a highly soluble orphan drug with unpleasant taste and high daily dose. The aim of this study was to develop a child appropriate, individually dosable, and taste masked dosage form utilizing lipids in melt granulation process and tableting. A saliva resistant coated lipid granule produced by extrusion served as reference product. Low melting hard fat was found to be appropriate as lipid binder in high-shear granulation. The resulting granules were compressed to minitablets without addition of other excipients. Compression to 2mm minitablets decreased the dissolved API amount within the first 2 min of dissolution from 33% to 23%. The Euclidean distances, calculated from electronic tongue measurements, were reduced, indicating an improved taste. The reference product showed a lag time in dissolution, which is desirable for taste masking. Although a lag time was not achieved for the lipidic minitablets, drug release in various food materials was reduced to 2%, assuming a suitable taste masking for oral sodium benzoate administration. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterization of new functionalized calcium carbonate-polycaprolactone composite material for application in geometry-constrained drug release formulation development.

PubMed

Wagner-Hattler, Leonie; Schoelkopf, Joachim; Huwyler, Jörg; Puchkov, Maxim

2017-10-01

A new mineral-polymer composite (FCC-PCL) performance was assessed to produce complex geometries to aid in development of controlled release tablet formulations. The mechanical characteristics of a developed material such as compactibility, compressibility and elastoplastic deformation were measured. The results and comparative analysis versus other common excipients suggest efficient formation of a complex, stable and impermeable geometries for constrained drug release modifications under compression. The performance of the proposed composite material has been tested by compacting it into a geometrically altered tablet (Tablet-In-Cup, TIC) and the drug release was compared to commercially available product. The TIC device exhibited a uniform surface, showed high physical stability, and showed absence of friability. FCC-PCL composite had good binding properties and good compactibility. It was possible to reveal an enhanced plasticity characteristic of a new material which was not present in the individual components. The presented FCC-PCL composite mixture has the potential to become a successful tool to formulate controlled-release dosage solid forms.

First study of the evolution of the SeDeM expert system parameters based on percolation theory: Monitoring of their critical behavior.

PubMed

Galdón, Eduardo; Casas, Marta; Gayango, Manuel; Caraballo, Isidoro

2016-12-01

The deep understanding of products and processes has become a requirement for pharmaceutical industries to follow the Quality by Design principles promoted by the regulatory authorities. With this aim, SeDeM expert system was developed as a useful preformulation tool to predict the likelihood to process drugs and excipients through direct compression. SeDeM system is a step forward in the rational development of a formulation, allowing the normalisation of the rheological parameters and the identification of the weaknesses and strengths of a powder or a powder blend. However, this method is based on the assumption of a linear behavior of disordered systems. As percolation theory has demonstrated, powder blends behave as non-linear systems that can suffer abrupt changes in their properties near to geometrical phase transitions of the components. The aim of this paper was to analyze for the first time the evolution of the SeDeM parameters in drug/excipient powder blends from the point of view of the percolation theory and to compare the changes predicted by SeDeM with the predictions of Percolation theory. For this purpose, powder blends of lactose and theophylline with varying concentrations of the model drug have been prepared and the SeDeM analysis has been applied to each blend in order to monitor the evolution of their properties. On the other hand, percolation thresholds have been estimated for these powder blends where critical points have been found for important rheological parameters as the powder flow. Finally, the predictions of percolation theory and SeDeM have been compared concluding that percolation theory can complement the SeDeM method for a more accurate estimation of the Design Space. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

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

2015-04-01

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

Multispectral UV imaging for surface analysis of MUPS tablets with special focus on the pellet distribution.

PubMed

Novikova, Anna; Carstensen, Jens M; Rades, Thomas; Leopold, Prof Dr Claudia S

2016-12-30

In the present study the applicability of multispectral UV imaging in combination with multivariate image analysis for surface evaluation of MUPS tablets was investigated with respect to the differentiation of the API pellets from the excipients matrix, estimation of the drug content as well as pellet distribution, and influence of the coating material and tablet thickness on the predictive model. Different formulations consisting of coated drug pellets with two coating polymers (Aquacoat ® ECD and Eudragit ® NE 30 D) at three coating levels each were compressed to MUPS tablets with various amounts of coated pellets and different tablet thicknesses. The coated drug pellets were clearly distinguishable from the excipients matrix using a partial least squares approach regardless of the coating layer thickness and coating material used. Furthermore, the number of the detected drug pellets on the tablet surface allowed an estimation of the true drug content in the respective MUPS tablet. In addition, the pellet distribution in the MUPS formulations could be estimated by UV image analysis of the tablet surface. In conclusion, this study revealed that UV imaging in combination with multivariate image analysis is a promising approach for the automatic quality control of MUPS tablets during the manufacturing process. Copyright © 2016 Elsevier B.V. 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.

Risperidone oral disintegrating mini-tablets: A robust-product for pediatrics.

PubMed

El-Say, Khalid M; Ahmed, Tarek A; Abdelbary, Maged F; Ali, Bahaa E; Aljaeid, Bader M; Zidan, Ahmed S

2015-12-01

This study was aimed at developing risperidone oral disintegrating mini-tablets (OD-mini-tablets) as age-appropriate formulations and to assess their suitability for infants and pediatric use. An experimental Box-Behnken design was applied to assure high quality of the OD-mini-tablets and reduce product variability. The design was employed to understand the influence of the critical excipient combinations on the production of OD-mini-tablets and thus guarantee the feasibility of obtaining products with dosage form uniformity. The variables selected were mannitol percent in Avicel (X1), swelling pressure of the superdisintegrant (X2), and the surface area of Aerosil as a glidant (X3). Risperidone-excipient compatibilities were investigated using FTIR and the spectra did not display any interaction. Fifteen formulations were prepared and evaluated for pre- and post-compression characteristics. The prepared OD-mini-tablet batches were also assessed for disintegration in simulated salivary fluid (SSF, pH 6.2) and in reconstituted skimmed milk. The optimized formula fulfilled the requirements for crushing strength of 5 kN with minimal friability, disintegration times of 8.4 and 53.7 s in SSF and skimmed milk, respectively. This study therefore proposes the risperidone OD-mini-tablet formula having robust mechanical properties, uniform and precise dosing of medication with short disintegration time suitable for pediatric use.

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.

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.

[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.

Photoimages and the release characteristics of lipophilic matrix tablets containing highly water-soluble potassium citrate with high drug loadings.

PubMed

Cao, Qing-Ri; Kim, Tae-Wan; Lee, Beom-Jin

2007-07-18

Two types of the carnauba wax-based lipophilic matrix tablet using spray-dried granules (SDT) or directly compressible powdered mixtures (DCT) were prepared for sustained release. The model drug was a highly water-soluble potassium citrate and loaded about 74% of the total tablet weight. The SDT slowly eroded and disintegrated during the release study without showing sustained release when the hydrophilic excipients were added. In contrast, the DCT was more efficient for sustained release. The release rate decreased with increasing carnauba wax concentration. In particular, the sustained release rate was markedly pronounced when the lipophilic stearyl alcohol and stearic acid were combined with the carnauba wax. The surface of the intact DCT appeared to be smooth and rusty. The DCT rose to the surface from the bottom of the vessel during the release test, and numerous pores and cracks with no signs of disintegration were also observed after the release test. The release profile was dependent on the formulation composition and preparation method of the matrix tablet. Diffusion-controlled leaching through the channels of the pores and cracks of the lipophilic matrix tablet (DCT) is a key to the sustained release.

Modulation of a pulsatile release drug delivery system using different swellable/rupturable materials.

PubMed

El-Maradny, Hoda A

2007-11-01

Diclofenac sodium tablets consisting of core coated with two layers of swelling and rupturable coatings were prepared and evaluated as a pulsatile drug delivery system. Cores containing the drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the ratio of 1:1. Cores were then coated sequentially with an inner swelling layer of different swellable materials; either Explotab, Croscarmellose sodium, or Starch RX 1500, and an outer rupturable layer of different levels of ethylcellulose. The effect of the nature of the swelling layer and the level of the rupturable coating on the lag time and the water uptake were investigated. Drug release rate studies were performed using USP paddle method. Results showed the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating levels. Explotab showed a significant decrease in the lag time, followed by Croscarmellose sodium and finally by Starch RX 1500. Increasing the level of ethylcellulose coating retarded the diffusion of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.

Optimization of formulation and processing of Moringa oleifera and spirulina complex tablets.

PubMed

Zheng, Yi; Zhu, Fan; Lin, Dan; Wu, Jun; Zhou, Yichao; Mark, Bohn

2017-01-01

Objective: To prepare a more comprehensive nutrition, more balanced proportion of natural nutritional supplement tablets with Moringa oleifera leaves and spirulina the two nutrients which have complementary natural food ingredients. Method: On the basis of research M. oleifera leaves with spirulina nutrient composition was determined on M. oleifera leaves and spirulina ratio of raw materials, and the choice of microcrystalline cellulose, sodium salt of caboxy methyl cellulose(CMC),magnesium stearate excipient, through single factor and orthogonal experiment, selecting the best formula tablets prepared by powder direct compression technology, for preparation of M. oleifera and spirulina complex tablets. Results: The best ratio of raw material for the M. oleifera leaves powder: spirulina powder was 7:3, the best raw materials for the tablet formulation was 88.5%, 8.0% microcrystalline cellulose, CMC 2.0%, stearin magnesium 1.5%, the optimum parameters for the raw material crushing 200-300 mesh particle size, moisture content of 7%, tableting pressure 40 kN. Conclusion: Through formulation and process optimization, we can prepare more comprehensive and balanced nutrition M. oleifera and spirulina complex tablets, its sheet-shaped appearance, piece weight variation, hardness, friability, disintegration and other indicators have reached the appropriate quality requirements.

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

PubMed

Chicco, D; Grabnar, I; Skerjanec, A; Vojnovic, D; Maurich, V; Realdon, N; Ragazzi, E; Belic, A; Karba, R; Mrhar, A

1999-11-05

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

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.

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.

Importance and globalization status of good manufacturing practice (GMP) requirements for pharmaceutical excipients

PubMed Central

Abdellah, Abubaker; Noordin, Mohamed Ibrahim; Wan Ismail, Wan Azman

2013-01-01

Pharmaceutical excipients are no longer inert materials but it is effective and able to improve the characteristics of the products’ quality, stability, functionality, safety, solubility and acceptance of patients. It can interact with the active ingredients and alter the medicament characteristics. The globalization of medicines’ supply enhances the importance of globalized good manufacturing practice (GMP) requirements for pharmaceutical excipients. This review was intended to assess the globalization status of good manufacturing practice (GMP) requirements for pharmaceutical excipients. The review outcomes demonstrate that there is a lack of accurately defined methods to evaluate and measure excipients’ safety. Furthermore good manufacturing practice requirements for excipients are not effectively globalized. PMID:25685037

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.

Gum Ghatti--a pharmaceutical excipient: development, evaluation and optimization of sustained release mucoadhesive matrix tablets of domperidone.

PubMed

Gurpreetarora; Malik, Karan; Rana, Vikas; Singh, Inderbir

2012-01-01

The objective of this study was to extend the GI residence time of the dosage form and to control the release of domperidone using directly compressible sustained release mucoadhesive matrix (SRMM) tablets. A 2-factor centre composite design (CCD) was employed to study the influence of independent variables like gum ghatti (GG) (X1) and hydroxylpropylmethyl cellulose K 15M (HPMC K 15M) (X2) on dependent variable like mucoadhesive strength, tensile strength, release exponent (n), t50 (time for 50% drug release), rel(10 h) (release after 10 h) and rel(18 h) (release after 18 h). Tablets were prepared by direct compression technology and evaluated for tablet parametric test (drug assay, diameter, thickness, hardness and tensile strength), mucoadhesive strength (using texture analyzer) and in vitro drug release studies. The tensile strength and mucoadhesive strength were found to be increased from 0.665 +/- 0.1 to 1.591 +/- 0.1 MN/cm2 (Z1 to Z9) and 10.789 +/- 0.985 to 50.924 +/- 1.150 N (Z1 to Z9), respectively. The release kinetics follows first order and Hixson Crowell equation indicating drug release following combination of diffusion and erosion. The n varies between 0.834 and 1.273, indicating release mechanism shifts from non fickian (anomalous release) to super case II, which depict that drug follows multiple drug release mechanism. The t50 time was found to increase from 5 +/- 0.12 to 11.4 +/- 0.14 h (Z1 to Z9) and release after 10 and 18 h decreases with increasing concentration of both polymers concluding with release controlling potential of polymers. The accelerated stability studies were performed on optimized formulation as per ICH guideline and the result showed that there was no significant change in tensile strength, mucoadhesive strength and drug assay.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Tabletted microspheres containing Cynara scolymus (var. Spinoso sardo) extract for the preparation of controlled release nutraceutical matrices.

PubMed

Gavini, E; Alamanni, M C; Cossu, M; Giunchedi, P

2005-08-01

Controlled release dosage forms based on tabletted microspheres containing fresh artichoke Cynara scolymus extract were performed for the oral administration of a nutritional supplement. Microspheres were prepared using a spray-drying technique; lactose or hypromellose have been chosen as excipients. Microspheres were characterized in terms of encapsulated extract content, size and morphology. Qualitative and quantitative composition of the extract before and after the spray process was determined. Compressed matrices (tablets) were prepared by direct compression of the spray-dried microspheres. In vitro release tests of microparticles and tablets prepared were carried out in both acidic and neutral media. Spray-drying is a good method to prepare microspheres containing the artichoke extract. The microspheres encapsulate an amount of extract close to the theoretical value. Particle size analyses indicate that the microparticles have dvs of approximately 6-7 microm. Electronic microscopy observations reveal that particles based on lactose have spherical shape and particles containing hypromellose are almost collapsed. The hydroalcoholic extract is stable to the microsphere production process: its polyphenolic composition (qualitative and quantitative) did not change after spraying. In vitro release studies show that microparticles characterized by a quick polyphenolic release both in acidic and neutral media due to the high water solubility of the carrier lactose. On the contrary, microspheres based hypromellose release only 20% of the loaded extract at pH 1.2 in 2 h and the total amount of polyphenols is released only after about further 6 h at pH 6.8. Matrices prepared tabletting lactose microspheres and hypromellose microparticles in the weight ratio 1:1 show a slow release rate, that lasts approximately 24 h. This one-a-day sustained release formulation containing Cynara scolymus extract could be proposed as a nutraceutical controlled release dosage form for oral administration.

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.

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.

Lornoxicam gastro retentive floating matrix tablets: Design and in vitro evaluation.

PubMed

Sathiyaraj, S; Devi, Ramya D; Hari, Vedha B N

2011-07-01

The objective of this present investigation is to prolong the gastric residence time of Lornoxicam by fabricating it into a floating sustained release matrix tablets. Lornoxicam, a potent oxicam group of non-steroidal anti-inflammatory drugs, suffers from relatively short half life of 2 to 3 hrs showing maximal absorption in proximal gastro intestinal tract region necessitating its need to be formulated as a floating sustained release matrix tablets. In this current investigation, hydroxyl propyl methyl cellulose K15M, a high viscous grade polymer with apparent viscosity of 15,000 cps, was kept as a variable (10-50%) and calcium carbonate (13%) was used as a gas generator. The prepared blends were subjected for its pre-formulation characterization. The directly compressed tablets were evaluated for physical parameters such as weight uniformity, hardness, friability, drug content, in-vitro buoyancy with axial and radial enlargement measurement, swelling index. From the investigation it was observed that the buoyancy lasted for up to 24 hrs. Fourier transform infra-red spectroscopy peaks assured the compatibility of the drug with excipients and confirmed the presence of pure drug in the formulation. It was supported by in-vitro dissolution studies; and the dissolution data was subjected to various release kinetic models to understand the mechanism of drug release.

Preparation and in vitro/in vivo characterization of porous sublingual tablets containing ternary kneaded solid system of vinpocetine with î-cyclodextrin and hydroxy Acid.

PubMed

Aburahma, Mona H; El-Laithy, Hanan M; Hamza, Yassin El-Said

2010-01-01

The demand for sublingual tablets has been growing during the previous decades especially for drugs with extensive hepatic first-pass metabolism. Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor aqueous solubility and marked first-pass metabolism. Accordingly, the aim of this work was to develop tablets for the sublingual delivery of vinpocetine. Initially, the feasibility of improving vinpocetineâs poor aqueous solubility by preparing kneaded solid systems of the drug with Î-Cyclodextrin and hydroxy acids (citric acid and tartaric acid) was assessed. The solid system with improved solubility and dissolution properties was incorporated into porous tablets that rapidly disintegrate permitting fast release of vinpocetine into the sublingual cavity. The pores were induced into these tablets by directly compressing the tabletsâ excipients with a sublimable material, either camphor or menthol, which was eventually sublimated leaving pores. The obtained results demonstrated that the tablets prepared using camphor attained sufficient mechanical strength for practical use together with rapid disintegration and dissolution. In vivo absorption study performed in rabbits indicated that the sublingual administration of the proposed porous tablets containing vinpocetine solid system with Î-Cyclodextrin and tartaric acid could be useful for therapeutic application.

Preparation and In Vitro/In Vivo Characterization of Porous Sublingual Tablets Containing Ternary Kneaded Solid System of Vinpocetine with β-Cyclodextrin and Hydroxy Acid

PubMed Central

Aburahma, Mona H.; El-Laithy, Hanan M.; Hamza, Yassin El-Said

2010-01-01

The demand for sublingual tablets has been growing during the previous decades especially for drugs with extensive hepatic first-pass metabolism. Vinpocetine, a widely used neurotropic agent, has low oral bioavailability due to its poor aqueous solubility and marked first-pass metabolism. Accordingly, the aim of this work was to develop tablets for the sublingual delivery of vinpocetine. Initially, the feasibility of improving vinpocetine’s poor aqueous solubility by preparing kneaded solid systems of the drug with β-Cyclodextrin and hydroxy acids (citric acid and tartaric acid) was assessed. The solid system with improved solubility and dissolution properties was incorporated into porous tablets that rapidly disintegrate permitting fast release of vinpocetine into the sublingual cavity. The pores were induced into these tablets by directly compressing the tablets’ excipients with a sublimable material, either camphor or menthol, which was eventually sublimated leaving pores. The obtained results demonstrated that the tablets prepared using camphor attained sufficient mechanical strength for practical use together with rapid disintegration and dissolution. In vivo absorption study performed in rabbits indicated that the sublingual administration of the proposed porous tablets containing vinpocetine solid system with β-Cyclodextrin and tartaric acid could be useful for therapeutic application. PMID:21179352

Enalapril maleate orally disintegrating tablets: tableting and in vivo evaluation in hypertensive rats.

PubMed

Tawfeek, Hesham M; Faisal, Waleed; Soliman, Ghareb M

2018-06-01

The aim of this study was to develop orally disintegrating tablets (ODTs) for enalapril maleate (EnM) to facilitate its administration to the elderly or other patients having dysphagia. Compatibility between EnM and various excipients was studied using differential scanning calorimetry. ODTs of EnM were prepared by direct compression of EnM mixtures with various superdisintegrants. The tablets were evaluated for physical properties including drug content, hardness, friability, disintegration time, wetting time, and drug release. The antihypertensive effect of the optimum EnM ODTs was evaluated in vivo in hypertensive rats and compared with commercial EnM formulation. EnM ODTs had satisfactory results in terms of drug content and friability. Tablet wetting and disintegration were fast and dependent on the used superdisintegrant where croscarmellose showed the fastest wetting and disintegration time of ∼7 s. EnM release from the tablets was rapid where complete release was obtained in 10-15 min. Selected EnM ODTs rapidly and efficiently reduced the rat's blood pressure to its normal value within 1 h, compared with 4 h for EnM commercial formulation. These results confirm that EnM ODTs could find application in the management of hypertension in the elderly or other patients having dysphagia.

Formulation Development and Evaluation of Fast Disintegrating Tablets of Salbutamol Sulphate for Respiratory Disorders

PubMed Central

Sharma, Deepak

2013-01-01

Recent developments in fast disintegrating tablets have brought convenience in dosing to pediatric and elderly patients who have trouble in swallowing tablets. The objective of the present study was to prepare the fast disintegrating tablet of salbutamol sulphate for respiratory disorders for pediatrics. As precision of dosing and patient's compliance become important prerequisites for a long-term treatment, there is a need to develop a formulation for this drug which overcomes problems such as difficulty in swallowing, inconvenience in administration while travelling, and patient's acceptability. Hence, the present investigation were undertaken with a view to develop a fast disintegrating tablet of salbutamol sulphate which offers a new range of products having desired characteristics and intended benefits. Superdisintegrants such as sodium starch glycolate was optimized. Different binders were optimized along with optimized superdisintegrant concentration. The tablets were prepared by direct compression technique. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and uniformity of content. Optimized formulation was evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. It was concluded that fast disintegrating tablets of salbutamol sulphate were formulated successfully with desired characteristics which disintegrated rapidly; provided rapid onset of action; and enhanced the patient convenience and compliance. PMID:23956881

Zein-based films and their usage for controlled delivery: Origin, classes and current landscape.

PubMed

Zhang, Yong; Cui, Lili; Che, Xiaoxia; Zhang, Heng; Shi, Nianqiu; Li, Chunlei; Chen, Yan; Kong, Wei

2015-05-28

Zein is a class of alcohol-soluble prolamine proteins present in maize endosperm, which was approved as a generally recognized as safe (GRAS) excipient in 1985 by the United States Food and Drug Administration (US-FDA) for film coating of pharmaceuticals, e.g., tablets. Despite its long-term application in tablet production, effects of zein coating on tablet properties are still not fully understood. Moreover, many studies have also been conducted to illustrate its potential as an active ingredient of direct compressed tablets and film-based delivery carriers. In addition, the use of zein as a functional film coating material for new biomedical applications was also widely investigated in recent reports, which involved medical devices, nanoparticles, quantum dots and nanofibers. In this review, the present status of zein in the form of a thin film and uniform layer for use as a biomedical material is discussed. In addition, studies related to the behaviors and properties of zein films are also summarized and analyzed based on published works to gain mechanistic insights into the relationship between zein film and various improved profiles. This review will benefit future prospects of the use of zein film in drug delivery and biomedical applications. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization, optimisation and process robustness of a co-processed mannitol for the development of orally disintegrating tablets.

PubMed

Soh, Josephine Lay Peng; Grachet, Maud; Whitlock, Mark; Lukas, Timothy

2013-02-01

This is a study to fully assess a commercially available co-processed mannitol for its usefulness as an off-the-shelf excipient for developing orally disintegrating tablets (ODTs) by direct compression on a pilot scale (up to 4 kg). This work encompassed material characterization, formulation optimisation and process robustness. Overall, this co-processed mannitol possessed favourable physical attributes including low hygroscopicity and compactibility. Two design-of-experiments (DoEs) were used to screen and optimise the placebo formulation. Xylitol and crospovidone concentrations were found to have the most significant impact on disintegration time (p < 0.05). Higher xylitol concentrations retarded disintegration. Avicel PH102 promoted faster disintegration than PH101, at higher levels of xylitol. Without xylitol, higher crospovidone concentrations yielded faster disintegration and reduced tablet friability. Lubrication sensitivity studies were later conducted at two fill loads, three levels for lubricant concentration and number of blend rotations. Even at 75% fill load, the design space plot showed that 1.5% lubricant and 300 blend revolutions were sufficient to manufacture ODTs with ≤ 0.1% friability and disintegrated within 15 s. This study also describes results using a modified disintegration method based on the texture analyzer as an alternative to the USP method.

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 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.

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.

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.

Investigating the effect of tablet thickness and punch curvature on density distribution using finite elements method.

PubMed

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

2015-09-30

Finite elements method was used to study the influence of tablet thickness and punch curvature on the density distribution inside convex faced (CF) tablets. The modeling of the process was conducted on 2 pharmaceutical excipients (anhydrous calcium phosphate and microcrystalline cellulose) by using Drucker-Prager Cap model in Abaqus(®) software. The parameters of the model were obtained from experimental tests. Several punch shapes based on industrial standards were used. A flat-faced (FF) punch and 3 convex faced (CF) punches (8R11, 8R8 and 8R6) with a diameter of 8mm were chosen. Different tablet thicknesses were studied at a constant compression force. The simulation of the compaction of CF tablets with increasing thicknesses showed an important change on the density distribution inside the tablet. For smaller thicknesses, low density zones are located toward the center. The density is not uniform inside CF tablets and the center of the 2 faces appears with low density whereas the distribution inside FF tablets is almost independent of the tablet thickness. These results showed that FF and CF tablets, even obtained at the same compression force, do not have the same density at the center of the compact. As a consequence differences in tensile strength, as measured by diametral compression, are expected. This was confirmed by experimental tests. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

The Impact of Disintegrant Type, Surfactant, and API Properties on the Processability and Performance of Roller Compacted Formulations of Acetaminophen and Aspirin.

PubMed

Zhao, Junshu; Koo, Otilia; Pan, Duohai; Wu, Yongmei; Morkhade, Dinesh; Rana, Sandeep; Saha, Partha; Marin, Arturo

2017-09-01

In formulation development, certain excipients, even though used in small quantities, can have a significant impact on the processability and performance of the dosage form. In this study, three common disintegrants, croscarmellose sodium (CCS), crospovidone (xPVP), and sodium starch glycolate (SSG) as well as the surfactant sodium lauryl sulfate (SLS) were evaluated for their impact on the processability and performance of a typical dry granulation formulation. Two model compounds, the mechanically brittle and chemically inert acetaminophen and the mechanically ductile carboxylic acid aspirin, were used for the evaluation. It was found that the disintegrants were generally identical in their impact on the processability and little difference was observed in the granulation and compression processes. The exception is that when xPVP was used in the formulation of the brittle acetaminophen, lower compression forces were needed to reach the same tablet hardness, suggesting a binding effect of xPVP for such systems. In general, CCS and xPVP tend to provide slightly better disintegration than SSG. However, in the case of aspirin, a strong hydrogen bonding interaction between the carboxylic acid group of aspirin and the carbonyl group of xPVP was observed, resulting in slower release of the drug after fast disintegration. SLS was found to have a significant impact on the processability due to its lubricating effect, resulting in higher compression forces needed to achieve the target tablet hardness. Due to the higher degree of compression, the disintegration and dissolution of both drugs became slower despite the wetting effect of SLS.

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.

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

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.

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

PubMed

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

2014-05-15

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

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.

Thermal behaviour of procaine and benzocaine Part II: compatibility study with some pharmaceutical excipients used in solid dosage forms

PubMed Central

2013-01-01

Background The compatibility study of active substances with excipients finds an important role in the domain of pharmaceutical research, being known the fact that final formulation is the one administered to the patient. In order to evaluate the compatibility between active substance and excipients, different analytical techniques can be used, based on their accuracy, reproducibility and fastness. Results Compatibility study of two well-known active substances, procaine and benzocaine, with four commonly used excipients, was carried out employing thermal analysis (TG/DTG/HF) and Fourier Transform Infrared Spectroscopy (UATR-FT-IR). The selected excipients were microcrystalline cellulose, lactose monohydrate, magnesium stearate and talc. Equal proportion of active substance and excipients (w/w) was utilized in the interaction study. The absolute value of the difference between the melting point peak of active substances and the one corresponding for the active substances in the analysed mixture, as well the absolute value of the difference between the enthalpy of the pure active ingredient melting peak and that of its melting peak in the different analysed mixtures were chosen as indexes of the drug-excipient interaction degree. All the results obtained through thermal analysis were also sustained by FT-IR spectroscopy. Conclusions The corroboration of data obtained by thermal analysis with the ones from FT-IR spectroscopy indicated that no interaction occurs between procaine and benzocaine, with microcrystalline cellulose and talc, as well for the benzocaine-lactose mixture. Interactions were confirmed between procaine and benzocaine respectively and magnesium stearate, and for procaine and lactose. PMID:23962059

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.

Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

PubMed

Nart, Viviane; Beringhs, André O'Reilly; França, Maria Terezinha; de Espíndola, Brenda; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

2017-01-01

Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat® SR 30D and Opadry® II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

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

2010-06-01

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

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.

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.

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

PubMed

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

2016-04-15

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

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

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.

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.

[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.

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.

Determination of the mechanical properties of solid and cellular polymeric dosage forms by diametral compression.

PubMed

Blaesi, Aron H; Saka, Nannaji

2016-07-25

At present, the immediate-release solid dosage forms, such as the oral tablets and capsules, are granular solids. They release drug rapidly and have adequate mechanical properties, but their manufacture is fraught with difficulties inherent in processing particulate matter. Such difficulties, however, could be overcome by liquid-based processing. Therefore, we have recently introduced polymeric cellular (i.e., highly porous) dosage forms prepared from a melt process. Experiments have shown that upon immersion in a dissolution medium, the cellular dosage forms with polyethylene glycol (PEG) as excipient and with predominantly open-cell topology disintegrate by exfoliation, thus enabling rapid drug release. If the volume fraction of voids of the open-cell structures is too large, however, their mechanical strength is adversely affected. At present, the common method for determining the tensile strength of brittle, solid dosage forms (such as select granular forms) is the diametral compression test. In this study, the theory of diametral compression is first refined to demonstrate that the relevant mechanical properties of ductile and cellular solids (i.e., the elastic modulus and the yield strength) can also be extracted from this test. Diametral compression experiments are then conducted on PEG-based solid and cellular dosage forms. It is found that the elastic modulus and yield strength of the open-cell structures are about an order of magnitude smaller than those of the non-porous solids, but still are substantially greater than the stiffness and strength requirements for handling the dosage forms manually. This work thus demonstrates that melt-processed polymeric cellular dosage forms that release drug rapidly can be designed and manufactured to have adequate mechanical properties. Copyright © 2016. Published by Elsevier B.V.

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.

Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms.

PubMed

Debotton, Nir; Dahan, Arik

2017-01-01

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products. © 2016 Wiley Periodicals, Inc.

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.

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).

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.

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.

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.

Xylitol as a potential co-crystal co-former for enhancing dissolution rate of felodipine: preparation and evaluation of sublingual tablets.

PubMed

Arafa, Mona F; El-Gizawy, Sanaa A; Osman, Mohamed A; El Maghraby, Gamal M

2018-06-01

Dissolution enhancement is a promising strategy for improving drug bioavailability. Co-crystallization of drugs with inert material can help in this direction. The benefit will become even greater if the inert material can form co-crystal while maintaining its main function as excipient. Accordingly, the objective of the current study was to investigate xylitol as a potential co-crystal co-former for felodipine with the goal of preparing felodipine sublingual tablets. Co-crystallization was achieved by wet co-grinding of the crystals deposited from methanolic solutions containing felodipine with increasing molar ratios of xylitol (1:1, 1:2 and 1:3). The developed co-crystals were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) before monitoring drug dissolution. These results reflected the development of new crystalline species depending on the relative proportions of felodipine and xylitol with complete co-crystallization of felodipine being achieved in the presence of double its molar concentration of xylitol. This co-crystal formulation was compressed into sublingual tablet with ultrashort disintegration time with subsequent fast dissolution. Co-crystal formation was associated with enhanced dissolution with the optimum formulation producing the fastest dissolution rate. In conclusion, xylitol can be considered as a co-crystal co-former for enhanced dissolution rate of drugs.

Influence of different types of low substituted hydroxypropyl cellulose on tableting, disintegration, and floating behaviour of floating drug delivery systems

PubMed Central

Diós, Péter; Pernecker, Tivadar; Nagy, Sándor; Pál, Szilárd; Dévay, Attila

2014-01-01

The object of the present study is to evaluate the effect of application of low-substituted hydroxypropyl cellulose (L-HPC) 11 and B1 as excipients promoting floating in gastroretentive tablets. Directly compressed tablets were formed based on experimental design. Face-centred central composite design was applied with two factors and 3 levels, where amount of sodium alginate (X1) and L-HPC (X2) were the numerical factors. Applied types of L-HPCs and their 1:1 mixture were included in a categorical factor (X3). Studied parameters were floating lag time, floating time, floating force, swelling behaviour of tablets and dissolution of paracetamol, which was used as a model active substance. Due to their physical character, L-HPCs had different water uptake and flowability. Lower flowability and lower water uptake was observed after 60 min at L-HPC 11 compared to L-HPC B1. Shorter floating times were detected at L-HPC 11 and L-HPC mixtures with 0.5% content of sodium alginate, whereas alginate was the only significant factor. Evaluating results of drug release and swelling studies on floating tablets revealed correlation, which can serve to help to understand the mechanism of action of L-HPCs in the field development of gastroretentive dosage forms. PMID:26702261

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.

An in vitro analysis of disintegration times of different formulations of olanzapine orodispersible tablet: a preliminary report.

PubMed

Hobbs, David; Karagianis, Jamie; Treuer, Tamas; Raskin, Joel

2013-12-01

Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies. Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab(®) was included as a non-olanzapine ODT comparator. Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis(®) ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva. The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations. The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis(®) was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST(®) (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration. Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.

3D extrusion printing of high drug loading immediate release paracetamol tablets.

PubMed

Khaled, Shaban A; Alexander, Morgan R; Wildman, Ricky D; Wallace, Martin J; Sharpe, Sonja; Yoo, Jae; Roberts, Clive J

2018-03-01

The manufacture of immediate release high drug loading paracetamol oral tablets was achieved using an extrusion based 3D printer from a premixed water based paste formulation. The 3D printed tablets demonstrate that a very high drug (paracetamol) loading formulation (80% w/w) can be printed as an acceptable tablet using a method suitable for personalisation and distributed manufacture. Paracetamol is an example of a drug whose physical form can present challenges to traditional powder compression tableting. Printing avoids these issues and facilitates the relatively high drug loading. The 3D printed tablets were evaluated for physical and mechanical properties including weight variation, friability, breaking force, disintegration time, and dimensions and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). X-ray Powder Diffraction (XRPD) was used to identify the physical form of the active. Additionally, XRPD, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to assess possible drug-excipient interactions. The 3D printed tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed a profile characteristic of the immediate release profile as intended based upon the active/excipient ratio used with disintegration in less than 60 s and release of most of the drug within 5 min. The results demonstrate the capability of 3D extrusion based printing to produce acceptable high-drug loading tablets from approved materials that comply with current USP standards. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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.

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.

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.

[Preparation and evaluation of taste masked orally disintegrating tablets with granules made by the wet granulation method].

PubMed

Kawano, Yayoi; Ito, Akihiko; Sasatsu, Masanaho; Machida, Yoshiharu; Onishi, Hiraku

2010-12-01

Using furosemide (FU) as a model drug, we examined the wet granulation method as a way to improve the taste masking and physical characteristics of orally disintegrating tablets (ODTs). In the wet granulation method, yogurt powder (YO) was used as a corrective and maltitol (MA) was used as a binding agent. The taste masked FU tablets were prepared using the direct compression method. Microcrystalline cellulose (Avicel® PH-302) and mannitol were added as excipients at a mixing ratio of 1/1 by weight. Based on the results of sensory test on taste, the prepared granules markedly improved the taste of FU, and a sufficient masking effect was obtained at the YO/FU ratio of 1 or more. Furthermore, it was found that the masking effect achieved by YO granules made with the wet granulation method was similar to or better than that produced by the granules made with dry granulation method. All types of tablets displayed sufficient hardness (over 3.5×10(-2) kN), and rapidly disintegrating tablets were obtained with YO granules produced at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s. Disintegration time lengthened as the mixing ratio of YO to FU increased. In the mixing ratio of FU/YO=1/1, the hardness of tablets with granules made by the wet granulation method exceeded that of tablets with granules made by the dry granulation method, with minimal differences in disintegration time. The hardness and disintegration time of the tablets with granules made by the wet granulation method could be controlled by varying the compression force. In conclusion, YO was found to be a useful additive for masking unpleasant tastes. FU ODTs with improved taste, rapid disintegration and greater hardness could be prepared with YO-containing granules made by the wet granulation method using MA as a binding agent.

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

¹³C solid-state NMR analysis of the most common pharmaceutical excipients used in solid drug formulations Part II: CP kinetics and relaxation analysis.

PubMed

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

2016-04-15

Excipients used in the solid drug formulations differ in their NMR relaxation and (13)C cross-polarization (CP) kinetics parameters. Therefore, experimental parameters like contact time of cross-polarization and repetition time have a major impact on the registered solid state NMR spectra and in consequence on the results of the NMR analysis. In this work the CP kinetics and relaxation of the most common pharmaceutical excipients: anhydrous α-lactose, α-lactose monohydrate, mannitol, sucrose, sorbitol, sodium starch glycolate type A and B, starch of different origin, microcrystalline cellulose, hypromellose, ethylcellulose, methylcellulose, hydroxyethylcellulose, sodium alginate, magnesium stearate, sodium laurilsulfate and Kollidon(®) were analyzed. The studied excipients differ significantly in their optimum repetition time (from 5 s to 1200 s) and T(1ρ)(I) parameters (from 2 ms to 73 ms). The practical use of those differences in the excipients composition analysis was demonstrated on the example of commercially available tablets containing indapamide as an API. The information presented in this article will help to choose the correct acquisition parameters and also will save the time and effort needed for their optimization in the NMR analysis of the solid drug formulations. Copyright © 2016 Elsevier B.V. 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

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.

Elemental Impurities in Pharmaceutical Excipients.

PubMed

Li, Gang; Schoneker, Dave; Ulman, Katherine L; Sturm, Jason J; Thackery, Lisa M; Kauffman, John F

2015-12-01

Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients. This paper summarizes a recent survey of elemental impurity levels in common pharmaceutical excipients as well as some drug substances. A widely applicable analytical procedure was developed and was shown to be suitable for analysis of elements that are subject to United States Pharmacopoeia Chapter <232> and International Conference on Harmonization's Q3D Guideline on Elemental Impurities. The procedure utilizes microwave-assisted digestion of pharmaceutical materials and inductively coupled plasma mass spectrometry for quantitative analysis of these elements. The procedure was applied to 190 samples from 31 different excipients and 15 samples from eight drug substances provided through the International Pharmaceutical Excipient Council of the Americas. The results of the survey indicate that, for the materials included in the study, relatively low levels of elemental impurities are present. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association.

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.

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

[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.

Characterization of compressibility and compactibility of poly(ethylene oxide) polymers for modified release application by compaction simulator.

PubMed

Yang, L; Venkatesh, G; Fassihi, R

1996-10-01

Poly(ethylene oxide) polymers (PEO) appear to have great potential for controlled release applications. These polymers are hydrophilic with good water solubility, low toxicity, and high swelling capacity. As part of formulation optimization for a large-scale solid dosage form production, physicomechanical characterization of PEO was undertaken using a compaction simulator. Heckel plots for all PEOs were constructed, and yield pressures (Py) at different punch velocities were calculated from the linear portion of the plots. Low Py values, increase of Py with increasing punch speed, upward curvature of the plot, and strain rate sensitivity values indicate that the densification process and consolidation mechanism for PEOs of various molecular weights (0.2 x 10(6) to 7 x 10(6)) are identical and follow plastic deformation. PEOs have a high degree of crystallinity (57-85%) and show significant axial recovery (15-25%) upon decompression and ejection. The low Py values (58-78 MPa) and low mean compaction pressures demonstrate that volume reduction (compressibility) under pressure is excellent. However, due to viscoelastic behavior and large axial expansion, tablets of relatively low tensile strength are produced. These observations suggest the need to blend PEO with highly compactible excipients in order to produce tables on a high-speed production press.

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.

77 FR 33399 - Citric Acid and Certain Citrate Salts From the People's Republic of China: Preliminary Results of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-06

... functional excipient, such as dextrose or starch, where the excipient constitutes at least 2 percent, by... Memorandum at 4; Corrosion- Resistant Carbon Steel Flat Products from the Republic of Korea: Final Results of...

Evaluation of beta-lactose, PVP K12 and PVP K90 as excipients to prepare piroxicam granules using two wet granulation techniques.

PubMed

Albertini, Beatrice; Cavallari, Cristina; Passerini, Nadia; González-Rodríguez, M L; Rodriguez, Lorenzo

2003-11-01

The present investigation aimed at evaluating the use of different excipients, beta-lactose and polyvinylpyrrolidone of two molecular weights (PVP K12 and PVP K90), in the production of improved release piroxicam granules, by wet granulation using both water and steam as granulation liquid. The formulations examined were: piroxicam (Px)/beta-lactose; Px/PVP K12 and Px/PVP K90, each one at a 1:9 weight ratio. The most significant difference between beta-lactose and PVP is that, using the first excipient, both steam and water granules were produced while, when PVP were employed, only steam granules were obtained. Image analysis revealed that beta-lactose steam granules had a larger surface area with respect to water granules, whereas lower values of this parameter were observed in PVP-s granules, confirming the Scanning Electron Microscopy micrographs and the fractal analysis results. As regards the enhancement of the dissolution profiles, the best result was obtained using beta-lactose steam granules followed by PVP K12 ones, even if the reactive dimension values indicated that during the dissolution process PVP K12 granules modified the surface more than beta-lactose granules. As regards PVP K90, this excipient was the one less influencing the granule morphology and the dissolution behaviour. Differential Scanning Calorimetry analysis suggested the partial amorphisation of the drug in the granules containing the three excipients. This result was then confirmed by X-ray powder diffraction analysis. Therefore, beta-lactose and PVP K12 could be proposed as useful excipients to enhance the dissolution rate of Px from granules prepared using the steam granulation technique.

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.

The effect of excipients on the release kinetics of diclofenac sodium and papaverine hydrochloride from composed tablets.

PubMed

Kasperek, Regina; Trebacz, Hanna; Zimmer, Łukasz; Poleszak, Ewa

2014-01-01

For increased analgesic effect, new composed tablets containing diclofenac sodium (DIC) with an addition of papaverine hydrochloride (PAP) were prepared to investigate the mechanism of release of the active substances from tablets with different excipients in eight different formulations. To detect the possible interactions between active substances and excipients differential scanning calorimetry (DSC) was used. A shift of the melting point and enthalpy values of the physical mixtures of tablets components suggested a kind of interaction between components in certain formulations, however, the tabletting process was not disturbed in any of them. Kinetics of drug release from formulations was estimated by zero order, first order and Higuchi and Korsmeyer-Peppas models using results of dissolution of DIC and PAP from tablets. The study revealed that the mechanism of release of active substances was dependent on the excipients contained in tablets and the best fitted kinetics models were obtained for formulations with potentially prolonged release of DIC and PAP.

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.

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

PubMed

Chattoraj, Sayantan; Sun, Changquan Calvin

2018-04-01

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

The effect of sesame and sunflower oils on the plasma disposition of ivermectin in goats.

PubMed

Gokbulut, C; Karademir, U; Boyacioglu, M; McKellar, Q A

2008-10-01

The effect of sesame oil (SSO) and sunflower oil (SFO) (the excipients) on the plasma disposition of ivermectin (IVM) following intravenous (i.v.) and subcutaneous (s.c.) administration at a dosage of 200 microg/kg was investigated in goats. Ten clinically healthy crossbred goats were used in the study. The animals were allocated by weight and sex into two groups of five animals each. Group 1 (n = 5) received the drug and excipient by the i.v. route only and group 2 received drug and excipient by the s.c. route only. The study was designed according to a two-phase crossover design protocol. In the first phase three animals in group 1 were i.v. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. In group 2 during the first phase, three animals were s.c. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals were received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. A 4-week washout period was allowed between the two phases. In group 2 significantly increased dermal thickness was observed at the s.c. injection site of the all animals which received IVM during phase I regardless of the excipient. There was almost no change observed at the injection site of any animal during the second phase of the study following s.c. administration. In group 2 the plasma concentrations of IVM in the second phase for both excipient combinations were much higher than the plasma concentrations following first administration and appeared to be related with the dermal changes. The mean plasma disposition of IVM in combination with SSO or SFO was similar following i.v. administration. Longer terminal elimination half-lives and resultant longer mean resident time were observed after s.c. administration of the both combinations compared with i.v. administration.

Distribution of Particles, Small Molecules and Polymeric Formulation Excipients in the Suprachoroidal Space after Microneedle Injection

PubMed Central

Chiang, Bryce; Venugopal, Nitin; Edelhauser, Henry F.; Prausnitz, Mark R.

2016-01-01

The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25–150 μL Hank’s Balanced Salt Solution (HBSS) containing 0.2 μm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02 – 2 μm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm – 2 μm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2 – 4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1 – 3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allow spreading over larger areas of the SCS until the particles and excipients dissociate. PMID:27742547

Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection.

PubMed

Chiang, Bryce; Venugopal, Nitin; Edelhauser, Henry F; Prausnitz, Mark R

2016-12-01

The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules, and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25-150 μL Hank's Balanced Salt Solution (HBSS) containing 0.2 μm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02-2 μm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein, and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm-2 μm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size, and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2-4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1-3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allows spreading over larger areas of the SCS until the particles and excipients dissociate. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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.

Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: drug release and fronts movement kinetics.

PubMed

Marinich, J A; Ferrero, C; Jiménez-Castellanos, M R

2012-04-01

A previous paper deals with the physicochemical and technological characterization of novel graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS). The results obtained suggested the potential application of these copolymers as excipients for compressed non-disintegrating matrix tablets. Therefore, the purpose of the present study was to investigate the mechanism governing drug release from matrix systems prepared with the new copolymers and anhydrous theophylline or diltiazem HCl as model drugs with different solubility. The influence of the carbohydrate nature, drying procedure and initial pore network on drug release kinetics was also evaluated. Drug release experiments were performed from free tablets. Radial drug release and fronts movement kinetics were also analysed, and several mathematical models were employed to ascertain the drug release mechanisms. The drug release markedly depends on the drug solubility and the carbohydrate nature but is practically not affected by the drying process and the initial matrix porosity. A faster drug release is observed for matrices containing diltiazem HCl compared with those containing anhydrous theophylline, in accordance with the higher drug solubility and the higher friability of diltiazem matrices. In fact, although diffusion is the prevailing drug release mechanism for all matrices, the erosion mechanism seems to have some contribution in several formulations containing diltiazem. A reduction in the surface exposed to the dissolution medium (radial release studies) leads to a decrease in the drug release rate, but the release mechanism is not essentially modified. The nearly constant erosion front movement confirms the behaviour of these systems as inert matrices where the drugs are released mainly by diffusion through the porous structure. Copyright © 2011 Elsevier B.V. All rights reserved.

Mechanistic Studies of the N-formylation of Edivoxetine, a Secondary Amine-Containing Drug, in a Solid Oral Dosage Form.

PubMed

Hoaglund Hyzer, Cherokee S; Williamson, Michele L; Jansen, Patrick J; Kopach, Michael E; Scherer, R Brian; Baertschi, Steven W

2017-05-01

Edivoxetine (LY2216684 HCl), although a chemically stable drug substance, has shown the tendency to degrade in the presence of carbohydrates that are commonly used tablet excipients, especially at high excipient:drug ratios. The major degradation product has been identified as N-formyl edivoxetine. Experimental evidence including solution and solid-state investigations, is consistent with the N-formylation degradation pathway resulting from a direct reaction of edivoxetine with (1) formic acid (generated from decomposition of microcrystalline cellulose or residual glucose) and (2) the reducing sugar ends (aldehydic carbons) of either residual glucose or the microcrystalline cellulose polymer. Results of labeling experiments indicate that the primary source of the formyl group is the C1 position from reducing sugars. Presence of water or moisture accelerates this degradation pathway. Investigations in solid and solution states support that the glucose Amadori Rearrangement Product does not appear to be a direct intermediate leading to N-formyl degradation of edivoxetine, and oxygen does not appear to play a significant role. Solution-phase studies, developed to rapidly assess propensity of amines toward Maillard reactivity and formylation, were extended to show comparative behavior with example systems. The cyclic amine systems, such as edivoxetine, showed the highest propensity toward these side reactions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet.

PubMed

El-Zahaby, Sally A; AbouGhaly, Mohamed H H; Abdelbary, Ghada A; El-Gazayerly, Omaima N

2017-06-08

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5 mg VNP composed of Maisine™ 35-1, Transcutol ® HP, and Cremophor ® EL was adsorbed on the solid carrier Aeroperl ® . S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel ® , HPMC-K4M, PVP-K30, and Lubripharm ® ), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 3 2 *2 1 full factorial design was adopted. The independent variables were: type of coating material (X 1 ), concentration of coating solution (X 2 ), and number of drills (X 3 ). The dependent variables included % release at 2 h (Y 1 ), at 4 h (Y 2 ), and at 8 h (Y 3 ). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry ® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.

Nanocrystal cellulose as drug excipient in transdermal patch for wound healing: an overview

NASA Astrophysics Data System (ADS)

Zuki, S. A. Mohd; Rahman, N. Abd; Abu Bakar, N. F.

2018-03-01

Wound must be carefully treated to avoid serious infection that needs costly treatment. Method to enhance the recovery of the wound is crucial to have effective wound treatment. One of the technologies in wound treatment is transdermal patch that has the benefits of being non-invasive, easy to handle and permits constant drug dosage. In order to obtain a good controlled drug release, drug excipient needs to be investigated. Recently, natural Nanocrystal Cellulose (NCC) which can be synthesized from animal, algae, microorganism or plant has been actively used in drug delivery system as excipient. The application of NCC is advantageous due to its large surface area, biodegradable, non-toxic and abundance source.

Regulating Drug Release Behavior and Kinetics from Matrix Tablets Based on Fine Particle-Sized Ethyl Cellulose Ether Derivatives: An In Vitro and In Vivo Evaluation

PubMed Central

Shah, Kifayat Ullah; Khan, Gul Majid

2012-01-01

The design and fabrication of sustained/controlled release dosage forms, employing new excipients capable of extending/controlling the release of drugs from the dosage forms over prolonged periods, has worked well in achieving optimally enhanced therapeutic levels of the drugs. In this sense, the objective of this study was to investigate the suitability of selected cellulose ether derivatives for use in direct compression (DC) and as efficient drug release controlling agents. Controlled release matrix tablets of ciprofloxacin were prepared at different drug-to-polymer (D : P) ratios by direct compression using a fine particle sized ethylcellulose ether derivative (ETHOCEL Standard Premium 7FP) as rate controlling polymer. The tablets obtained were evaluated for various physico-chemical characteristics and in-vitro drug release studies were conducted in phosphate buffer (pH 7.4) using PharmaTest dissolution apparatus at constant temperature of 37°C ± 0.1. Similarity factor f 2 was employed to the release profiles of test formulations and were compared with marketed ciprofloxacin conventional tablets. Drug release mechanism and the kinetics involved were investigated by fitting the release profile data to various kinetic models. It was found that with increasing the proportion of ethylcellulose ether derivative in the matrix, the drug release was significantly extended up to 24 hours. The tablets exhibited zero order or nearly zero order drug transport mechanism. In vivo drug release performance of the developed controlled release tablets and reference conventional tablets containing ciprofloxacin were determined in rabbit serum according to randomized two-way crossover study design using High Performance Liquid Chromatography. Several bioavailability parameters of both the test tablets and conventional tablets including C max⁡, T max⁡ and AUC0-t were compared which showed an optimized C max⁡ and T max⁡ (P < 0.05). A good correlation was obtained between in vitro drug release and in vivo drug absorption with correlation value (R 2 = 0.934). Relative bioavailability was found to be 93%. Reproducibility of manufacturing process and accelerated stability of the developed tablets were performed in stability chamber at 40 ± 2°C and 75 ± 5% relative humidity for a period of 6 months and were found to be stable throughout the stability period. PMID:22649325

In Vitro and Ex Vivo Evaluation of Novel Curcumin-Loaded Excipient for Buccal Delivery.

PubMed

Laffleur, Flavia; Schmelzle, Franziska; Ganner, Ariane; Vanicek, Stefan

2017-08-01

This study aimed to develop a mucoadhesive polymeric excipient comprising curcumin for buccal delivery. Curcumin encompasses broad range of benefits such as antioxidant, anti-inflammatory, and chemotherapeutic activity. Hyaluronic acid (HA) as polymeric excipient was modified by immobilization of thiol bearing ligands. L-Cysteine (SH) ethyl ester was covalently attached via amide bond formation between cysteine and the carboxylic moiety of hyaluronic acid. Succeeded synthesis was proved by H-NMR and IR spectra. The obtained thiolated polymer hyaluronic acid ethyl ester (HA-SH) was evaluated in terms of stability, safety, mucoadhesiveness, drug release, and permeation-enhancing properties. HA-SH showed 2.75-fold higher swelling capacity over time in comparison to unmodified polymer. Furthermore, mucoadhesion increased 3.4-fold in case of HA-SH and drug release was increased 1.6-fold versus HA control, respectively. Curcumin-loaded HA-SH exhibits a 4.4-fold higher permeation compared with respective HA. Taking these outcomes in consideration, novel curcumin-loaded excipient, namely thiolated hyaluronic acid ethyl ester appears as promising tool for pharyngeal diseases.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

NASA Astrophysics Data System (ADS)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

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.

Evaluation of microwave oven heating for prediction of drug-excipient compatibilities and accelerated stability studies.

PubMed

Schou-Pedersen, Anne Marie V; Østergaard, Jesper; Cornett, Claus; Hansen, Steen Honoré

2015-05-15

Microwave ovens have been used extensively in organic synthesis in order to accelerate reaction rates. Here, a set up comprising a microwave oven combined with silicon carbide (SiC) plates for the controlled microwave heating of model formulations has been applied in order to investigate, if a microwave oven is applicable for accelerated drug stability testing. Chemical interactions were investigated in three selected model formulations of drug and excipients regarding the formation of ester and amide reaction products. In the accelerated stability studies, a design of experiments (DoE) approach was applied in order to be able to rank excipients regarding reactivity: Study A: cetirizine with PEG 400, sorbitol, glycerol and propylene glycol. Study B: 6-aminocaproic acid with citrate, acetate, tartrate and gluconate. Study C: atenolol with citric, tartaric, malic, glutaric, and sorbic acid. The model formulations were representative for oral solutions (co-solvents), parenteral solutions (buffer species) and solid dosage forms (organic acids applicable for solubility enhancement). The DoE studies showed overall that the same impurities were generated by microwave oven heating leading to temperatures between 150°C and 180°C as compared to accelerated stability studies performed at 40°C and 80°C using a conventional oven. Ranking of the reactivity of the excipients could be made in the DoE studies performed at 150-180°C, which was representative for the ranking obtained after storage at 40°C and 80°C. It was possible to reduce the time needed for drug-excipient compatibility testing of the three model formulations from weeks to less than an hour in the three case studies. The microwave oven is therefore considered to be an interesting alternative to conventional thermal techniques for the investigation of drug-excipient interactions during preformulation. Copyright © 2015 Elsevier B.V. All rights reserved.

The intramammary efficacy of first generation cephalosporins against Staphylococcus aureus mastitis in mice.

PubMed

Demon, Dieter; Ludwig, Carolin; Breyne, Koen; Guédé, David; Dörner, Julia-Charlotte; Froyman, Robrecht; Meyer, Evelyne

2012-11-09

Staphylococcus aureus-induced mastitis in cattle causes important financial losses in the dairy industry due to lower yield and bad milk quality. Although S. aureus is susceptible to many antimicrobials in vitro, treatment often fails to cure the infected udder. Hence, comprehensive evaluation of antimicrobials against S. aureus mastitis is desirable to direct treatment strategies. The mouse mastitis model is an elegant tool to evaluate antimicrobials in vivo while circumventing the high costs associated with bovine experiments. An evaluation of the antimicrobial efficacy of the intramammary (imam) applied first generation cephalosporins cefalexin, cefalonium, cefapirin and cefazolin, was performed using the S. aureus mouse mastitis model. In vivo determination of the effective dose 2log(10) (ED(2log10)), ED(4log10), protective dose 50 (PD(50)) and PD(100) in mouse mastitis studies, support that in vitro MIC data of the cephalosporins did not fully concur with the in vivo clinical outcome. Cefazolin was shown to be the most efficacious first generation cephalosporin to treat S. aureus mastitis whereas the MIC data indicate that cefalonium and cefapirin were more active in vitro. Changing the excipient for imam application from mineral oil to miglyol 812 further improved the antimicrobial efficacy of cefazolin, confirming that the excipient can influence the in vivo efficacy. Additionally, statistical analysis of the variation of S. aureus-infected, excipient-treated mice from fourteen studies emphasizes the strength of the mouse mastitis model as a fast, cost-effective and highly reproducible screening tool to assess the efficacy of antimicrobial compounds against intramammary S. aureus infection. Copyright © 2012 Elsevier B.V. All rights reserved.

Numerical Assessment of the Role of Slip and Twinning in Magnesium Alloy AZ31B During Loading Path Reversal

NASA Astrophysics Data System (ADS)

Wang, Huamiao; Wu, Peidong; Wang, Jian

2015-07-01

Magnesium alloy AZ31B plastically deforms via twinning and slip. Corresponding to the unidirectional nature of twinning, the activity of twinning/detwinning is directly related to loading history and materials texture. Using the elastic viscoplastic self-consistent model implementing with the twinning and detwinning model (EVPSC-TDT), we revisited experimental data of AZ31B sheets under four different strain paths: (1) tension-compression-tension along rolling direction, (2) tension-compression-tension along transverse direction, (3) compression-tension-compression along rolling direction, and (4) compression-tension-compression along transverse direction, and identified the dominant deformation mechanisms with respect to the strain path. We captured plastic deformation behaviors observed in experiments and quantitatively interpreted experimental observations in terms of the activities of different deformation mechanisms and the evolution of texture. It is found that the in-plane pre-tension has slight effect on the subsequent deformation, and the pre-compression and the reverse tension after compression have significant effect on the subsequent deformation. The inelastic behavior under compressive unloading is found to be insignificant at a small strain level but pronounced at a large strain level. Such significant effect is mainly ascribed to the activity of twinning and detwinning.

A rapid method for the determination of some antihypertensive and antipyretic drugs by thermometric titrimetry.

PubMed

Abbasi, U M; Chand, F; Bhanger, M I; Memon, S A

1986-02-01

A simple and rapid method is described for the direct thermometric determination of milligram amounts of methyl dopa, propranolol hydrochloride, 1-phenyl-3-methylpyrazolone (MPP) and 2,3-dimethyl-1-phenylpyrazol-5-one (phenazone) in the presence of excipients. The compounds are reacted with N'-bromosuccinimide and the heat of reaction is used to determine the end-point of the titration. The time required is approximately 2 min, and the accuracy is analytically acceptable.

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

Excipients in topical corticosteroid preparations in Canada.

PubMed Central

Searles, G E; DesGroseilliers, J P

1989-01-01

Topical corticosteroids are widely used for the treatment of dermatoses in Canada. The effects of the various nontherapeutic components of these formulations are less well known than those of the active ingredients and may cause adverse reactions. Information on the components is fragmentary and is scattered throughout the literature. We have attempted to consolidate this information into one source. Recent provincial legislation requiring the generic substitution of interchangeable products and the nondisclosure of all ingredients in product labelling hinder the search for an excipient that has caused an adverse reaction. Practitioner participation in the Cutaneous Adverse Reaction Registry of the Canadian Dermatology Association will identify sensitizing excipients and will support efforts by the profession to obtain more effective and safer products. PMID:2766179

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.

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.

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.

Quality by Design (QbD) Approach for Development of Co-Processed Excipient Pellets (MOMLETS) By Extrusion-Spheronization Technique.

PubMed

Patel, Hetal; Patel, Kishan; Tiwari, Sanjay; Pandey, Sonia; Shah, Shailesh; Gohel, Mukesh

2016-01-01

Microcrystalline cellulose (MCC) is an excellent excipient for the production of pellets by extrusion spheronization. However, it causes slow release rate of poorly water soluble drugs from pellets. Co-processed excipient prepared by spray drying (US4744987; US5686107; WO2003051338) and coprecipitation technique (WO9517831) are patented. The objective of present study was to develop co-processed MCC pellets (MOMLETS) by extrusion-spheronization technique using the principle of Quality by Design (QbD). Co-processed excipient core pellets (MOMLETS) were developed by extrusion spheronization technique using Quality by Design (QbD) approach. BCS class II drug (telmisartan) was layered onto it in a fluidized bed processor. Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA) for pellets were identified. Risk assessment was reported using Ishikawa diagram. Plackett Burman design was used to check the effect of seven independent variables; superdisintegrant, extruder speed, ethanol: water, spheronizer speed, extruder screen, pore former and MCC: lactose; on percentage drug release at 30 min. Pareto chart and normal probability plot was constructed to identify the significant factors. Box-Behnken design (BBD) using three most significant factors (Extruder screen size, type of superdisintegrant and type of pore former) was used as an optimization design. The control space was identified in which desired quality of the pellets can be obtained. Co-processed excipient core pellets (MOMLETS) were successfully developed by QbD approach. Versatility, Industrial scalability and simplicity are the main features of the proposed research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Interaction between curcumin and human serum albumin in the presence of excipients and the effect of binding on curcumin photostability.

PubMed

Vukićević, Milica; Tønnesen, Hanne Hjorth

2016-01-01

Curcumin (Cur) is known to bind to human serum albumin (HSA) which may lead to a reduced phototoxic effect of the compound in the presence of serum or saliva. The influence of excipients on the Cur-HSA binding was studied by HSA florescence quenching and Cur absorption and emission spectroscopy in the presence and absence of the selected excipients. Photostabilty of Cur in the presence of HSA was evaluated, as well as the effect of excipients on HSA bound Cur photodegradation. Cyclodextrins (CDs) (2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin) and polymers (polyethylene glycol 400, PEG 400 and Pluronic F-127, PF-127) were selected for the study. CDs and PF-127 seem to decrease Cur binding to HSA, probably through competitive binding. Cur was still bound to HSA in polyethylene glycol (PEG) solutions at the highest investigated concentration (5% w/v). However, high PEG concentration appears to have effect on the protein conformation, as shown by the fluorescence quenching study. Low Cur photostability in the presence of HSA could be improved by the addition of hydroxylpropyl-γ-cyclodextrin (HPγCD) to the samples, whereas PEG and PF-127 showed no effect.

Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance.

PubMed

Bosquillon, C; Lombry, C; Préat, V; Vanbever, R

2001-02-23

The objective of this study was to determine the effects of formulation excipients and physical characteristics of inhalation particles on their in vitro aerosolization performance, and thereby to maximize their respirable fraction. Dry powders were produced by spray-drying using excipients that are FDA-approved for inhalation as lactose, materials that are endogenous to the lungs as albumin and dipalmitoylphosphatidylcholine (DPPC); and/or protein stabilizers as trehalose or mannitol. Dry powders suitable for deep lung deposition, i.e. with an aerodynamic diameter of individual particles <3 microm, were prepared. They presented 0.04--0.25 g/cm(3) bulk tap densities, 3--5 microm geometric particle sizes, up to 90% emitted doses and 50% respirable fractions in the Andersen cascade impactor using a Spinhaler inhaler device. The incorporation of lactose, albumin and DPPC in the formulation all improved the aerosolization properties, in contrast to trehalose and the mannitol which decreased powder flowability. The relative proportion of the excipients affected aerosol performance as well. The lower the bulk powder tap density, the higher the respirable fraction. Optimization of in vitro aerosolization properties of inhalation dry powders can be achieved by appropriately selecting composition and physical characteristics of the particles.

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients.

PubMed

Minne, Antoine; Boireau, Hélène; Horta, Maria Joao; Vanbever, Rita

2008-11-01

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 microm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm(3). The particles were spherical with a granular surface and had a 4 microm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.

Effect of Excipients on Liquid-Liquid Phase Separation and Aggregation in Dual Variable Domain Immunoglobulin Protein Solutions.

PubMed

Raut, Ashlesha S; Kalonia, Devendra S

2016-03-07

Liquid-liquid phase separation (LLPS) and aggregation can reduce the physical stability of therapeutic protein formulations. On undergoing LLPS, the protein-rich phase can promote aggregation during storage due to high concentration of the protein. Effect of different excipients on aggregation in protein solution is well documented; however data on the effect of excipients on LLPS is scarce in the literature. In this study, the effect of four excipients (PEG 400, Tween 80, sucrose, and hydroxypropyl beta-cyclodextrin (HPβCD)) on liquid-liquid phase separation and aggregation in a dual variable domain immunoglobulin protein solution was investigated. Sucrose suppressed both LLPS and aggregation, Tween 80 had no effect on either, and PEG 400 increased LLPS and aggregation. Attractive protein-protein interactions and liquid-liquid phase separation decreased with increasing concentration of HPβCD, indicating its specific binding to the protein. However, HPβCD had no effect on the formation of soluble aggregates and fragments in this study. LLPS and aggregation are highly temperature dependent; at low temperature protein exhibits LLPS, at high temperature protein exhibits aggregation, and at an intermediate temperature both phenomena occur simultaneously depending on the solution conditions.

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.

Structure-activity relationship for hydrophobic salts as viscosity-lowering excipients for concentrated solutions of monoclonal antibodies.

PubMed

Guo, Zheng; Chen, Alvin; Nassar, Roger A; Helk, Bernhard; Mueller, Claudia; Tang, Yu; Gupta, Kapil; Klibanov, Alexander M

2012-11-01

To discover, elucidate the structure-activity relationship (SAR), and explore the mechanism of action of excipients able to drastically lower the viscosities of concentrated aqueous solutions of humanized monoclonal antibodies (MAbs). Salts prepared from hydrophobic cations and anions were dissolved into humanized MAbs solutions. Viscosities of the resulting solutions were measured as a function of the nature and concentration of the salts and MAbs. Even at moderate concentrations, some of the salts prepared herein were found to reduce over 10-fold the viscosities of concentrated aqueous solutions of several MAbs at room temperature. To be potent viscosity-lowering excipients, the ionic constituents of the salts must be hydrophobic, bulky, and aliphatic. A mechanistic hypothesis explaining the observed salt effects on MAb solutions' viscosities was proposed and verified.

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.

[Impact of directly compressed auxiliary materials on powder property of fermented cordyceps powder].

PubMed

Chen, Li-Hua; Yue, Guo-Chao; Guan, Yong-Mei; Yang, Ming; Zhu, Wei-Feng

2014-01-01

To investigate such physical indexes as hygroscopicity, angle of repose, bulk density, fillibility of compression of mixed powder of directly compressed auxiliary materials and fermented cordyceps powder by using micromeritic study methods. The results showed that spray-dried lactose Flowlac100 and microcrystalline cellulose Avicel PH102 had better effect in liquidity and compressibility on fermented cordyceps powder than pregelatinized starch. The study on the impact of directly compressed auxiliary materials on the powder property of fermented cordyceps powder had guiding significant to the research of fermented cordyceps powder tablets, and could provide basis for the development of fermented cordyceps powder tablets.

Rapid distortion analysis and direct simulation of compressible homogeneous turbulence at finite Mach number

NASA Technical Reports Server (NTRS)

Cambon, C.; Coleman, G. N.; Mansour, N. N.

1992-01-01

The effect of rapid mean compression on compressible turbulence at a range of turbulent Mach numbers is investigated. Rapid distortion theory (RDT) and direct numerical simulation results for the case of axial (one-dimensional) compression are used to illustrate the existence of two distinct rapid compression regimes. These regimes are set by the relationships between the timescales of the mean distortion, the turbulence, and the speed of sound. A general RDT formulation is developed and is proposed as a means of improving turbulence models for compressible flows.

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.

Hip adductor activations during run-to-cut maneuvers in compression shorts: Implications for return to sport after groin injury

PubMed Central

CHAUDHARI, AJIT M. W.; JAMISON, STEVEN T.; MCNALLY, MICHAEL P.; PAN, XUELIANG; SCHMITT, LAURA C.

2014-01-01

Athletes at high risk of groin strains in sports such as hockey and soccer often choose to wear shorts with directional compression to aid in prevention or recovery from hip adductor strains. Large eccentric contractions are known to result in or exacerbate strain injuries, but it is unknown if these shorts have a beneficial effect on hip adductor muscle activity. In this study, surface electromyography of the adductor longus and ground reaction force (GRF) data were obtained simultaneously on 29 healthy individuals without previous history of serious injury while performing unanticipated 45° run-to-cut maneuvers in a laboratory setting wearing shorts with non-directional compression (control, HeatGear, Under Armour, USA) or shorts with directional compression (directional, CoreShort PRO, Under Armour, USA), in random order. Average adductor activity in the stance leg was significantly lower in the directional condition than in the control condition during all parts of stance phase (all p<0.042). From this preliminary analysis, wearing directional compression shorts appears to be associated with reduced stance limb hip adductor activity. Athletes seeking to reduce demand on the hip adductors as they approach full return to activities may benefit from the use of directional compression shorts. PMID:24669858

Hip adductor activations during run-to-cut manoeuvres in compression shorts: implications for return to sport after groin injury.

PubMed

Chaudhari, Ajit M W; Jamison, Steven T; McNally, Michael P; Pan, Xueliang; Schmitt, Laura C

2014-01-01

Athletes at high risk of groin strains in sports such as hockey and soccer often choose to wear shorts with directional compression to aid in prevention of or recovery from hip adductor strains. Large, eccentric contractions are known to result in or exacerbate strain injuries, but it is unknown if these shorts have a beneficial effect on hip adductor muscle activity. In this study, surface electromyography (EMG) of the adductor longus and ground reaction force (GRF) data were obtained simultaneously on 29 healthy individuals without previous history of serious injury while performing unanticipated 45° run-to-cut manoeuvres in a laboratory setting wearing shorts with non-directional compression (control, HeatGear, Under Armour, USA) or shorts with directional compression (directional, CoreShort PRO, Under Armour, USA), in random order. Average adductor activity in the stance leg was significantly lower in the directional condition than in the control condition during all parts of stance phase (all P < 0.042). From this preliminary analysis, wearing directional compression shorts appears to be associated with reduced stance limb hip adductor activity. Athletes seeking to reduce demand on the hip adductors as they approach full return to activities may benefit from the use of directional compression shorts.

Stability of polymorphic forms of ranitidine hydrochloride.

PubMed

Wu, V; Rades, T; Saville, D J

2000-07-01

Ranitidine-HCl can exist in two different polymorphic forms: form I (m.p. 134-140 degrees C) and form II (m.p. 140-144 degrees C). In the present study the stability of form I of ranitidine-HCl to a selection of powder pretreatments, to reflect conditions which might occur in manufacturing procedures, and also to a limited range of storage conditions was investigated. The original samples of form I and form II used were characterised by X-ray powder diffraction (XRPD), hot stage microscopy (HSM) and differential scanning calorimetry (DSC). A quantitative XRPD method for determining the fraction of form II in the presence of form I was used. XRPD data were analysed using regression techniques and artificial neural networks (ANN). The quantitative XRPD technique was then used to monitor the relative proportion of form II in each treated sample. Pretreatments of form I included (i) mixing with form II or with common excipients (ii) compression and grinding (iii) contact with solvents (followed by drying) before storage. Storage conditions involved three temperatures (20 degrees C, 30 degrees C, 42 degrees C) and three relative humidities (45% RH; 55% RH; 75% RH). Samples were stored for a period of 6 months. A limited factorial design was used. No increase in the form II:form I ratio was observed in the following pretreatment processes: introduction of form II nuclei into form I; introduction of excipients to form I; compression of form I powder at 5 and 15 tons; normal mixing and grinding processes; addition of isopropanol (IPA) or water/IPA mix followed by drying. In the pretreatment process where water was added to form I powder (with most or all of the powder dissolving), drying of the liquefied mass led to a mix of form I and form II. On storage at room temperature (20-30 degrees C), low relative humidity (45-55% RH), and in an air-tight container there was no increase in the form II:form I ratio. Storage of form I/form II mixes, particularly at high humidity, resulted in a preferential loss of form II (compared to form I). Loss was greater at 30 degrees C/75% RH than at 20 degrees C/75% RH. Form II was also preferentially lost under low humidity conditions created by a saturated solution of potassium carbonate (45% RH) at the elevated temperature of 42 degrees C. This environment was shown to be acidic.

Preparation of orally disintegrating tablets with taste-masking function: masking effect in granules prepared with correctives using the dry granulation method and evaluation of tablets prepared using the taste-masked granules.

PubMed

Kawano, Yayoi; Ito, Akihiko; Sasatsu, Masanaho; Machida, Yoshiharu

2010-01-01

We investigated several methods of taste masking in the preparation of orally disintegrating tablets (ODTs), using furosemide (FU) as a model drug. Four types of FU preparations were prepared: granules with maltitol (MA), granules with yogurt powder (YO), a physical mixture of FU and MA, and a physical mixture of FU and YO. All taste-masking granules were prepared using the dry granulation method. The taste of each type of preparation was evaluated. All four preparations markedly improved the taste of the FU tablets, but the mixing ratios of the correctives did not affect the masking effect. No difference in masking effect was found between MA and YO in the physical mixtures, but the masking effect in the granules with YO was superior to that of the granules with MA. Taste-masked FU tablets were prepared using the direct compression method; crystalline cellulose (Avicel PH-302) and mannitol were added as excipients at the mixing ratio of 1/1. All four types of tablets displayed sufficient hardness, but MA-containing tablets were harder than YO-containing tablets. The hardness of the tablets prepared from YO granules increased as the YO content increased. The most rapidly disintegrating tablets were those of YO granules prepared at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s, followed by the tablets of MA granules prepared at a mixing ratio of FU/MA=1/1. The disintegration times of the tablets made from physical mixtures, in contrast, were longer than 200 s. Disintegration time lengthened as the mixing ratio of YO or MA increased. The hardness and disintegration time of these tablets could be controlled by varying the compression pressure. We found that YO is more useful than MA in masking unpleasant tastes and confirmed that orally disintegrating tablets with taste-masking function can be prepared using granules of YO prepared using the dry granulation method as a new corrective.

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.

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.

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.

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.

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.

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties.

PubMed

Huang, Yuh-Tyng; Tsai, Tong-Rong; Cheng, Chun-Jen; Cham, Thau-Ming; Lai, Tsun-Fwu; Chuo, Wen-Ho

2007-11-01

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2(3) full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T(max) was prolonged (from 0.65 +/- 0.082 hr to 4.83 +/- 1.60 hr) and AUC(0-t) (from 734.88 +/- 230.68 ng/ml.hr to 1153.34 +/- 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.

Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation

PubMed Central

Çelik, Burak

2017-01-01

The aim of this study was to design and optimize risperidone (RIS) mucoadhesive buccal tablets for systemic delivery as an alternative route. Direct compression method was used for the preparation of buccal tablets, and screening studies were conducted with different polymers to determine their effects on tablet characteristics. Carbopol® (CP) and sodium alginate (SA) were selected as two polymer types for further optimization studies by applying response surface methodology. Tablet hardness (TH), ex vivo residence time (RT), and peak detachment force (DF) from buccal mucosa were selected as three important responses. Physicochemical compatibility of formulation excipients and RIS was evaluated by using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) analysis. In vitro drug release profiles and release kinetics were investigated; swelling index and matrix erosion studies were conducted. Optimum formulation consisted of 16.4% CP and 20.3% SA, which provided 7.67±0.29 hour ex vivo RT, 45.52±4.85 N TH, and 2.12±0.17 N DF. FT-IR spectroscopy and DSC analysis revealed that there was no chemical interaction present between tablet ingredients. Cumulative RIS release of >90% was achieved after 8 hours of in vitro dissolution studies, which was supported by swelling and matrix erosion analysis. Mechanism of RIS release was fitted best to zero-order model, while release exponent (n) value of 0.77 demonstrated an anomalous (non-Fickian) release, indicating combined erosion and swelling mechanism. The results suggested that optimized buccal tablets of RIS would be a promising and alternative delivery system for the treatment of schizophrenia. PMID:29225461

Native and microwave-modified Terminalia mantaly gums as sustained-release and bioadhesive excipients in naproxen matrix tablet formulations.

PubMed

Odeniyi, Michael Ayodele; Oyedokun, Babatunde Mukhtar; Bamiro, Oluyemisi Adebowale

2017-01-01

Hydrophilic polymers provide a means of sustaining drug delivery. Native gums may be limited in function, but modification may improve their activity. The aim of the study was to evaluate native and modified forms of Terminalia mantaly gum for their sustained-release and bioadhesive properties. The native gum (NTM) was modified by microwave irradiation for 20 seconds (MTM20) and 60 seconds (MTM60) and characterized using microscopy, Fourier transform infrared spectroscopy (FTIR) and packing properties. The effects of the thermally induced molecular reorientation were determined. Tablet formulations of naproxen were produced by direct compression. The mechanical, bioadhesive and release properties of the formulations were determined. Irradiation of NTM improved the gum's flow properties, resulting in Carr's Index and Hausner's ratios lower than 16% and 1.25, respectively. Swelling studies showed that MTM20 and MTM60 had lower water absorption capacity and swelling index values, while packing properties improved upon irradiation, as depicted by lower tapped density values. FTIR spectra of samples showed that the irradiated gums were distinct from the native gums and did not interact with naproxen sodium. The gum's mechanical properties improved with MTM20 and MTM60 and sustained-release action of up 12 h was obtained. Inclusion of hydroxypropyl methylcellulose (HPMC) in the tablet formulations proved critical for bioadhesion. Microwave irradiation of native Terminalia mantaly gum improved the flow, mechanical and sustained-release properties of Naproxen tablets, and the addition of HPMC increased bioadhesion properties. The tablet properties of the native gum were significantly improved after 20 s of microwave irradiation.

Formulation and evaluation of microsphere based oro dispersible tablets of itopride hcl

PubMed Central

2012-01-01

Background The purpose of the present work is to mask the intensely bitter taste of Itopride HCl and to formulate an Oro dispersible tablet (ODT) of the taste-masked drug by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing. Methods With this objective in mind, microspheres loaded with Itopride HCl were prepared by solvent evaporation method using acetone as solvent for pH-sensitive polymer, Eudragit EPO and light liquid paraffin as the encapsulating medium. The prepared microspheres were characterized with regard to yield, drug content, flow properties, particle size and size distribution, surface features, in vitro drug release and taste. The ODTs so prepared from these microspheres were evaluated for hardness, thickness, weight variation, friability, disintegration time, drug content, wetting time, water absorption ratio, moisture uptake, in vitro dispersion, in vitro disintegration, in vitro drug release and stability. Results The average size of microspheres was found to be satisfactory in terms of the size and size distribution. Microspheres prepared were of a regular spherical shape. Comparison of the dissolution profiles of microspheres in different pH media showed that microspheres having drug: polymer ratio of 1:2 produced a retarding effect in simulated salivary fluid (pH 6.8) and were further used for formulation into ODTs after addition of suitable amounts of excipients such as superdisintegrant, diluent, sweetener and flavor of directly compressible grade. Conclusions Effective taste-masking was achieved for Itopride HCl by way of preparation of microspheres and ODTs of acceptable characteristics. PMID:23351176

Formulation and evaluation of microsphere based oro dispersible tablets of itopride hcl.

PubMed

Shah, Sanjay; Madan, Sarika; Agrawal, Ss

2012-09-03

The purpose of the present work is to mask the intensely bitter taste of Itopride HCl and to formulate an Oro dispersible tablet (ODT) of the taste-masked drug by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing. With this objective in mind, microspheres loaded with Itopride HCl were prepared by solvent evaporation method using acetone as solvent for pH-sensitive polymer, Eudragit EPO and light liquid paraffin as the encapsulating medium. The prepared microspheres were characterized with regard to yield, drug content, flow properties, particle size and size distribution, surface features, in vitro drug release and taste. The ODTs so prepared from these microspheres were evaluated for hardness, thickness, weight variation, friability, disintegration time, drug content, wetting time, water absorption ratio, moisture uptake, in vitro dispersion, in vitro disintegration, in vitro drug release and stability. The average size of microspheres was found to be satisfactory in terms of the size and size distribution. Microspheres prepared were of a regular spherical shape. Comparison of the dissolution profiles of microspheres in different pH media showed that microspheres having drug: polymer ratio of 1:2 produced a retarding effect in simulated salivary fluid (pH 6.8) and were further used for formulation into ODTs after addition of suitable amounts of excipients such as superdisintegrant, diluent, sweetener and flavor of directly compressible grade. Effective taste-masking was achieved for Itopride HCl by way of preparation of microspheres and ODTs of acceptable characteristics.

Effect of moisture content, temperature and exposure time on the physical stability of chitosan powder and tablets.

PubMed

Viljoen, Joe M; Steenekamp, Jan H; Marais, Andries F; Kotzé, Awie F

2014-06-01

Chitosan does not rank highly regarding its employment as tablet filler due to certain limitations. Undesirable properties that limit its utilization as excipient in solid dosage forms include its hydration propensity that negatively affects tablet stability, strength and disintegration. The objective of this study was to investigate the physical stability of chitosan powder, mixtures, granules and tablets under accelerated conditions such as elevated temperatures and humidity over different periods of time. Selected physico-chemical properties of pure chitosan powder, physical mixtures of chitosan with Kollidon® VA64 (BASF, Ludwigshafen, Germany), chitosan granules, as well as tablets were evaluated under conditions of elevated humidity and temperature. The physical stability of chitosan tablets exhibited sensitivity towards varying exposure conditions. It was furthermore evident that the presence of moisture (sorbed water) had a marked influence on the physical stability of chitosan powder and tablets. It was evident that the presence of Kollidon® VA64 as well as the method of inclusion of this binder influenced the properties of chitosan tablets. The physical stability of chitosan powder deteriorated to a greater extent compared to that of the chitosan tablets, which were subjected to the same conditions. It is recommended that tablets containing chitosan should be stored at a temperature not exceeding 25 °C as well as at a relatively low humidity (<60%) to prevent deterioration of physical properties. Direct compression of chitosan granules which contained 5%w/w Kollidon® VA64 produced the best formulation in terms of physical stability at the different conditions.

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.

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.

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.

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.

Beam width evolution of astigmatic hollow Gaussian beams in highly nonlocal nonlinear media

NASA Astrophysics Data System (ADS)

Yang, Zhen-Feng; Jiang, Xue-Song; Yang, Zhen-Jun; Li, Jian-Xing; Zhang, Shu-Min

We investigate the beam width evolution of astigmatic hollow Gaussian beams propagating in highly nonlocal nonlinear media. The input-power-induced different evolutions of the beam width are illustrated: (i) the beam widths in two transverse directions are compressed or broadened at the same time; (ii) the beam width in one transverse direction keeps invariant, and the other is compressed or broadened; (iii) furthermore, the beam width in one transverse direction is compressed, whereas it in the other transverse direction is broadened.

Some Results Relevant to Statistical Closures for Compressible Turbulence

NASA Technical Reports Server (NTRS)

Ristorcelli, J. R.

1998-01-01

For weakly compressible turbulent fluctuations there exists a small parameter, the square of the fluctuating Mach number, that allows an investigation using a perturbative treatment. The consequences of such a perturbative analysis in three different subject areas are described: 1) initial conditions in direct numerical simulations, 2) an explanation for the oscillations seen in the compressible pressure in the direct numerical simulations of homogeneous shear, and 3) for turbulence closures accounting for the compressibility of velocity fluctuations. Initial conditions consistent with small turbulent Mach number asymptotics are constructed. The importance of consistent initial conditions in the direct numerical simulation of compressible turbulence is dramatically illustrated: spurious oscillations associated with inconsistent initial conditions are avoided, and the fluctuating dilatational field is some two orders of magnitude smaller for a compressible isotropic turbulence. For the isotropic decay it is shown that the choice of initial conditions can change the scaling law for the compressible dissipation. A two-time expansion of the Navier-Stokes equations is used to distinguish compressible acoustic and compressible advective modes. A simple conceptual model for weakly compressible turbulence - a forced linear oscillator is described. It is shown that the evolution equations for the compressible portions of turbulence can be understood as a forced wave equation with refraction. Acoustic modes of the flow can be amplified by refraction and are able to manifest themselves in large fluctuations of the compressible pressure.

Stability of Proteins in Carbohydrates and Other Additives during Freezing: The Human Growth Hormone as a Case Study.

PubMed

Arsiccio, Andrea; Pisano, Roberto

2017-09-21

Molecular dynamics is here used to elucidate the mechanism of protein stabilization by carbohydrates and other additives during freezing. More specifically, we used molecular dynamics simulations to obtain a quantitative estimation of the capability of various cryoprotectants to preserve a model protein, the human growth hormone, against freezing stresses. Three mechanisms were investigated, preferential exclusion, water replacement, and vitrification. Model simulations were finally validated upon experimental data in terms of the ability of excipients to prevent protein aggregation. Overall, we found that the preferential exclusion and vitrification mechanisms are important during the whole freezing process, while water replacement becomes dominant only toward the end of the cryoconcentration phase. The disaccharides were found to be the most efficient excipients, in regard to both preferential exclusion and water replacement. Moreover, sugars were in general more efficient than other excipients, such as glycine or sorbitol.

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.

Detection of compatibility between baclofen and excipients with aid of infrared spectroscopy and chemometry

NASA Astrophysics Data System (ADS)

Rojek, Barbara; Wesolowski, Marek; Suchacz, Bogdan

2013-12-01

In the paper infrared (IR) spectroscopy and multivariate exploration techniques: principal component analysis (PCA) and cluster analysis (CA) were applied as supportive methods for the detection of physicochemical incompatibilities between baclofen and excipients. In the course of research, the most useful rotational strategy in PCA proved to be varimax normalized, while in CA Ward's hierarchical agglomeration with Euclidean distance measure enabled to yield the most interpretable results. Chemometrical calculations confirmed the suitability of PCA and CA as the auxiliary methods for interpretation of infrared spectra in order to recognize whether compatibilities or incompatibilities between active substance and excipients occur. On the basis of IR spectra and the results of PCA and CA it was possible to demonstrate that the presence of lactose, β-cyclodextrin and meglumine in binary mixtures produce interactions with baclofen. The results were verified using differential scanning calorimetry, differential thermal analysis, thermogravimetry/differential thermogravimetry and X-ray powder diffraction analyses.

Therapeutic surfactant-stripped frozen micelles

NASA Astrophysics Data System (ADS)

Zhang, Yumiao; Song, Wentao; Geng, Jumin; Chitgupi, Upendra; Unsal, Hande; Federizon, Jasmin; Rzayev, Javid; Sukumaran, Dinesh K.; Alexandridis, Paschalis; Lovell, Jonathan F.

2016-05-01

Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like `top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and `bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2-3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated.

Composition profiling of seized ecstasy tablets by Raman spectroscopy.

PubMed

Bell, S E; Burns, D T; Dennis, A C; Matchett, L J; Speers, J S

2000-10-01

Raman spectroscopy with far-red excitation has been investigated as a simple and rapid technique for composition profiling of seized ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine) tablets. The spectra obtained are rich in vibrational bands and allow the active drug and excipient used to bulk the tablets to be identified. Relative band heights can be used to determine drug/excipient ratios and the degree of hydration of the drug while the fact that 50 tablets per hour can be analysed allows large numbers of spectra to be recorded. The ability of Raman spectroscopy to distinguish between ecstasy tablets on the basis of their chemical composition is illustrated here by a sample set of 400 tablets taken from a large seizure of > 50,000 tablets that were found in eight large bags. The tablets are all similar in appearance and carry the same logo. Conventional analysis by GC-MS showed they contained MDMA. Initial Raman studies of samples from each of the eight bags showed that despite some tablet-to-tablet variation within each bag the contents could be classified on the basis of the excipients used. The tablets in five of the bags were sorbitol-based, two were cellulose-based and one bag contained tablets with a glucose excipient. More extensive analysis of 50 tablets from each of a representative series of sample bags have distribution profiles that showed the contents of each bag were approximately normally distributed about a mean value, rather than being mixtures of several discrete types. Two of the sorbitol-containing sample sets were indistinguishable while a third was similar but not identical to these, in that it contained the same excipient and MDMA with the same degree of hydration but had a slightly different MDMA/sorbitol ratio. The cellulose-based samples were badly manufactured and showed considerable tablet-to-tablet variation in their drug/excipient ratio while the glucose-based tablets had a tight distribution in their drug/excipient ratios. The degree of hydration in the MDMA feedstocks used to manufacture the cellulose-, glucose- and sorbitol-based tablets were all different from each other. This study, because it centres on a single seizure of physically similar tablets with the same active drug, highlights the fact that simple physical descriptions coupled with active drug content do not in themselves fully characterize the nature of the seized materials. There is considerable variation in the composition of the tablets within this single seizure and the fact that this variation can be detected from Raman spectra demonstrates that the potential benefits of obtaining highly detailed spectra can indeed translate into information that is not readily available from other methods but would be useful for tracing of drug distribution networks.

A comparative study of roll compaction of free-flowing and cohesive pharmaceutical powders.

PubMed

Yu, Shen; Gururajan, Bindhu; Reynolds, Gavin; Roberts, Ron; Adams, Michael J; Wu, Chuan-Yu

2012-05-30

Roll compaction is widely adopted as a dry granulation method in the pharmaceutical industry. The roll compaction behaviour of feed powders is primarily governed by two parameters: the maximum pressure and the nip angle. Although the maximum pressure can be measured directly using pressure sensors fitted in the rolls, it is not a trivial task to determine the nip angle, which is a measure of the size of the compaction zone and hence the degree of compression. Thus a robust approach based upon the calculation of the pressure gradient, which can be obtained directly from experiments using an instrumented roll compactor, was developed. It has been shown that the resulting nip angles are comparable to those obtained using the methods reported in literature. Nevertheless, the proposed approach has distinctive advantages including (1) it is based on the intrinsic features of slip and no-slip interactions between the powder and roll surface and (2) it is not necessary to carry out wall friction measurements that involve plates that may not be representative of the roll compactor in terms of the surface topography and surface energy. The method was evaluated by investigating the effect of roll speed for two pharmaceutical excipients with distinctive material properties: microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD). It was found that the maximum pressure and nip angle for DCPD, which is a cohesive powder, decrease sharply with increasing roll speed whereas they are essentially independent of roll speed for MCC, which is an easy flowing powder. The roll compaction behaviour of MCC-DCPD mixtures with various compositions was also investigated in order to evaluate the effect of flowability. It was found that the nip angle and maximum pressure generally increased with improved flowability of the feed powders. Copyright © 2012 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.

Radiator debris removing apparatus and work machine using same

DOEpatents

Martin, Kevin L [Washburn, IL; Elliott, Dwight E [Chillicothe, IL

2008-09-02

A radiator assembly includes a finned radiator core and a debris removing apparatus having a compressed air inlet and at least one compressed air outlet configured to direct compressed air through the radiator core. A work machine such as a wheel loader includes a radiator and a debris removing apparatus coupled with on-board compressed air and having at least one pressurized gas outlet configured to direct a gas toward the face of the radiator.

The analysis and modelling of dilatational terms in compressible turbulence

NASA Technical Reports Server (NTRS)

Sarkar, S.; Erlebacher, G.; Hussaini, M. Y.; Kreiss, H. O.

1991-01-01

It is shown that the dilatational terms that need to be modeled in compressible turbulence include not only the pressure-dilatation term but also another term - the compressible dissipation. The nature of these dilatational terms in homogeneous turbulence is explored by asymptotic analysis of the compressible Navier-Stokes equations. A non-dimensional parameter which characterizes some compressible effects in moderate Mach number, homogeneous turbulence is identified. Direct numerical simulations (DNS) of isotropic, compressible turbulence are performed, and their results are found to be in agreement with the theoretical analysis. A model for the compressible dissipation is proposed; the model is based on the asymptotic analysis and the direct numerical simulations. This model is calibrated with reference to the DNS results regarding the influence of compressibility on the decay rate of isotropic turbulence. An application of the proposed model to the compressible mixing layer has shown that the model is able to predict the dramatically reduced growth rate of the compressible mixing layer.

The analysis and modeling of dilatational terms in compressible turbulence

NASA Technical Reports Server (NTRS)

Sarkar, S.; Erlebacher, G.; Hussaini, M. Y.; Kreiss, H. O.

1989-01-01

It is shown that the dilatational terms that need to be modeled in compressible turbulence include not only the pressure-dilatation term but also another term - the compressible dissipation. The nature of these dilatational terms in homogeneous turbulence is explored by asymptotic analysis of the compressible Navier-Stokes equations. A non-dimensional parameter which characterizes some compressible effects in moderate Mach number, homogeneous turbulence is identified. Direct numerical simulations (DNS) of isotropic, compressible turbulence are performed, and their results are found to be in agreement with the theoretical analysis. A model for the compressible dissipation is proposed; the model is based on the asymptotic analysis and the direct numerical simulations. This model is calibrated with reference to the DNS results regarding the influence of compressibility on the decay rate of isotropic turbulence. An application of the proposed model to the compressible mixing layer has shown that the model is able to predict the dramatically reduced growth rate of the compressible mixing layer.

Efficacy of chest compressions directed by end-tidal CO2 feedback in a pediatric resuscitation model of basic life support.

PubMed

Hamrick, Jennifer L; Hamrick, Justin T; Lee, Jennifer K; Lee, Benjamin H; Koehler, Raymond C; Shaffner, Donald H

2014-04-14

End-tidal carbon dioxide (ETCO2) correlates with systemic blood flow and resuscitation rate during cardiopulmonary resuscitation (CPR) and may potentially direct chest compression performance. We compared ETCO2-directed chest compressions with chest compressions optimized to pediatric basic life support guidelines in an infant swine model to determine the effect on rate of return of spontaneous circulation (ROSC). Forty 2-kg piglets underwent general anesthesia, tracheostomy, placement of vascular catheters, ventricular fibrillation, and 90 seconds of no-flow before receiving 10 or 12 minutes of pediatric basic life support. In the optimized group, chest compressions were optimized by marker, video, and verbal feedback to obtain American Heart Association-recommended depth and rate. In the ETCO2-directed group, compression depth, rate, and hand position were modified to obtain a maximal ETCO2 without video or verbal feedback. After the interval of pediatric basic life support, external defibrillation and intravenous epinephrine were administered for another 10 minutes of CPR or until ROSC. Mean ETCO2 at 10 minutes of CPR was 22.7±7.8 mm Hg in the optimized group (n=20) and 28.5±7.0 mm Hg in the ETCO2-directed group (n=20; P=0.02). Despite higher ETCO2 and mean arterial pressure in the latter group, ROSC rates were similar: 13 of 20 (65%; optimized) and 14 of 20 (70%; ETCO2 directed). The best predictor of ROSC was systemic perfusion pressure. Defibrillation attempts, epinephrine doses required, and CPR-related injuries were similar between groups. The use of ETCO2-directed chest compressions is a novel guided approach to resuscitation that can be as effective as standard CPR optimized with marker, video, and verbal feedback.

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.

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.

A Systematic Approach Toward Stabilization of CagL, a Protein Antigen from Helicobacter pylori That Is a Candidate Subunit Vaccine

PubMed Central

Choudhari, Shyamal P.; Pendleton, Kirk P.; Ramsey, Joshua D.; Blanchard, Thomas G.; Picking, William D.

2013-01-01

An important consideration in the development of subunit vaccines is loss of activity caused by physical instability of the protein. Such instability often results from suboptimal solution conditions related to pH and temperature. Excipients can help to stabilize vaccines, but it is important to screen and identify excipients that adequately contribute to stabilization of a given formulation. CagL is a protein present in strains of Helicobacter pylori that possess type IV secretion systems. It contributes to bacterial adherence via α5β1 integrin, thereby making it an attractive subunit vaccine candidate. We characterized the stability of CagL in different pH and temperature conditions using a variety of spectroscopic techniques. Stability was assessed in terms of transition temperature (Tm) with the accumulated data then incorporated into an empirical phase diagram (EPD) that provided an overview of CagL physical stability. These analyses indicated maximum CagL stability at pH 4–6 up to 40 °C in the absence of excipient. Using this EPD analysis, aggregation assays were developed to screen a panel of excipients with some found to inhibit CagL aggregation. Candidate stabilizers were selected to confirm their enhanced stabilizing effect. These analyses will help in the formulation of a stable vaccine against H. pylori. PMID:23794457

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.

Synergistic Effect of Hydrotrope and Surfactant on Solubility and Dissolution of Atorvastatin Calcium: Screening Factorial Design Followed by Ratio Optimization

PubMed Central

Patel, V. F.; Sarai, J.

2014-01-01

The present study was aimed at investigating the effect of hydrotrope and surfactant on poor solubility of atorvastatin calcium. Excipients screening followed by factorial design was performed to study effect of excipients and manufacturing methods on solubility of drug. Three independent factors (carrier, surfactant and manufacturing method) were evaluated at two levels using solubility as a dependant variable. Solid-state characterisation was performed using Fourier transform infrared spectroscopy and differential scanning calorimetry. Optimised complex were incorporated into orally disintegrating micro tablets and in vitro dissolution test was performed. Nicotinamide, Plasdone and sodium dodecyl sulphate were emerged as promising excipients from excipient screening. General regression analysis revealed only the type of carrier has significantly enhanced (P<0.05) the solubility of drug while other factors were found to be nonsignificant. Ratio optimisation trial revealed that drug to nicotinamide ratio is more critical in enhancing the solubility of drug (40 fold increases in solubility compared to pure drug) in comparison to drug-surfactant ratio; however the presence of surfactant deemed essential. Significantly higher rate and extent of dissolution was observed from solid dispersion complex and tablets compared to dissolution of pure drug (P<0.05). Study revealed hydrotrope and surfactant have synergistic effect on solubility and dissolution of atorvastatin calcium and this can be explored further. PMID:25593381

Utility of High Throughput Screening Techniques to Predict Stability of Monoclonal Antibody Formulations During Early Stage Development.

PubMed

Goldberg, Deborah S; Lewus, Rachael A; Esfandiary, Reza; Farkas, David C; Mody, Neil; Day, Katrina J; Mallik, Priyanka; Tracka, Malgorzata B; Sealey, Smita K; Samra, Hardeep S

2017-08-01

Selecting optimal formulation conditions for monoclonal antibodies for first time in human clinical trials is challenging due to short timelines and reliance on predictive assays to ensure product quality and adequate long-term stability. Accelerated stability studies are considered to be the gold standard for excipient screening, but they are relatively low throughput and time consuming. High throughput screening (HTS) techniques allow for large amounts of data to be collected quickly and easily, and can be used to screen solution conditions for early formulation development. The utility of using accelerated stability compared to HTS techniques (differential scanning light scattering and differential scanning fluorescence) for early formulation screening was evaluated along with the impact of excipients of various types on aggregation of monoclonal antibodies from multiple IgG subtypes. The excipient rank order using quantitative HTS measures was found to correlate with accelerated stability aggregation rate ranking for only 33% (by differential scanning fluorescence) to 42% (by differential scanning light scattering) of the antibodies tested, due to the high intrinsic stability and minimal impact of excipients on aggregation rates and HTS data. Also explored was a case study of employing a platform formulation instead of broader formulation screening for early formulation development. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Biophysical stability of hyFc fusion protein with regards to buffers and various excipients.

PubMed

Lim, Jun Yeul; Kim, Nam Ah; Lim, Dae Gon; Eun, Chang-yong; Choi, Donghoon; Jeong, Seong Hoon

2016-05-01

A novel non-cytolytic hybrid Fc (hyFc) with an intact Ig structure without any mutation in the hyFc region, was developed to construct a long-acting agonistic protein. The stability of interleukin-7 (IL-7) fused with the hyFc (GXN-04) was evaluated to develop early formulations. Various biophysical methods were utilized and three different buffer systems with various pH ranges were investigated including histidine-acetate, sodium citrate, and tris buffers. Various excipients were incorporated into the systems to obtain optimum protein stability. Two evident thermal transitions were observed with the unfolding of IL-7 and hyFc. The Tm and ΔH increased with pH, suggesting increased conformational stability. Increased Z-average size with PDI and decreased zeta potential with pH increase, with the exception of tris buffer, showed aggregation issues. Moreover, tris buffer at higher pH showed aggregation peaks from DLS. Non-ionic surfactants were effective against agitation by outcompeting protein molecules for hydrophobic surfaces. Sucrose and sorbitol accelerated protein aggregation during agitation, but exhibited a protective effect against oxidation, with preferential exclusion favoring the compact states of GXN-04. The stability of GXN-04 was varied by basal buffers and excipients, hence the buffers and excipients need to be evaluated carefully to achieve the maximum stability of proteins. 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.

Development of biodegradable methylprednisolone microparticles for treatment of articular pathology using a spray-drying technique

PubMed Central

Tobar-Grande, Blanca; Godoy, Ricardo; Bustos, Paulina; von Plessing, Carlos; Fattal, Elias; Tsapis, Nicolas; Olave, Claudia; Gómez-Gaete, Carolina

2013-01-01

In this work, microparticles were prepared by spray-drying using albumin, chondroitin sulfate, and hyaluronic acid as excipients to create a controlled-release methylprednisolone system for use in inflammatory disorders such as arthritis. Scanning electron microscopy demonstrated that these microparticles were almost spherical, with development of surface wrinkling as the methylprednisolone load in the formulation was increased. The methylprednisolone load also had a direct influence on the mean diameter and zeta potential of the microparticles. Interactions between formulation excipients and the active drug were evaluated by x-ray diffraction, differential scanning calorimetry, and thermal gravimetric analysis, showing limited amounts of methylprednisolone in a crystalline state in the loaded microparticles. The encapsulation efficiency of methylprednisolone was approximately 89% in all formulations. The rate of methylprednisolone release from the microparticles depended on the initial drug load in the formulation. In vitro cytotoxic evaluation using THP-1 cells showed that none of the formulations prepared triggered an inflammatory response on release of interleukin-1β, nor did they affect cellular viability, except for the 9.1% methylprednisolone formulation, which was the maximum test concentration used. The microparticles developed in this study have characteristics amenable to a therapeutic role in inflammatory pathology, such as arthritis. PMID:23737670

Molecular dynamics simulation of the plastic behavior anisotropy of shock-compressed monocrystal nickel

NASA Astrophysics Data System (ADS)

Chen, Ya-Zhou; Zhou, Liu-Cheng; He, Wei-Feng; Sun, Yu; Li, Ying-Hong; Jiao, Yang; Luo, Si-Hai

2017-01-01

Molecular dynamics simulations were used to study the plastic behavior of monocrystalline nickel under shock compression along the [100] and [110] orientations. The shock Hugoniot relation, local stress curve, and process of microstructure development were determined. Results showed the apparent anisotropic behavior of monocrystalline nickel under shock compression. The separation of elastic and plastic waves was also obvious. Plastic deformation was more severely altered along the [110] direction than the [100] direction. The main microstructure phase transformed from face-centered cubic to body-centered cubic and generated a large-scale and low-density stacking fault along the family of { 111 } crystal planes under shock compression along the [100] direction. By contrast, the main mechanism of plastic deformation in the [110] direction was the nucleation of the hexagonal, close-packed phase, which generated a high density of stacking faults along the [110] and [1̅10] directions.

A study of compressibility and compactibility of directly compressible tableting materials containing tramadol hydrochloride.

PubMed

Mužíková, Jitka; Kubíčková, Alena

2016-09-01

The paper evaluates and compares the compressibility and compactibility of directly compressible tableting materials for the preparation of hydrophilic gel matrix tablets containing tramadol hydrochloride and the coprocessed dry binders Prosolv® SMCC 90 and Disintequik™ MCC 25. The selected types of hypromellose are Methocel™ Premium K4M and Methocel™ Premium K100M in 30 and 50 % concentrations, the lubricant being magnesium stearate in a 1 % concentration. Compressibility is evaluated by means of the energy profile of compression process and compactibility by the tensile strength of tablets. The values of total energy of compression and plasticity were higher in the tableting materials containing Prosolv® SMCC 90 than in those containing Disintequik™ MCC 25. Tramadol slightly decreased the values of total energy of compression and plasticity. Tableting materials containing Prosolv® SMCC 90 yielded stronger tablets. Tramadol decreased the strength of tablets from both coprocessed dry binders.

Pulse compression and prepulse suppression apparatus

DOEpatents

Dane, Clifford B.; Hackel, Lloyd A.; George, Edward V.; Miller, John L.; Krupke, William F.

1993-01-01

A pulse compression and prepulse suppression apparatus (10) for time compressing the output of a laser (14). A pump pulse (46) is separated from a seed pulse (48) by a first polarized beam splitter (20) according to the orientation of a half wave plate (18). The seed pulse (48) is directed into an SBS oscillator (44) by two plane mirrors (22, 26) and a corner mirror (24), the corner mirror (24) being movable to adjust timing. The pump pulse (46) is directed into an SBS amplifier 34 wherein SBS occurs. The seed pulse (48), having been propagated from the SBS oscillator (44), is then directed through the SBS amplifier (34) wherein it sweeps the energy of the pump pulse (46) out of the SBS amplifier (34) and is simultaneously compressed, and the time compressed pump pulse (46) is emitted as a pulse output (52). A second polarized beam splitter (38) directs any undepleted pump pulse 58 away from the SBS oscillator (44).

Pulse compression and prepulse suppression apparatus

DOEpatents

Dane, C.B.; Hackel, L.A.; George, E.V.; Miller, J.L.; Krupke, W.F.

1993-11-09

A pulse compression and prepulse suppression apparatus (10) for time compressing the output of a laser (14). A pump pulse (46) is separated from a seed pulse (48) by a first polarized beam splitter (20) according to the orientation of a half wave plate (18). The seed pulse (48) is directed into an SBS oscillator (44) by two plane mirrors (22, 26) and a corner mirror (24), the corner mirror (24) being movable to adjust timing. The pump pulse (46) is directed into an SBS amplifier 34 wherein SBS occurs. The seed pulse (48), having been propagated from the SBS oscillator (44), is then directed through the SBS amplifier (34) wherein it sweeps the energy of the pump pulse (46) out of the SBS amplifier (34) and is simultaneously compressed, and the time compressed pump pulse (46) is emitted as a pulse output (52). A second polarized beam splitter (38) directs any undepleted pump pulse 58 away from the SBS oscillator (44).

Molecular dynamics study of strain-induced diffusivity of nitrogen in pure iron nanocrystalline

NASA Astrophysics Data System (ADS)

Mohammadzadeh, Roghayeh; Razmara, Naiyer; Razmara, Fereshteh

2016-12-01

In the present study, the self-diffusion process of nitrogen in pure iron nanocrystalline under strain conditions has been investigated by Molecular Dynamics (MD). The interactions between particles are modeled using Modified Embedded Atom Method (MEAM). Mean Square Displacement (MSD) of nitrogen in iron structure under strain is calculated. Strain is applied along [ 11 2 ¯ 0 ] and [ 0001 ] directions in both tensile and compression conditions. The activation energy and pre-exponential diffusion factor for nitrogen diffusion is comparatively high along [ 0001 ] direction of compressed structure of iron. The strain-induced diffusion coefficient at 973 K under the compression rate of 0.001 Å/ps along [ 0001 ] direction is about 6.72E-14 m2/s. The estimated activation energy of nitrogen under compression along [ 0001 ] direction is equal to 12.39 kcal/mol. The higher activation energy might be due to the fact that the system transforms into a more dense state when compressive stress is applied.

A systematic evaluation of solubility enhancing excipients to enable the generation of permeability data for poorly soluble compounds in Caco-2 model.

PubMed

Shah, Devang; Paruchury, Sundeep; Matta, Muralikrishna; Chowan, Gajendra; Subramanian, Murali; Saxena, Ajay; Soars, Matthew G; Herbst, John; Haskell, Roy; Marathe, Punit; Mandlekar, Sandhya

2014-01-01

The study presented here identified and utilized a panel of solubility enhancing excipients to enable the generation of flux data in the Human colon carcinoma (Caco-2) system for compounds with poor solubility. Solubility enhancing excipients Dimethyl acetamide (DMA) 1 % v/v, polyethylene glycol (PEG) 400 1% v/v, povidone 1% w/v, poloxamer 188 2.5% w/v and bovine serum albumin (BSA) 4% w/v did not compromise Caco-2 monolayer integrity as assessed by trans-epithelial resistance measurement (TEER) and Lucifer yellow (LY) permeation. Further, these excipients did not affect P-glycoprotein (P-gp) mediated bidirectional transport of digoxin, permeabilities of high (propranolol) or low permeability (atenolol) compounds, and were found to be inert to Breast cancer resistant protein (BCRP) mediated transport of cladribine. This approach was validated further using poorly soluble tool compounds, atazanavir (poloxamer 188 2.5% w/v) and cyclosporine A (BSA 4% w/v) and also applied to new chemical entity (NCE) BMS-A in BSA 4% w/v, for which Caco-2 data could not be generated using the traditional methodology due to poor solubility (<1 µM) in conventional Hanks balanced salt solution (HBSS). Poloxamer 188 2.5% w/v increased solubility of atazanavir by >8 fold whereas BSA 4% w/v increased the solubility of cyclosporine A and BMS-A by >2-4 fold thereby enabling permeability as well as efflux liability estimation in the Caco-2 model with reasonable recovery values. To conclude, addition of excipients such as poloxamer 188 2.5% w/v and BSA 4% w/v to HBSS leads to a significant improvement in the solubility of the poorly soluble compounds resulting in enhanced recoveries without modulating transporter-mediated efflux, expanding the applicability of Caco-2 assays to poorly soluble compounds.

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.

A novel 3D Cartesian random sampling strategy for Compressive Sensing Magnetic Resonance Imaging.

PubMed

Valvano, Giuseppe; Martini, Nicola; Santarelli, Maria Filomena; Chiappino, Dante; Landini, Luigi

2015-01-01

In this work we propose a novel acquisition strategy for accelerated 3D Compressive Sensing Magnetic Resonance Imaging (CS-MRI). This strategy is based on a 3D cartesian sampling with random switching of the frequency encoding direction with other K-space directions. Two 3D sampling strategies are presented. In the first strategy, the frequency encoding direction is randomly switched with one of the two phase encoding directions. In the second strategy, the frequency encoding direction is randomly chosen between all the directions of the K-Space. These strategies can lower the coherence of the acquisition, in order to produce reduced aliasing artifacts and to achieve a better image quality after Compressive Sensing (CS) reconstruction. Furthermore, the proposed strategies can reduce the typical smoothing of CS due to the limited sampling of high frequency locations. We demonstrated by means of simulations that the proposed acquisition strategies outperformed the standard Compressive Sensing acquisition. This results in a better quality of the reconstructed images and in a greater achievable acceleration.

Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue.

PubMed

McRae, A; Hjorth, S; Mason, D; Dillon, L; Tice, T

1990-01-01

Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] 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) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.

Comparative studies of binding potential of Prunus armeniaca and Prunus domestica gums in tablets formulations.

PubMed

Rahim, Haroon; Khan, Mir Azam; Sadiq, Abdul; Khan, Shahzeb; Chishti, Kamran Ahmad; Rahman, Inayat U

2015-05-01

The current study was undertaken to compare the binding potential of Prunus armeniaca L. and Prunus domestica L. gums in tablets' formulations. Tablet batches (F-1 to F-9) were prepared Diclofenac sodium as model drug using 5%, 7.5% and 10% of each Prunus armeniaca L., Prunus domestica L. gums as binder. PVP K30 was used as a standard binder. Magnesium stearate was used as lubricant. Flow properties of granules (like bulk density, tapped density, Carr's index, Hausner's ratio, angle of repose) as well as the physical parameters of compressed tablets including hardness, friability, thickness and disintegration time were determined. Flow parameters of granules of all the batches were found good. Physical parameters (drug content, weight variation, thickness, hardness, friability, disintegration time) of formulated tablets were found within limit when tested. The dissolution studies showed that tablets formulations containing each Prunus domestica showed better binding capacity compared to Prunus armeniaca gum. The binding potential increased as the concentration of gums increased. The FTIR spectroscopic investigation showed that the formulations containing plant gum are compatible with the drug and other excipients used.

Preparation and characterization of ibuprofen-cetyl alcohol beads by melt solidification technique: effect of variables.

PubMed

Maheshwari, Manish; Ketkar, Anant R; Chauhan, Bhaskar; Patil, Vinay B; Paradkar, Anant R

2003-08-11

Ibuprofen (IBU) exhibits short half-life, poor compressibility, flowability and caking tendency. IBU melt has sufficiently low viscosity and exhibits interfacial tension sufficient to form droplet even at low temperature. A single step novel melt solidification technique (MST) was developed to produce IBU beads with lower amounts of excipient. Effect of variables was studied using a 3(2) factorial approach with speed of agitation and amount of cetyl alcohol (CA) as variables. The beads were evaluated using DSC, FT-IR and scanning electron microscope (SEM). Yield, micromeritic properties, crushing strength and release kinetics were also studied. Spherical beads with a method yield of above 90% were obtained. The data was analyzed by response surface methodology. The variables showed curvilinear relationship with yield in desired particle size range, crushing strength and, bulk and tap density. The drug release followed non-Fickian case II transport and the release rate decreased linearly with respect to amount of CA in the initial stages followed by curvilinearity at later stages of elution. The effect of changing porosity and tortuosity was well correlated.

Properties of hot-melt extruded theophylline tablets containing poly(vinyl acetate).

PubMed

Zhang, F; McGinity, J W

2000-09-01

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70 degrees C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.

Paclitaxel Encapsulated in Halloysite Clay Nanotubes for Intestinal and Intracellular Delivery.

PubMed

Yendluri, Raghuvara; Lvov, Yuri; de Villiers, Melgardt M; Vinokurov, Vladimir; Naumenko, Ekaterina; Tarasova, Evgenya; Fakhrullin, Rawil

2017-10-01

Naturally formed halloysite tubules have a length of 1 μm and lumens with a diameter of 12-15 nm which can be loaded with drugs. Halloysite's biocompatibility allows for its safe delivering to cells at a concentration of up to 0.5 mg/mL. We encapsulated the anticancer drug paclitaxel in halloysite and evaluated the drug release kinetics in simulated gastric and intestinal conditions. To facilitate maximum drug release in intestinal tract, halloysite tubes were coated with the pH-responsive polymer poly(methacrylic acid-co-methyl methacrylate). Release kinetics indicated a triggered drug release pattern at higher pH, corresponding to digestive tract environment. Tablets containing halloysite, loaded with paclitaxel, as a compression excipient were formulated with drug release occurring at a sustained rate. In vitro anticancer effects of paclitaxel-loaded halloysite nanotubes were evaluated on human cancer cells. In all the treated cell samples, polyploid nuclei of different sizes and fragmented chromatin were observed, indicating a high therapeutic effect of halloysite formulated paclitaxel. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Continious production of exfoliated graphite composite compositions and flow field plates

DOEpatents

Shi, Jinjun; Zhamu, Aruna; Jang, Bor Z.

2010-07-20

A process of continuously producing a more isotropic, electrically conductive composite composition is provided. The process comprises: (a) continuously supplying a compressible mixture comprising exfoliated graphite worms and a binder or matrix material, wherein the binder or matrix material is in an amount of between 3% and 60% by weight based on the total weight of the mixture; (b) continuously compressing the compressible mixture at a pressure within the range of from about 5 psi or 0.035 MPa to about 50,000 psi or 350 MPa in at least a first direction into a cohered graphite composite compact; and (c) continuously compressing the composite compact in a second direction, different from the first direction, to form the composite composition in a sheet or plate form. The process leads to composite plates with exceptionally high thickness-direction electrical conductivity.

30 CFR 57.13020 - Use of compressed air.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Use of compressed air. 57.13020 Section 57... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Compressed Air and Boilers § 57.13020 Use of compressed air. At no time shall compressed air be directed toward a...

30 CFR 56.13020 - Use of compressed air.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Use of compressed air. 56.13020 Section 56... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Compressed Air and Boilers § 56.13020 Use of compressed air. At no time shall compressed air be directed toward a person...

30 CFR 57.13020 - Use of compressed air.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Use of compressed air. 57.13020 Section 57... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Compressed Air and Boilers § 57.13020 Use of compressed air. At no time shall compressed air be directed toward a...

30 CFR 56.13020 - Use of compressed air.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Use of compressed air. 56.13020 Section 56... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Compressed Air and Boilers § 56.13020 Use of compressed air. At no time shall compressed air be directed toward a person...

30 CFR 56.13020 - Use of compressed air.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Use of compressed air. 56.13020 Section 56... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Compressed Air and Boilers § 56.13020 Use of compressed air. At no time shall compressed air be directed toward a person...

30 CFR 57.13020 - Use of compressed air.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Use of compressed air. 57.13020 Section 57... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Compressed Air and Boilers § 57.13020 Use of compressed air. At no time shall compressed air be directed toward a...

30 CFR 56.13020 - Use of compressed air.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Use of compressed air. 56.13020 Section 56... MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-SURFACE METAL AND NONMETAL MINES Compressed Air and Boilers § 56.13020 Use of compressed air. At no time shall compressed air be directed toward a person...

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.

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).

Criterion for excipients screening in the development of nanoemulsion formulation of three anti-inflammatory drugs.

PubMed

Shakeel, Faiyaz

2010-01-01

The present study was undertaken for screening of different excipients in the development of nanoemulsion formulations of three anti-inflammatory drugs namely ketoprofen, celecoxib (CXB) and meloxicam. Based on solubility profiles of each drug in oil, Triacetin (ketoprofen and CXB) and Labrafil (meloxicam) were selected as the oil phase. Based on maximum solubilization potential of oil in different surfactants, Cremophor-EL (ketoprofen and CXB) and Tween-80 (meloxicam) were selected as surfactants. Based on maximum nanoemulsion region in the pseudoternary phase diagrams, Transcutol-HP was selected as cosurfactant for all three drugs. 1:1 (ketoprofen and CXB) and 2:1 (meloxicam) mass ratio of surfactant to cosurfactant was selected for selection of different nanoemulsions on the basis of maximum nanoemulsion region in the phase diagrams. All selected nanoemulsion formulations were found thermodynamically stable. Results of these studies showed that all excipients were properly optimized for the development of nanoemulsion formulation of ketoprofen, CXB and meloxicam.

Optimization of glibenclamide tablet composition through the combined use of differential scanning calorimetry and D-optimal mixture experimental design.

PubMed

Mura, P; Furlanetto, S; Cirri, M; Maestrelli, F; Marras, A M; Pinzauti, S

2005-02-07

A systematic analysis of the influence of different proportions of excipients on the stability of a solid dosage form was carried out. In particular, a d-optimal mixture experimental design was applied for the evaluation of glibenclamide compatibility in tablet formulations, consisting of four classic excipients (natrosol as binding agent, stearic acid as lubricant, sorbitol as diluent and cross-linked polyvinylpyrrolidone as disintegrant). The goal was to find the mixture component proportions which correspond to the optimal drug melting parameters, i.e. its maximum stability, using differential scanning calorimetry (DSC) to quickly obtain information about possible interactions among the formulation components. The absolute value of the difference between the melting peak temperature of pure drug endotherm and that in each analysed mixture and the absolute value of the difference between the enthalpy of the pure glibenclamide melting peak and that of its melting peak in the different analyzed mixtures, were chosen as indexes of the drug-excipient interaction degree.

Degradation of components in drug formulations: a comparison between HPLC and DSC methods.

PubMed

Ceschel, G C; Badiello, R; Ronchi, C; Maffei, P

2003-08-08

Information about the stability of drug components and drug formulations is needed to predict the shelf-life of the final products. The studies on the interaction between the drug and the excipients may be carried out by means of accelerated stability tests followed by analytical determination of the active principle (HPLC and other methods) and by means of the differential scanning calorimetry (DSC). This research has been focused to the acetyl salicylic acid (ASA) physical-chemical characterisation by using DSC method in order to evaluate its compatibility with some of the most used excipients. It was possible to show, with the DSC method, the incompatibility of magnesium stearate with ASA; the HPLC data confirm the reduction of ASA concentration in the presence of magnesium stearate. With the other excipients the characteristic endotherms of the drug were always present and no or little degradation was observed with the accelerated stability tests. Therefore, the results with the DSC method are comparable and in good agreement with the results obtained with other methods.

Direct compression of chitosan: process and formulation factors to improve powder flow and tablet performance.

PubMed

Buys, Gerhard M; du Plessis, Lissinda H; Marais, Andries F; Kotze, Awie F; Hamman, Josias H

2013-06-01

Chitosan is a polymer derived from chitin that is widely available at relatively low cost, but due to compression challenges it has limited application for the production of direct compression tablets. The aim of this study was to use certain process and formulation variables to improve manufacturing of tablets containing chitosan as bulking agent. Chitosan particle size and flow properties were determined, which included bulk density, tapped density, compressibility and moisture uptake. The effect of process variables (i.e. compression force, punch depth, percentage compaction in a novel double fill compression process) and formulation variables (i.e. type of glidant, citric acid, pectin, coating with Eudragit S®) on chitosan tablet performance (i.e. mass variation, tensile strength, dissolution) was investigated. Moisture content of the chitosan powder, particle size and the inclusion of glidants had a pronounced effect on its flow ability. Varying the percentage compaction during the first cycle of a double fill compression process produced chitosan tablets with more acceptable tensile strength and dissolution rate properties. The inclusion of citric acid and pectin into the formulation significantly decreased the dissolution rate of isoniazid from the tablets due to gel formation. Direct compression of chitosan powder into tablets can be significantly improved by the investigated process and formulation variables as well as applying a double fill compression process.

Anisotropy of demineralized bone matrix under compressive load.

PubMed

Trębacz, Hanna; Zdunek, Artur

2011-01-01

Two groups of cubic specimens from diaphysis of bovine femur, intact and completely demineralized, were axially compressed. One half of the samples from each group were loaded along the axis of the femur (L) and the other - perpendicularly (T). Intact samples were characterized in terms of elastic modulus; for demineralized samples secant modulus of elasticity was calculated. During compression an acoustic emission (AE) signal was recorded and AE events and energy were analyzed. Samples of intact bone did not reveal any anisotropy under compression at the stress of 80 MPa. However, AE signal indicated an initiation of failure in samples loaded in T direction. Demineralized samples were anisotropic under compression. Both secant modulus of elasticity and AE parameters were significantly higher in T direction than in L direction, which is attributed to shifting and separation of lamellae of collagen fibrils and lamellae in bone matrix.

Anomalous elastic response of silicon to uniaxial shock compression on nanosecond time scales.

PubMed

Loveridge-Smith, A; Allen, A; Belak, J; Boehly, T; Hauer, A; Holian, B; Kalantar, D; Kyrala, G; Lee, R W; Lomdahl, P; Meyers, M A; Paisley, D; Pollaine, S; Remington, B; Swift, D C; Weber, S; Wark, J S

2001-03-12

We have used x-ray diffraction with subnanosecond temporal resolution to measure the lattice parameters of orthogonal planes in shock compressed single crystals of silicon (Si) and copper (Cu). Despite uniaxial compression along the (400) direction of Si reducing the lattice spacing by nearly 11%, no observable changes occur in planes with normals orthogonal to the shock propagation direction. In contrast, shocked Cu shows prompt hydrostaticlike compression. These results are consistent with simple estimates of plastic strain rates based on dislocation velocity data.

Anisotropic Constitutive Relationships in Energetic Materials: Nitromethane and Rdx

NASA Astrophysics Data System (ADS)

Oleynik, I. I.; Conroy, M.; White, C. T.

2007-12-01

The anisotropic constitutive relationships in solid nitromethane (NM) and α-RDX were studied using first-principles density functional theory (DFT). In addition to hydrostatic compressions, we performed uniaxial compressions in the [100], [010], [001], [110], [101], [011], and [111] directions up to the compression ratio V/V0 = 0.70. Equilibrium properties, including lattice parameters and elastic constants, as well as hydrostatic EOS, are in good agreement with available experimental data. The shear stresses of uniaxially compressed NM and α-RDX were used to predict the relative shock sensitivity between different crystallographic directions.

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.

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.

Inadvertent prescription of gelatin-containing oral medication: its acceptability to patients.

PubMed

Vissamsetti, Bharat; Payne, Mark; Payne, Stephen

2012-09-01

When prescribing, doctors usually only consider the 'active' component of any drug's formulation ignoring the majority of the agents which make up the bulk of the tablet or capsule, collectively known as excipients. Many urological drugs contain the excipient gelatin which is, universally, of animal origin; this may conflict with the dietetic ideals of patients. A questionnaire-based study, undertaken between January and June 2010 in a mixed ethnicity inner-city population presenting with urological symptoms, asked which patients preferred not to ingest animal-based products, who would ask about the content of their prescribed treatment and who would refuse to take that medication if alternatives were available. Ultimately, the authors sought to find out how many patients had been inadvertently prescribed gelatin-containing oral medications and to suggest ways in which prescriptions might be more congruous with an individual patient's dietetic wishes. This study demonstrated that 43.2% of the study population would prefer not to take animal product-containing medication even if no alternative were available. 51% of men with lower urinary tract symptoms were also found to have inadvertently been prescribed gelatin-containing products against their preferred dietary restriction. Education of healthcare professionals about excipients and getting them to ask about a patient's dietetic preferences may help avoid inadvertent prescription of the excipient gelatin in oral medications. Substitution of gelatin with vegetable-based alternatives and clearer labelling on drug packaging are alternative strategies to help minimise the risks of inadvertently contravening a patient's dietetic beliefs when prescribing oral medication.

[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.

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.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation

PubMed Central

El-Nabarawi, Mohamed A; Ali, Adel A; Aboud, Heba M; Hassan, Amira H; Godah, Amany H

2016-01-01

Objective Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière’s disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. Methods A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. Results Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. Conclusion The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl. PMID:28008227

Development of Multiple-Unit Floating Drug Delivery System of Clarithromycin: Formulation, in vitro Dissolution by Modified Dissolution Apparatus, in vivo Radiographic Studies in Human Volunteers.

PubMed

Reddy, Arun B; Reddy, Narendar D

2017-07-01

Clarithromycin (CM), a broad spectrum macrolide antibiotic used to eradicate H. pylori in peptic ulcer. Clarithromycin (CM) is well absorbed from the gastrointestinal tract, but has a bioavailability of 50% due to rapid biodegradation. The aim of this investigation was to increase the gastric residence time, and to control the drug release of clarithromycin by formulating into multiple unit floating mini-tablets. Floating tablets were prepared by using direct compression method with HPMC K 4 M and Polyox WSR 1105 as release retarded polymers and sodium bicarbonate as gas generating agent. The prepared mini-tablets were evaluated for thickness, weight variation, friability, hardness, drug content, in vitro buoyancy, swelling studies, in vitro dissolution studies by using modified Rossett-Rice test and in vivo radiographic studies in healthy human volunteers in fasting conditions. DSC analysis revealed that no interaction between drug and excipients. All the physical parameters of the tablets were within the acceptable limits. The optimized formulation (F6) had showed controlled drug release of 99.16±3.22% in 12 h, by zero-order release kinetics, along with floating lag time of 9.5±1.28 s and total floating time of 12±0.14 h. X-ray imaging studies revealed that in vivo gastric residence time of clarithromycin floating mini-tablet in the stomach was about 3.5 h. The results demonstrated that the developed floating mini-tablets of clarithromycin caused significant enhancement in gastric retention time along with sustained effect and increased oral bioavailability. © Georg Thieme Verlag KG Stuttgart · New York.

Novel tablet formulation of amorphous candesartan cilexetil solid dispersions involving P-gp inhibition for optimal drug delivery: in vitro and in vivo evaluation.

PubMed

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

2016-09-01

The aim of this study was to develop a novel tablet formulation of amorphous candesartan cilexetil (CAN) solid dispersion involving effective P-gp inhibition for optimal drug delivery by direct compression (DC) method. To accomplish DC, formulation blends were evaluated for micromeritic properties. The Carr index, Hausner ratio, flow rate and cotangent of the angle α were determined. The tablets with and without naringin prepared by DC technique were evaluated for average weight, hardness, disintegration time and friability assessments. The drug release profiles were determined to study the dissolution kinetics. In vivo pharmacokinetic studies were conducted in rabbits. Accelerated stability studies were performed for tablets at 40 ± 2 °C/75% RH ± 5% for 6 months. FTIR studies confirmed no discoloration, liquefaction and physical interaction between naringin and drug. The results indicated that tablets prepared from naringin presented a dramatic release (82%) in 30 min with a similarity factor (76.18), which is most likely due to the amorphous nature of drug and the higher micromeritic properties of blends. Our findings noticed 1.7-fold increase in oral bioavailability of tablet prepared from naringin with mean C max and AUC 0-12 h values as 35.81 ± 0.13 μg/mL and 0.14 ± 0.09 μg h/mL, respectively. The tablets with and without naringin prepared by DC technique were physically and chemically stable under accelerated stability conditions upon storage for 6 months. These results are attractive for further development of an oral tablet formulation of CAN through P-gp inhibition using naringin, a natural flavonoid as a pharmaceutical excipient.

Compressing a spinodal surface at fixed area: bijels in a centrifuge.

PubMed

Rumble, Katherine A; Thijssen, Job H J; Schofield, Andrew B; Clegg, Paul S

2016-05-11

Bicontinuous interfacially jammed emulsion gels (bijels) are solid-stabilised emulsions with two inter-penetrating continuous phases. Employing the method of centrifugal compression we find that macroscopically the bijel yields at relatively low angular acceleration. Both continuous phases escape from the top of the structure, making any compression immediately irreversible. Microscopically, the bijel becomes anisotropic with the domains aligned perpendicular to the compression direction which inhibits further liquid expulsion; this contrasts strongly with the sedimentation behaviour of colloidal gels. The original structure can, however, be preserved close to the top of the sample and thus the change to an anisotropic structure suggests internal yielding. Any air bubbles trapped in the bijel are found to aid compression by forming channels aligned parallel to the compression direction which provide a route for liquid to escape.

Compression-induced texture change in NiMnGa-polymer composites observed by synchrotron radiation

NASA Astrophysics Data System (ADS)

Scheerbaum, Nils; Hinz, Dietrich; Gutfleisch, Oliver; Skrotzki, Werner; Schultz, Ludwig

2007-05-01

Composites consisting of magnetic shape memory (MSM) particles embedded in a polyester matrix were prepared. Single-crystalline MSM particles were obtained by mortar grinding of melt-extracted and subsequently annealed Ni50.9Mn27.1Ga22.0 (at. %) fibers. The crystal structure of the martensite is tetragonal (5M) with c

Swirling midframe flow for gas turbine engine having advanced transitions

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

Montgomery, Matthew D.; Charron, Richard C.; Rodriguez, Jose L.

A gas turbine engine can-annular combustion arrangement (10), including: an axial compressor (82) operable to rotate in a rotation direction (60); a diffuser (100, 110) configured to receive compressed air (16) from the axial compressor; a plenum (22) configured to receive the compressed air from the diffuser; a plurality of combustor cans (12) each having a combustor inlet (38) in fluid communication with the plenum, wherein each combustor can is tangentially oriented so that a respective combustor inlet is circumferentially offset from a respective combustor outlet in a direction opposite the rotation direction; and an airflow guiding arrangement (80) configuredmore » to impart circumferential motion to the compressed air in the plenum in the direction opposite the rotation direction.« less

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.

Role of excipients and polymeric advancements in preparation of floating drug delivery systems

PubMed Central

Kaushik, Avinash Y; Tiwari, Ajay K; Gaur, Ajay

2015-01-01

Since decade or two, the development of floating drug delivery systems becomes a significant and novel tool as having low density than gastric content. There are various advanced polymers including chitosan, eudragit, etc., and excipients such as; pore forming agent, surfactants, etc. All of them are discussed briefly, and results are concluded from various reputed researches. We have discussed all natural and synthetic systems with their effect on the release and other parameters which are essential for the floating formulation development. PMID:25599027

Compressible homogeneous shear: Simulation and modeling

NASA Technical Reports Server (NTRS)

Sarkar, S.; Erlebacher, G.; Hussaini, M. Y.

1992-01-01

Compressibility effects were studied on turbulence by direct numerical simulation of homogeneous shear flow. A primary observation is that the growth of the turbulent kinetic energy decreases with increasing turbulent Mach number. The sinks provided by compressible dissipation and the pressure dilatation, along with reduced Reynolds shear stress, are shown to contribute to the reduced growth of kinetic energy. Models are proposed for these dilatational terms and verified by direct comparison with the simulations. The differences between the incompressible and compressible fields are brought out by the examination of spectra, statistical moments, and structure of the rate of strain tensor.

Compressible homogeneous shear - Simulation and modeling

NASA Technical Reports Server (NTRS)

Sarkar, S.; Erlebacher, G.; Hussaini, M. Y.

1991-01-01

Compressibility effects were studied on turbulence by direct numerical simulation of homogeneous shear flow. A primary observation is that the growth of the turbulent kinetic energy decreases with increasing turbulent Mach number. The sinks provided by compressible dissipation and the pressure dilatation, along with reduced Reynolds shear stress, are shown to contribute to the reduced growth of kinetic energy. Models are proposed for these dilatational terms and verified by direct comparison with the simulations. The differences between the incompressible and compressible fields are brought out by the examination of spectra, statistical moments, and structure of the rate of strain tensor.

Numerical assessment of the role of slip and twinning in magnesium alloy AZ31B during loading path reversal

DOE PAGES

Wang, Huamiao; Wu, Peidong; Wang, Jian

2015-04-17

Magnesium alloy AZ31B plastically deforms via twinning and slip. Corresponding to the unidirectional nature of twinning, the activity of twinning/detwinning is directly related to loading history and materials texture. Using the elastic viscoplastic self-consistent model implementing with the twinning and detwinning model (EVPSC–TDT), we revisited experimental data of AZ31B sheets under four different strain paths: (1) tension–compression–tension along rolling direction, (2) tension–compression–tension along transverse direction, (3) compression–tension–compression along rolling direction, and (4) compression–tension–compression along transverse direction, and identified the dominant deformation mechanisms with respect to the strain path. We captured plastic deformation behaviors observed in experiments and quantitatively interpreted experimentalmore » observations in terms of the activities of different deformation mechanisms and the evolution of texture. It is found that the in-plane pre-tension has slight effect on the subsequent deformation, and the pre-compression and the reverse tension after compression have significant effect on the subsequent deformation. The inelastic behavior under compressive unloading is found to be insignificant at a small strain level but pronounced at a large strain level. Lastly, such significant effect is mainly ascribed to the activity of twinning and detwinning.« less

Rapid analysis of ecstasy and related phenethylamines in seized tablets by Raman spectroscopy.

PubMed

Bell, S E; Burns, D T; Dennis, A C; Speers, J S

2000-03-01

Raman spectroscopy with far-red excitation has been used to study seized, tableted samples of MDMA (N-methyl-3,4-methylenedioxyamphetamine) and related compounds (MDA, MDEA, MBDB, 2C-B and amphetamine sulfate), as well as pure standards of these drugs. We have found that by using far-red (785 nm) excitation the level of fluorescence background even in untreated seized samples is sufficiently low that there is little difficulty in obtaining good quality data with moderate 2 min data accumulation times. The spectra can be used to distinguish between even chemically-similar substances, such as the geometrical isomers MDEA and MBDB, and between different polymorphic/hydrated forms of the same drug. Moreover, these differences can be found even in directly recorded spectra of seized samples which have been bulked with other materials, giving a rapid and non-destructive method for drug identification. The spectra can be processed to give unambiguous identification of both drug and excipients (even when more than one compound has been used as the bulking agent) and the relative intensities of drug and excipient bands can be used for quantitative or at least semi-quantitative analysis. Finally, the simple nature of the measurements lends itself to automatic sample handling so that sample throughputs of 20 samples per hour can be achieved with no real difficulty.

Lipolysis of the semi-solid self-emulsifying excipient Gelucire 44/14 by digestive lipases.

PubMed

Fernandez, Sylvie; Rodier, Jean-David; Ritter, Nicolas; Mahler, Bruno; Demarne, Frédéric; Carrière, Frédéric; Jannin, Vincent

2008-08-01

Gelucire 44/14 is a semi-solid self-emulsifying excipient used for the oral delivery of poorly water-soluble drugs. It is composed of C8-C18 acylglycerols and PEG-32 esters, all of which are potential substrates for digestive lipases. Here we studied the lipolysis of Gelucire 44/14 by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases. Human pancreatic lipase (HPL), the main lipase involved in the digestion of triacylglycerols, did not show any significant activity on Gelucire 44/14 or on either of its individual compounds, C8-C18 acylglycerols and PEG-32 esters. Other pancreatic lipases such as human pancreatic lipase-related protein 2 (HPLRP2) showed low activity on Gelucire 44/14 although the highest activity of HPLRP2 was that observed on the C8-C18 acylglycerol fraction, which accounts for 20% (w/w) of Gelucire 44/14. In addition, HPLRP2 showed low activities on the PEG-32 esters, whether these were tested individually or mixed together. Carboxyl ester hydrolase (CEH) showed high activity on Gelucire 44/14, and the highest activities of CEH were those recorded on the total PEG-32 ester fraction and on each individual PEG-32 ester, except for PEG-32 monostearate. The highest activity of all the enzymes tested was that of dog gastric lipase (DGL) on Gelucire 44/14, although DGL showed low activity on the PEG-32 ester fraction and on each individual PEG-32 ester. We compared the lipolysis of Gelucire 44/14 with that of Labrasol, another self-emulsifying excipient, which is liquid at room temperature. Human pancreatic juice showed similar rates of activity on both Gelucire 44/14 and Labrasol. This finding means that these excipients are hydrolyzed in vivo during pancreatic digestion, mainly by CEH in the case of Gelucire 44/14 and by both HPLRP2 and CEH in that of Labrasol, whereas HPL showed very low activities on each of these two excipients. This is the first time the effects of PEG and acyl chain length on the lipolytic activity of digestive lipases on PEG esters have been investigated.

Study of factors influencing the mechanical properties of polyurethane foams under dynamic compression

NASA Astrophysics Data System (ADS)

Linul, E.; Marsavina, L.; Voiconi, T.; Sadowski, T.

2013-07-01

Effect of density, loading rate, material orientation and temperature on dynamic compression behavior of rigid polyurethane foams are investigated in this paper. These parameters have a very important role, taking into account that foams are used as packing materials or dampers which require high energy impact absorption. The experimental study was carried out on closed-cell rigid polyurethane (PUR) foam specimens of different densities (100, 160 respectively 300 kg/m3), having a cubic shape. The specimens were subjected to uniaxial dynamic compression with loading rate in range of 1.37-3.25 m/s, using four different temperatures (20, 60, 90, 110°C) and two loading planes (direction (3) - rise direction and direction (2) - in plane). Experimental results show that Young's modulus, yield stress and plateau stress values increases with increasing density. One of the most significant effects of mechanical properties in dynamic compression of rigid PUR foams is the density, but also the loading speed, material orientation and temperature influences the behavior in compression

Reactive Material Structures

DTIC Science & Technology

2014-03-31

dissimilar materials ( steel end fixtures and RMS). 2.6.4 Compression Tests To prevent the ends of the specimens from mushrooming during compression ...RMS cylinder. The compression test was modeled in ANSYS by applying a fixed displacement in the axial direction. The first ply to exceed the...four phases of loading: 1) a compressive acceleration during gun launch, 2) a tensile unloading on exit from the barrel , 3) a compressive decelera

Determination of As, Cd, Hg and Pb in continuous use drugs and excipients by plasma-based techniques in compliance with the United States Pharmacopeia requirements

NASA Astrophysics Data System (ADS)

da Silva, Caroline Santos; Pinheiro, Fernanda Costa; do Amaral, Clarice Dias Britto; Nóbrega, Joaquim Araújo

2017-12-01

Some inorganic impurities are toxic to human health even when present at low concentrations and therefore must be carefully monitored in products as continuous use drugs. This work aimed the development of a simple microwave-assisted digestion procedure for different types of drugs and excipients and the analytical determination of elemental impurities according to the new regulations of the United States Pharmacopeia (USP) 232 and 233 using inductively coupled plasma optical emission spectrometry (ICP-OES) or inductively coupled plasma mass spectrometry (ICP-MS). Eight drugs samples and two excipients of different brands were microwave-assisted digested with inverse aqua regia. Addition and recovery experiments were performed according to J values, once permissible daily exposure value is specific for each element and estimated according to the maximum daily dose of drug indicated by the label. Samples were spiked with values of 1.5J in order to check accuracies for As, Cd, Hg, and Pb. Recoveries obtained by ICP-OES ranged from 75 to 148% and for ICP-MS ranged from 74 to 120%. The limits of detection for ICP-OES ranged from 0.4 to 17 mg kg- 1 and for ICP-MS from 7.4 to 41.6 μg kg- 1. Both analytical methods were adequate in terms of accuracies and sensitivities. Considering the maximum daily dose, all drugs samples and excipients contained As, Cd, Hg and Pb below the maximum limits stipulated by USP since all of them presented contents below respective limits of detection.

The impact of particle preparation methods and polymorphic stability of lipid excipients on protein distribution in microparticles.

PubMed

Liu, Jingying; Christophersen, Philip C; Yang, Mingshi; Nielsen, Hanne M; Mu, Huiling

2017-12-01

The present study aimed at elucidating the influence of polymorphic stability of lipid excipients on the physicochemical characters of different solid lipid microparticles (SLM), with the focus on the alteration of protein distribution in SLM. Labeled lysozyme was incorporated into SLM prepared with different excipients, i.e. trimyristin (TG14), glyceryl distearate (GDS), and glyceryl monostearate (GMS), by water-oil-water (w/o/w) or solid-oil-water (s/o/w) method. The distribution of lysozyme in SLM and the release of the protein from SLM were evaluated by confocal laser scanning microscopy. The storage stability of SLM was characterized by HPLC, differential scanning calorimetry, X-ray powder diffraction, and scanning electron microscopy. Lysozyme was displayed as small scattered domains inside GDS and GMS SLM, whereas it was incorporated in the core of TG14 SLM formulated by the w/o/w method or evenly distributed in TG14 SLM prepared by the s/o/w method. Stability study at 37 °C revealed that only TG14 SLM made by the w/o/w method was able to maintain the lysozyme amount both on the particle surface and released from the SLM. Elevated storage temperature induced polymorphic transition of lipids in GDS and GMS SLM, which was, however, not remarkable for the TG14 SLM. Lipid excipients and particle preparation methods were found to differently affect the lysozyme distribution in SLM, owning to varied storage stabilities of the lipids. The present study provides updated knowledge for rational development of lipid-based formulations for oral delivery of peptide or protein drugs.

Rapidly dissolving repaglinide powders produced by the ultra-rapid freezing process.

PubMed

Purvis, Troy; Mattucci, Michal E; Crisp, M Todd; Johnston, Keith P; Williams, Robert O

2007-07-20

The objective of the study was to produce rapidly dissolving formulations of the poorly water-soluble drug repaglinide using an innovative new technology, ultra-rapid freezing (URF), and to investigate the influence of excipient type on repaglinide stability. Repaglinide compositions containing different types and levels of excipients and different drug potencies (50%-86%) were produced by the URF technology. Repaglinide/excipient solutions were frozen on a cryogenic substrate, collected, and lyophilized to form a dry powder. Surfactants, including sodium dodecyl sulfate, and alkalizing agents such as diethanolamine (DEA) and tromethamine (TRIS) were incorporated into the compositions. Forced degradation of repaglinide was conducted under stressed conditions (eg, elevated temperature, exposure to peroxide) to determine the stability of the drug in such environments. The solubility of repaglinide increased as a function of increasing pH; therefore, incorporation of an alkalizing agent into the URF formulations increased the drug's solubility. Drug instability resulted when the drug was exposed to pH values above 9.0. URF formulations containing alkalizing agents showed no degradation or spontaneous recrystallization in the formulation, indicating that increased stability was afforded by processing. URF processing created nanostructured drug/excipient particles with higher dissolution rates than were achieved for unprocessed drug. Alkalizing agents such as TRIS and DEA, present at levels of 25% to 33% wt/wt in the formulations, did not cause degradation of the drug when processed using URF. URF processing, therefore, yielded fast-dissolving formulations that were physically and chemically stable, resistant to alkali degradation or spontaneous recrystallization in the formulation.

Effectiveness of supersaturation promoting excipients on albendazole concentrations in upper gastrointestinal lumen of fasted healthy adults.

PubMed

Kourentas, Alexandros; Vertzoni, Maria; Symillides, Mira; Goumas, Konstantinos; Gibbon, Robert; Butler, James; Reppas, Christos

2016-08-25

To evaluate the impact of dosage form relevant levels of a polymeric precipitation inhibitor and of lipid excipients on supersaturation of upper gastrointestinal contents with albendazole, a lipophilic weak base. Albendazole concentrations in stomach and in duodenum were evaluated after administration of 1) a suspension in water (Susp-Control), 2) a suspension in water in which hydroxyprolylmethylcellulose E5 (HPMC E5) had been pre-dissolved (Susp-HPMC), and 3) and 4) two contrasting designs of lipid based suspensions dispersed in water (Susp-IIIA and Susp-IV), on a cross-over basis to fasted healthy adults. Limited, but statistically significant supersaturation of duodenal contents was observed after Susp-HPMC, Susp-IIIA, and Susp-IV; supersaturation was more consistent after Susp-HPMC administration. Based on total albendazole amount per volume, gastric secretions did not significantly alter volumes of bulk gastric contents during the first 40min post administration of a glass of non-caloric water-based fluid. Αlbendazole gastric concentrations were higher than in the administered suspensions, but similar for all four formulations. Gastric emptying of albendazole after administration of Susp-Control or Susp-HPMC was slower than after administration of Susp-IIIA or Susp-IV. Small amounts of HPMC E5 were as effective as lipid excipients in achieving supersaturation of duodenal contents with albendazole, a fast precipitating weak base, in fasted adults. However, compared with the effect of HPMC E5 the effect of lipid excipients was delayed and variable. Copyright © 2016 Elsevier B.V. All rights reserved.

Tools for Early Prediction of Drug Loading in Lipid-Based Formulations

PubMed Central

2015-01-01

Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R2 0.85; Polysorbate 80, R2 0.90; Cremophor EL, R2 0.93). A melting point below 150 °C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug. PMID:26568134

Tools for Early Prediction of Drug Loading in Lipid-Based Formulations.

PubMed

Alskär, Linda C; Porter, Christopher J H; Bergström, Christel A S

2016-01-04

Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R(2) 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R(2) 0.85; Polysorbate 80, R(2) 0.90; Cremophor EL, R(2) 0.93). A melting point below 150 °C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R(2) 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R(2) 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.

Formulation and evaluation of floating tablet of H2-receptor antagonist.

PubMed

Kesarla, Rajesh S; Vora, Pratik Ashwinbhai; Sridhar, B K; Patel, Gunvant; Omri, Abdelwahab

2015-01-01

Conventional sustained dosage form of ranitidine hydrochloride (HCl) does not prevent frequent administration due to its degradation in colonic media and limited absorption in the upper part of GIT. Ranitidine HCl floating tablet was formulated with sublimation method to overcome the stated problem. Compatibility study for screening potential excipients was carried out using Fourier transform infrared spectroscopy (FT-IR) and differential scanning chromatography (DSC). Selected excipients were further evaluated for optimizing the formulation. Preliminary screening of binder, polymer and sublimating material was based on hardness and drug release, drug release with release kinetics and floating lag time with total floatation time, respectively. Selected excipients were subjected to 3(2) factorial design with polymer and sublimating material as independent factors. Matrix tablets were obtained by using 16/32" flat-faced beveled edges punches followed by sublimation. FT-IR and DSC indicated no significant incompatibility with selected excipients. Klucel-LF, POLYOX WSR N 60 K and l-menthol were selected as binder, polymer and sublimating material, respectively, for factorial design batches after preliminary screening. From the factorial design batches, optimum concentration to release the drug within 12 h was found to be 420 mg of POLYOX and 40 mg of l-menthol. Stability studies indicated the formulation as stable. Ranitidine HCl matrix floating tablets were formulated to release 90% of drug in stomach within 12 h. Hence, release of the drug could be sustained within narrow absorption site. Moreover, the dosage form was found to be floating within a fraction of second independent of the pH of media ensuring a robust formulation.

Compressed domain indexing of losslessly compressed images

NASA Astrophysics Data System (ADS)

Schaefer, Gerald

2001-12-01

Image retrieval and image compression have been pursued separately in the past. Only little research has been done on a synthesis of the two by allowing image retrieval to be performed directly in the compressed domain of images without the need to uncompress them first. In this paper methods for image retrieval in the compressed domain of losslessly compressed images are introduced. While most image compression techniques are lossy, i.e. discard visually less significant information, lossless techniques are still required in fields like medical imaging or in situations where images must not be changed due to legal reasons. The algorithms in this paper are based on predictive coding methods where a pixel is encoded based on the pixel values of its (already encoded) neighborhood. The first method is based on an understanding that predictively coded data is itself indexable and represents a textural description of the image. The second method operates directly on the entropy encoded data by comparing codebooks of images. Experiments show good image retrieval results for both approaches.

Evaluation on Compressive Characteristics of Medical Stents Applied by Mesh Structures

NASA Astrophysics Data System (ADS)

Hirayama, Kazuki; He, Jianmei

2017-11-01

There are concerns about strength reduction and fatigue fracture due to stress concentration in currently used medical stents. To address these problems, meshed stents applied by mesh structures were interested for achieving long life and high strength perfromance of medical stents. The purpose of this study is to design basic mesh shapes to obatin three dimensional (3D) meshed stent models for mechanical property evaluation. The influence of introduced design variables on compressive characteristics of meshed stent models are evaluated through finite element analysis using ANSYS Workbench code. From the analytical results, the compressive stiffness are changed periodically with compressive directions, average results need to be introduced as the mean value of compressive stiffness of meshed stents. Secondly, compressive flexibility of meshed stents can be improved by increasing the angle proportional to the arm length of the mesh basic shape. By increasing the number of basic mesh shapes arranged in stent’s circumferential direction, compressive rigidity of meshed stent tends to be increased. Finaly reducing the mesh line width is found effective to improve compressive flexibility of meshed stents.

Image compression-encryption scheme based on hyper-chaotic system and 2D compressive sensing

NASA Astrophysics Data System (ADS)

Zhou, Nanrun; Pan, Shumin; Cheng, Shan; Zhou, Zhihong

2016-08-01

Most image encryption algorithms based on low-dimensional chaos systems bear security risks and suffer encryption data expansion when adopting nonlinear transformation directly. To overcome these weaknesses and reduce the possible transmission burden, an efficient image compression-encryption scheme based on hyper-chaotic system and 2D compressive sensing is proposed. The original image is measured by the measurement matrices in two directions to achieve compression and encryption simultaneously, and then the resulting image is re-encrypted by the cycle shift operation controlled by a hyper-chaotic system. Cycle shift operation can change the values of the pixels efficiently. The proposed cryptosystem decreases the volume of data to be transmitted and simplifies the keys distribution simultaneously as a nonlinear encryption system. Simulation results verify the validity and the reliability of the proposed algorithm with acceptable compression and security performance.

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.

Identifying overarching excipient properties towards an in-depth understanding of process and product performance for continuous twin-screw wet granulation.

PubMed

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

2017-04-30

The overall objective of this work is to understand how excipient characteristics influence the process and product performance for a continuous twin-screw wet granulation process. The knowledge gained through this study is intended to be used for a Quality by Design (QbD)-based formulation design approach and formulation optimization. A total of 9 preferred fillers and 9 preferred binders were selected for this study. The selected fillers and binders were extensively characterized regarding their physico-chemical and solid state properties using 21 material characterization techniques. Subsequently, principal component analysis (PCA) was performed on the data sets of filler and binder characteristics in order to reduce the variety of single characteristics to a limited number of overarching properties. Four principal components (PC) explained 98.4% of the overall variability in the fillers data set, while three principal components explained 93.4% of the overall variability in the data set of binders. Both PCA models allowed in-depth evaluation of similarities and differences in the excipient properties. Copyright © 2017. Published by Elsevier B.V.

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.

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.

Process Options for Nominal 2-K Helium Refrigeration System Designs

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

Peter Knudsen, Venkatarao Ganni

Nominal 2-K helium refrigeration systems are frequently used for superconducting radio frequency and magnet string technologies used in accelerators. This paper examines the trade-offs and approximate performance of four basic types of processes used for the refrigeration of these technologies; direct vacuum pumping on a helium bath, direct vacuum pumping using full or partial refrigeration recovery, cold compression, and hybrid compression (i.e., a blend of cold and warm sub-atmospheric compression).

Interfraction variation in lung tumor position with abdominal compression during stereotactic body radiotherapy

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

Mampuya, Wambaka Ange; Nakamura, Mitsuhiro; Matsuo, Yukinori

2013-09-15

Purpose: To assess the effect of abdominal compression on the interfraction variation in tumor position in lung stereotactic body radiotherapy (SBRT) using cone-beam computed tomography (CBCT) in a larger series of patients with large tumor motion amplitude.Methods: Thirty patients with lung tumor motion exceeding 8 mm who underwent SBRT were included in this study. After translational and rotational initial setup error was corrected based on bone anatomy, CBCT images were acquired for each fraction. The residual interfraction variation was defined as the difference between the centroid position of the visualized target in three dimensions derived from CBCT scans and thosemore » derived from averaged intensity projection images. The authors compared the magnitude of the interfraction variation in tumor position between patients treated with [n= 16 (76 fractions)] and without [n= 14 (76 fractions)] abdominal compression.Results: The mean ± standard deviation (SD) of the motion amplitude in the longitudinal direction before abdominal compression was 19.9 ± 7.3 (range, 10–40) mm and was significantly (p < 0.01) reduced to 12.4 ± 5.8 (range, 5–30) mm with compression. The greatest variance of the interfraction variation with abdominal compression was observed in the longitudinal direction, with a mean ± SD of 0.79 ± 3.05 mm, compared to −0.60 ± 2.10 mm without abdominal compression. The absolute values of the 95th percentile of the interfraction variation for one side in each direction were 3.97/6.21 mm (posterior/anterior), 4.16/3.76 mm (caudal/cranial), and 2.90/2.32 mm (right/left) without abdominal compression, and 2.14/5.03 mm (posterior/anterior), 3.93/9.23 mm (caudal/cranial), and 2.37/5.45 mm (right/left) with abdominal compression. An absolute interfraction variation greater than 5 mm was observed in six (9.2%) fractions without and 13 (17.1%) fractions with abdominal compression.Conclusions: Abdominal compression was effective for reducing the amplitude of tumor motion. However, in most of the authors’ patients, the use of abdominal compression seemed to increase the interfraction variation in tumor position, despite reducing lung tumor motion. The daily tumor position deviated more systematically from the tumor position in the planning CT scan in the lateral and longitudinal directions in patients treated with abdominal compression compared to those treated without compression. Therefore, target matching is required to correct or minimize the interfraction variation.« less

Effect of pre-straining on the evolution of material anisotropy in rolled magnesium alloy AZ31 sheet

NASA Astrophysics Data System (ADS)

Qiao, H.; Guo, X. Q.; Wu, P. D.

2013-12-01

The large strain Elastic Visco-Plastic Self-Consistent (EVPSC) model and the recently developed Twinning and De-Twinning (TDT) model are applied to study the mechanical behavior of rolled magnesium alloy AZ31 sheet. Three different specimen orientations with tilt angles of 0°, 45° and 90° between the rolling direction and longitudinal specimen axis are used to study the mechanical anisotropy under both uniaxial tension and compression. The effect of pre-strain in uniaxial compression along the rolling direction on subsequent uniaxial tension/compression along the three directions is also investigated. It is demonstrated that the twinning during pre-strain in compression and the detwinning in the subsequent deformation have a significant influence on the mechanical anisotropy. Numerical results are in good agreement with the experimental observations found in the literature.

Scan-Line Methods in Spatial Data Systems

DTIC Science & Technology

1990-09-04

algorithms in detail to show some of the implementation issues. Data Compression Storage and transmission times can be reduced by using compression ...goes through the data . Luckily, there are good one-directional compression algorithms , such as run-length coding 13 in which each scan line can be...independently compressed . These are the algorithms to use in a parallel scan-line system. Data compression is usually only used for long-term storage of

Evaluation of the lubricating effect of magnesium stearate and glyceryl behenate solid lipid nanoparticles in a direct compression process.

PubMed

Martínez-Acevedo, Lizbeth; Zambrano-Zaragoza, María de la Luz; Vidal-Romero, Gustavo; Mendoza-Elvira, Susana; Quintanar-Guerrero, David

2018-05-02

The aim of this study was to develop solid lipid nanoparticles (SLN) and introduce them into a direct compression process to evaluate their lubricant properties. The study consisted of preparing glyceryl behenate SLN (Compritol® 888 ATO) by hot dispersion, and magnesium stearate SLN by a novel nanoprecipitation/ion exchange method. The ejection force was measured for nanosystems and raw materials in a formulation typically used for direct compression. The smallest particle sizes obtained were 456 nm for Compritol® 888 ATO and 330 nm for magnesium stearate. Results show that the NPs used as lubricants in a direct compression model formulation provided efficient lubrication by maintaining the lubricating properties of the system, thereby decreasing the amount of lubricant used compared to the raw material. The lubricating effect showed an increase of 15-30% for magnesium stearate and Compritol® 888 ATO, compared to the raw material at concentrations above 2%. Copyright © 2018 Elsevier B.V. All rights reserved.

High-resolution quantization based on soliton self-frequency shift and spectral compression in a bi-directional comb-fiber architecture

NASA Astrophysics Data System (ADS)

Zhang, Xuyan; Zhang, Zhiyao; Wang, Shubing; Liang, Dong; Li, Heping; Liu, Yong

2018-03-01

We propose and demonstrate an approach that can achieve high-resolution quantization by employing soliton self-frequency shift and spectral compression. Our approach is based on a bi-directional comb-fiber architecture which is composed of a Sagnac-loop-based mirror and a comb-like combination of N sections of interleaved single-mode fibers and high nonlinear fibers. The Sagnac-loop-based mirror placed at the terminal of a bus line reflects the optical pulses back to the bus line to achieve additional N-stage spectral compression, thus single-stage soliton self-frequency shift (SSFS) and (2 N - 1)-stage spectral compression are realized in the bi-directional scheme. The fiber length in the architecture is numerically optimized, and the proposed quantization scheme is evaluated by both simulation and experiment in the case of N = 2. In the experiment, a quantization resolution of 6.2 bits is obtained, which is 1.2-bit higher than that of its uni-directional counterpart.

Effects of gas sorption-induced swelling/shrinkage on the cleat compressibility of coal under different bedding directions.

PubMed

Peng, Shoujian; Fang, Zhiming; Shen, Jian; Xu, Jiang; Wang, Geoff

2017-10-30

The cleat compressibility of coal is a key parameter that is extensively used in modeling the coal reservoir permeability for Coal Bed Methane (CBM) recovery. Cleat compressibility is often determined from the permeability measurement made at different confining pressures but with a constant pore pressure. Hence, this parameter ignores the sorption strain effects on the cleat compressibility. By using the transient pulse decay (TPD) technique, this study presents the results from a laboratory characterization program using coal core drilled from different bedding directions to estimate gas permeability and coal cleat compressibility under different pore pressures while maintaining effective stress constant. Cleat compressibility was determined from permeability and sorption strain measurements that are made at different pore pressures under an effective stress constant. Results show that the cleat compressibility of coal increases slightly with the increase of pore pressure. Moreover, the cleat compressibility of Sample P (representing the face cleats in coal) is larger than that of Sample C (representing the butt cleats in coal). This result suggests that cleat compressibility should not be regarded as constant in the modeling of the CBM recovery. Furthermore, the compressibility of face cleats is considerably sensitive to the sorption-induced swelling/shrinkage and offers significant effects on the coal permeability.

Fabrication, pore structure and compressive behavior of anisotropic porous titanium for human trabecular bone implant applications.

PubMed

Li, Fuping; Li, Jinshan; Xu, Guangsheng; Liu, Gejun; Kou, Hongchao; Zhou, Lian

2015-06-01

Porous titanium with average pore size of 100-650 μm and porosity of 30-70% was fabricated by diffusion bonding of titanium meshes. Pore structure was characterized by Micro-CT scan and SEM. Compressive behavior of porous titanium in the out-of-plane direction was studied. The effect of porosity and pore size on the compressive properties was also discussed based on the deformation mode. The results reveal that the fabrication process can control the porosity precisely. The average pore size of porous titanium can be tailored by adjusting the pore size of titanium meshes. The fabricated porous titanium possesses an anisotropic structure with square pores in the in-plane direction and elongated pores in the out-of-plane direction. The compressive Young's modulus and yield stress are in the range of 1-7.5 GPa and 10-110 MPa, respectively. The dominant compressive deformation mode is buckling of mesh wires, but some uncoordinated buckling is present in porous titanium with lower porosity. Relationship between compressive properties and porosity conforms well to the Gibson-Ashby model. The effect of pore size on compressive properties is fundamentally ascribed to the aspect ratio of titanium meshes. Porous titanium with 60-70% porosity has potential for trabecular bone implant applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Retinex Image Processing: Improved Fidelity To Direct Visual Observation

NASA Technical Reports Server (NTRS)

Jobson, Daniel J.; Rahman, Zia-Ur; Woodell, Glenn A.

1996-01-01

Recorded color images differ from direct human viewing by the lack of dynamic range compression and color constancy. Research is summarized which develops the center/surround retinex concept originated by Edwin Land through a single scale design to a multi-scale design with color restoration (MSRCR). The MSRCR synthesizes dynamic range compression, color constancy, and color rendition and, thereby, approaches fidelity to direct observation.

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.

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

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.

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.

Optimized conditions for MDCK permeability and turbidimetric solubility studies using compounds representative of BCS classes I-IV.

PubMed

Taub, Mitchell E; Kristensen, Lisbeth; Frokjaer, Sven

2002-05-01

The solubility enhancing effects of various excipients, including their compatibility with in vitro permeability (P(app)) systems, was investigated using drugs representative of Biopharmaceutics Classification System (BCS) classes I-IV. Turbidimetric solubility determination using nephelometry and transport experiments using MDCK Strain I cell monolayers were employed. The highest usable concentration of each excipient [dimethyl sulfoxide (DMSO), ethanol, hydroxypropyl-beta-cyclodextrin (HPCD), and sodium taurocholate] was determined by monitoring apical (AP) to basolateral (BL) [14C]mannitol apparent permeability (P(app)) and the transepithelial electrical resistance (TEER) in transport experiments done at pH 6.0 and 7.4. The excipients were used in conjunction with compounds demonstrating relatively low aqueous solubility (amphotericin B, danazol, mefenamic acid, and phenytoin) in order to obtain a drug concentration >50 microM in the donor compartment. The addition of at least one of the selected excipients enhanced the solubility of the inherently poorly soluble compounds to >50 microM as determined via turbidimetric evaluation at pH 6.0 and 7.4. Ethanol and DMSO were found to be generally disruptive to the MDCK monolayer and were not nearly as useful as HPCD and sodium taurocholate. Sodium taurocholate (5 mM) was compatible with MDCK monolayers under all conditions investigated. Additionally, a novel in vitro system aimed at more accurately simulating in vivo conditions, i.e., a pH gradient (6.0 AP/7.4 BL), sodium taurocholate (5 mM, AP), and bovine serum albumin (0.25%, BL), was shown to generate more reliable P(app) values for compounds that are poorly soluble and/or highly protein bound.

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.

Improvement of enalapril maleate chemical stability by high shear melting granulation.

PubMed

de Oliveira, Ana Paula Montandon; Cunha, Talita Amorim; Serpa, Raphael Caixeta; Taveira, Stephânia Fleury; Lima, Eliana Martins; Almeida Diniz, Danielle Guimarães; de Freitas, Luis Alexandre Pedro; Marreto, Ricardo Neves

2014-09-18

Abstract Enalapril maleate is a widely used drug, which is chemically unstable when mixed with excipients resulting in enalaprilat and diketopiperazine as the main degradation products. The preparation of enalapril sodium salt has been used to improve drug stability in solid dosage forms; however, product rejection is observed when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. In this study, granules were prepared by melting granulation using stearic acid or glyceryl monostearate, with a view to developing more stable enalapril maleate solid dosage forms. The granules were prepared in a laboratory-scale high shear mixer and compressed in a rotary machine. Size distribution, flow properties, in vitro drug release and enalapril maleate chemical stability were evaluated and compared with data obtained from tablets prepared without hydrophobic binders. All formulations showed good physical properties and immediate drug release. The greatest improvement in the enalapril maleate stability was observed in formulations containing stearic acid. This study showed that hot melting granulation could be successfully used to prepare enalapril maleate granules which could substitute the in situ formation of enalapril sodium salt, since they provided better enalapril stability in solid dosage forms.

The development and in vitro evaluation of herbal pellets coated with Eudragit FS 30.

PubMed

Kaledaite, Rasa; Bernatoniene, Jurga; Dvořáčková, Kateřina; Gajdziok, Jan; Muselík, Jan; Pečiūra, Rimantas; Masteikova, Ruta

2014-05-20

Abstract The objective of this study was to prepare pellets of thyme (Thymus vulgaris L.), stinging nettle (Urtica dioica L.) and sage (Salvia officinalis L.) dry extracts by extrusion-spheronization technique to improve technological properties and investigate dissolution profiles of pellets covered different levels of pH-sensitive polymer Eudragit® FS. Optimal sample of pellets were prepared using microcrystalline cellulose and lactose as excipients and demonstrated excellent technological quality properties such as Hausner ratio (1.07 ± 0.11) and compressibility index (6.73 ± 0.94%) value, spericity (0.87 ± 0.001) and friability (0.22 ± 0.08 N). Pellets were coated by 10-35% (w/w) of Eudragit® FS. Dissolution studies showed that less than 20% of coating could not prevent dissolution of phenols in pH 1.2, 20% Eudragit® FS coating is enough to prevent herbal extract against dissolution in the stomach. There were observed no statistical significant differences between 20% and 25% or higher amount of coating polymer to a dissolution of phenols in low pH.

Coil Compression for Accelerated Imaging with Cartesian Sampling

PubMed Central

Zhang, Tao; Pauly, John M.; Vasanawala, Shreyas S.; Lustig, Michael

2012-01-01

MRI using receiver arrays with many coil elements can provide high signal-to-noise ratio and increase parallel imaging acceleration. At the same time, the growing number of elements results in larger datasets and more computation in the reconstruction. This is of particular concern in 3D acquisitions and in iterative reconstructions. Coil compression algorithms are effective in mitigating this problem by compressing data from many channels into fewer virtual coils. In Cartesian sampling there often are fully sampled k-space dimensions. In this work, a new coil compression technique for Cartesian sampling is presented that exploits the spatially varying coil sensitivities in these non-subsampled dimensions for better compression and computation reduction. Instead of directly compressing in k-space, coil compression is performed separately for each spatial location along the fully-sampled directions, followed by an additional alignment process that guarantees the smoothness of the virtual coil sensitivities. This important step provides compatibility with autocalibrating parallel imaging techniques. Its performance is not susceptible to artifacts caused by a tight imaging fieldof-view. High quality compression of in-vivo 3D data from a 32 channel pediatric coil into 6 virtual coils is demonstrated. PMID:22488589

An efficient coding algorithm for the compression of ECG signals using the wavelet transform.

PubMed

Rajoub, Bashar A

2002-04-01

A wavelet-based electrocardiogram (ECG) data compression algorithm is proposed in this paper. The ECG signal is first preprocessed, the discrete wavelet transform (DWT) is then applied to the preprocessed signal. Preprocessing guarantees that the magnitudes of the wavelet coefficients be less than one, and reduces the reconstruction errors near both ends of the compressed signal. The DWT coefficients are divided into three groups, each group is thresholded using a threshold based on a desired energy packing efficiency. A binary significance map is then generated by scanning the wavelet decomposition coefficients and outputting a binary one if the scanned coefficient is significant, and a binary zero if it is insignificant. Compression is achieved by 1) using a variable length code based on run length encoding to compress the significance map and 2) using direct binary representation for representing the significant coefficients. The ability of the coding algorithm to compress ECG signals is investigated, the results were obtained by compressing and decompressing the test signals. The proposed algorithm is compared with direct-based and wavelet-based compression algorithms and showed superior performance. A compression ratio of 24:1 was achieved for MIT-BIH record 117 with a percent root mean square difference as low as 1.08%.

Characterization of particle deformation during compression measured by confocal laser scanning microscopy.

PubMed

Guo, H X; Heinämäki, J; Yliruusi, J

1999-09-20

Direct compression of riboflavin sodium phosphate tablets was studied by confocal laser scanning microscopy (CLSM). The technique is non-invasive and generates three-dimensional (3D) images. Tablets of 1% riboflavin sodium phosphate with two grades of microcrystalline cellulose (MCC) were individually compressed at compression forces of 1.0 and 26.8 kN. The behaviour and deformation of drug particles on the upper and lower surfaces of the tablets were studied under compression forces. Even at the lower compression force, distinct recrystallized areas in the riboflavin sodium phosphate particles were observed in both Avicel PH-101 and Avicel PH-102 tablets. At the higher compression force, the recrystallization of riboflavin sodium phosphate was more extensive on the upper surface of the Avicel PH-102 tablet than the Avicel PH-101 tablet. The plastic deformation properties of both MCC grades reduced the fragmentation of riboflavin sodium phosphate particles. When compressed with MCC, riboflavin sodium phosphate behaved as a plastic material. The riboflavin sodium phosphate particles were more tightly bound on the upper surface of the tablet than on the lower surface, and this could also be clearly distinguished by CLSM. Drug deformation could not be visualized by other techniques. Confocal laser scanning microscopy provides valuable information on the internal mechanisms of direct compression of tablets.

Effect of Variation in Viscosity Grade of Ethycellulose on Theophylline Microcapsule Properties Prepared by Emulsion Solvent Evaporation.

PubMed

Garekani, Hadi Afrasiabi; Ahmadi, Behzad; Sadeghi, Fatemeh

2017-01-01

There are conflicting reports regarding the effect of polymer viscosity grade on microcapsule properties. The aim of the present study was to investigate the effect of just viscosity grade of ethylcellulose (EC) (not polymeric solution) on properties of theophylline microcapsules prepared by emulsion solvent evaporation. The effect of EC viscosity grade and drug:polymer ratio was investigated on microcapsule properties (yield, particle size, morphology, surface characteristics and drug release). Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) were implemented to study the interaction and solid state of drug. The microcapsules were compressed in the presence of excipients and drug release was evaluated. The yield of microencapsulation and encapsulation efficiency at 1:1 drug:polymer ratio was dependent on EC viscosity. Microcapsules were spherical with some pores on their surfaces. The number of pores was more and their size was bigger for EC 100 cP microcapsules. Theophylline remained in crystalline form after encapsulation. DSC studies confirmed lack of interaction between drug and polymer. The drug release was rapid at 2:1 drug:polymer whilst it was slowed down at 1:1 drug:polymer ratio. Microcapsules obtained from EC 100 cP showed slightly faster drug release at latter ratio. Marginal changes in release rate were observed after compression of microcapsules. All viscosity grades of EC were able to sustain the release of the drug from microcapsules. Considering the similar release profiles for microcapsules prepared from different viscosities of EC, the use of lower viscosity grade of EC is recommended due to the ease of production and also less processing time. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multiple Compressions in the Middle Energy Plasma Focus Device

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

Yousefi, H. R.; Ejiri, Y.; Ito, H.

This paper reports some of the results that are aimed to investigate the neutron emission from the middle energy Mather-type plasma focus. These results indicated that with increase the pressure, compression time is increase but there is not any direct relation between the compression time and neutron yield. Also it seems that multiple compression regimes is occurred in low pressure and single compression is appeared at higher pressure where is the favorable to neutron production.

Texture Studies and Compression Behaviour of Apple Flesh

NASA Astrophysics Data System (ADS)

James, Bryony; Fonseca, Celia

Compressive behavior of fruit flesh has been studied using mechanical tests and microstructural analysis. Apple flesh from two cultivars (Braeburn and Cox's Orange Pippin) was investigated to represent the extremes in a spectrum of fruit flesh types, hard and juicy (Braeburn) and soft and mealy (Cox's). Force-deformation curves produced during compression of unconstrained discs of apple flesh followed trends predicted from the literature for each of the "juicy" and "mealy" types. The curves display the rupture point and, in some cases, a point of inflection that may be related to the point of incipient juice release. During compression these discs of flesh generally failed along the centre line, perpendicular to the direction of loading, through a barrelling mechanism. Cryo-Scanning Electron Microscopy (cryo-SEM) was used to examine the behavior of the parenchyma cells during fracture and compression using a purpose designed sample holder and compression tester. Fracture behavior reinforced the difference in mechanical properties between crisp and mealy fruit flesh. During compression testing prior to cryo-SEM imaging the apple flesh was constrained perpendicular to the direction of loading. Microstructural analysis suggests that, in this arrangement, the material fails along a compression front ahead of the compressing plate. Failure progresses by whole lines of parenchyma cells collapsing, or rupturing, with juice filling intercellular spaces, before the compression force is transferred to the next row of cells.

Video compression via log polar mapping

NASA Astrophysics Data System (ADS)

Weiman, Carl F. R.

1990-09-01

A three stage process for compressing real time color imagery by factors in the range of 1600-to-i is proposed for remote driving'. The key is to match the resolution gradient of human vision and preserve only those cues important for driving. Some hardware components have been built and a research prototype is planned. Stage 1 is log polar mapping, which reduces peripheral image sampling resolution to match the peripheral gradient in human visual acuity. This can yield 25-to-i compression. Stage 2 partitions color and contrast into separate channels. This can yield 8-to-i compression. Stage 3 is conventional block data compression such as hybrid DCT/DPCM which can yield 8-to-i compression. The product of all three stages is i600-to-i data compression. The compressed signal can be transmitted over FM bands which do not require line-of-sight, greatly increasing the range of operation and reducing the topographic exposure of teleoperated vehicles. Since the compressed channel data contains the essential constituents of human visual perception, imagery reconstructed by inverting each of the three compression stages is perceived as complete, provided the operator's direction of gaze is at the center of the mapping. This can be achieved by eye-tracker feedback which steers the center of log polar mapping in the remote vehicle to match the teleoperator's direction of gaze.

Comparative study on twinning characteristics during two post-weld compression paths and their effects on joint enhancement.

PubMed

Liu, Zhe; Xin, Renlong; Li, Dongrong; Sun, Liyun; Liu, Qing

2016-12-23

Friction stir welding (FSW) has promising application potential in Mg alloys. However, the texture distribution in stir zone (SZ) is usually complicated for Mg alloys, which deterioriates the joint performance. In this study, the texture distribution in SZ was tailored by applying two kinds of post-weld compression deformation along normal direction (ND) or welding direction (WD) of the FSWed AZ31 Mg alloy plates. The twinning behavior and texture change in the various regions of SZ were then evaluated by electron back scatter diffraction (EBSD) characterization. The effect of texture change on the joint performance was discussed in terms of Schmid factors (SFs) for basal slip and extension twinning. The results showed that profuse extension twins were formed through the whole SZ for the sample subjected to compression along ND, whereas they were observed mainly in SZ-side for the sample compressed along WD. Most of the twins were present in the forms of twin bands or chains. The directions of the twin bands or chains were related to the habit plane traces of selected twin variants. The ND post-weld compression had better strengthening effects on the joints compared to the WD compression, and the underline mechanism was discussed.

Comparative study on twinning characteristics during two post-weld compression paths and their effects on joint enhancement

PubMed Central

Liu, Zhe; Xin, Renlong; Li, Dongrong; Sun, Liyun; Liu, Qing

2016-01-01

Friction stir welding (FSW) has promising application potential in Mg alloys. However, the texture distribution in stir zone (SZ) is usually complicated for Mg alloys, which deterioriates the joint performance. In this study, the texture distribution in SZ was tailored by applying two kinds of post-weld compression deformation along normal direction (ND) or welding direction (WD) of the FSWed AZ31 Mg alloy plates. The twinning behavior and texture change in the various regions of SZ were then evaluated by electron back scatter diffraction (EBSD) characterization. The effect of texture change on the joint performance was discussed in terms of Schmid factors (SFs) for basal slip and extension twinning. The results showed that profuse extension twins were formed through the whole SZ for the sample subjected to compression along ND, whereas they were observed mainly in SZ-side for the sample compressed along WD. Most of the twins were present in the forms of twin bands or chains. The directions of the twin bands or chains were related to the habit plane traces of selected twin variants. The ND post-weld compression had better strengthening effects on the joints compared to the WD compression, and the underline mechanism was discussed. PMID:28008982

Strain distribution in the lumbar vertebrae under different loading configurations.

PubMed

Cristofolini, Luca; Brandolini, Nicola; Danesi, Valentina; Juszczyk, Mateusz M; Erani, Paolo; Viceconti, Marco

2013-10-01

The stress/strain distribution in the human vertebrae has seldom been measured, and only for a limited number of loading scenarios, at few locations on the bone surface. This in vitro study aimed at measuring how strain varies on the surface of the lumbar vertebral body and how such strain pattern depends on the loading conditions. Eight cadaveric specimens were instrumented with eight triaxial strain gauges each to measure the magnitude and direction of principal strains in the vertebral body. Each vertebra was tested in a three adjacent vertebrae segment fashion. The loading configurations included a compressive force aligned with the vertebral body but also tilted (15°) in each direction in the frontal and sagittal planes, a traction force, and torsion (both directions). Each loading configuration was tested six times on each specimen. The strain magnitude varied significantly between strain measurement locations. The strain distribution varied significantly when different loading conditions were applied (compression vs. torsion vs. traction). The strain distribution when the compressive force was tilted by 15° was also significantly different from the axial compression. Strains were minimal when the compressive force was applied coaxial with the vertebral body, compared with all other loading configurations. Also, strain was significantly more uniform for the axial compression, compared with all other loading configurations. Principal strains were aligned within 19° to the axis of the vertebral body for axial-compression and axial-traction. Conversely, when the applied force was tilted by 15°, the direction of principal strain varied by a much larger angle (15° to 28°). This is the first time, to our knowledge, that the strain distribution in the vertebral body is measured for such a variety of loading configurations and a large number of strain sensors. The present findings suggest that the structure of the vertebral body is optimized to sustain compressive forces, whereas even a small tilt angle makes the vertebral structure work under suboptimal conditions. Copyright © 2013 Elsevier Inc. All rights reserved.

Valeriana officinalis Dry Plant Extract for Direct Compression: Preparation and Characterization.

PubMed

Gallo, Loreana; Ramírez-Rigo, María Veronica; Piña, Juliana; Palma, Santiago; Allemandi, Daniel; Bucalá, Verónica

2012-01-01

Valeriana officinalis L. (Valerianaceae) is one of the most widely used plants for the treatment of anxiety and insomnia. Usually dry plant extracts, including V. officinalis, are hygroscopic materials with poor physico-mechanical properties that can be directly compressed.A V. officinalis dry extract with moderate hygroscocity is suitable for direct compression, and was obtained by using a simple and economical technique. The V. officinalis fluid extract was oven-dried with colloidal silicon dioxide as a drying adjuvant. The addition of colloidal silicon dioxide resulted in a dry plant extract with good physico-mechanical properties for direct compression and lower hygroscopicity than the dry extract without the carrier. The dry plant extract glass transition temperature was considerably above room temperature (about 72 °C). The colloidal silicon dioxide also produced an antiplasticizing effect, improving the powder's physical stability.The pharmaceutical performance of the prepared V. officinalis dry extract was studied through the design of tablets. The manufactured tablets showed good compactability, friability, hardness, and disintegration time. Those containing a disintegrant (Avicel PH 101) exhibited the best pharmaceutical performance, having the lowest disintegration time of around 40 seconds.

An image compression survey and algorithm switching based on scene activity

NASA Technical Reports Server (NTRS)

Hart, M. M.

1985-01-01

Data compression techniques are presented. A description of these techniques is provided along with a performance evaluation. The complexity of the hardware resulting from their implementation is also addressed. The compression effect on channel distortion and the applicability of these algorithms to real-time processing are presented. Also included is a proposed new direction for an adaptive compression technique for real-time processing.

Determination of tocopheryl acetate and ascorbyl tetraisopalmitate in cosmetic formulations by HPLC.

PubMed

Almeida, M M; Alves, J M P; Patto, D C S; Lima, C R R C; Quenca-Guillen, J S; Santoro, M I R M; Kedor-Hackmann, E R M

2009-12-01

A rapid HPLC method was developed for the assay of tocopheryl acetate and ascorbyl tetraisopalmitate in cosmetic formulations. The validated method was applied for quantitative determination of these vitamins in simulated emulsion formulation. Samples were analysed directly on a RP-18 reverse phase column with UV detection at 222 nm. A mixture of methanol and isopropanol (25 : 75 v/v) was used as mobile phase. The retention time of tocopheryl acetate and ascorbyl tetraisopalmitate were 3.0 min and 5.9 min, respectively. Recovery was between 95% and 104%. In addition, the excipients did not interfere in the analysis. The method is simple, reproducible, selective and is suitable for routine analyses of commercial products.

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.

Radiosterilization of drugs in aqueous solutions may be achieved by the use of radioprotective excipients.

PubMed

Maquille, Aubert; Jiwan, Jean-Louis Habib; Tilquin, Bernard

2008-02-12

The aim of this study was to assess the feasibility of radiosterilization of drugs aqueous solutions and to evaluate the effects of some additives, such as mannitol, nicotinamide and pyridoxine, which might protect the drug from degradation. Metoclopramide was selected as a model drug. The structures of the degradation products were determined to gain insight on the radiolysis mechanisms in aqueous solution in order to design strategies to lower the drug degradation. Metoclopramide hydrochloride aqueous solutions with and without excipients were irradiated either with gamma rays or high-energy electrons. HPLC-DAD was used to measure the loss of chemical potency and to quantify the degradation products which were also characterized by LC-APCI-MS-MS. Metoclopramide recovery for gamma and electron beam-irradiated solutions containing either mannitol, pyridoxine or nicotinamide meets the pharmacopoeial specifications for metoclopramide content up to a 15 kGy irradiation so that metoclopramide solutions containing these excipients might be radiosterilized at 15 kGy either with gamma rays or high-energy electrons. Structures are proposed for the majority of radiolysis products. Similar radiolysis products were detected for gamma and electron beam irradiations but the chromatographic profiles were different (differences in the distribution of radiolysis products).

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.

Thiomers and thiomer-based nanoparticles in protein and DNA drug delivery.

PubMed

Hauptstein, Sabine; Bernkop-Schnürch, Andreas

2012-09-01

Thanks to advances in biotechnology, more and more highly efficient protein- and DNA-based drugs have been developed. Unfortunately, these kinds of drugs underlie poor non-parental bioavailability. To overcome hindrances like low mucosal permeability and enzymatic degradation polymeric excipients are utilized as drug carrier whereat thiolated excipients showed several promising qualities in comparison to the analogical unmodified polymer. The article deals with the comparatively easy modification of well-established polymers like chitosan or poly(acrylates) to synthesize thiomers. Further, the recently developed "next generation" thiomers e.g. preactivated or S-protected thiomers are introduced. Designative properties like mucoadhesion, uptake and permeation enhancement, efflux pump inhibition and protection against enzymatic degradation will be discussed and differences between first and next generation thiomers will be pointed out. Additionally, nanoparticles prepared with thiomers will be dealt with regarding to protein and DNA drug delivery as thiomers seem to be a promising approach to avoid parenteral application. Properties of thiomers per se and results of in vivo studies carried out so far for peptide and DNA drugs demonstrate their potential as multifunctional excipients. However, further investigations and optimizations have to be done before establishing a carrier system ready for clinical approval.

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.

Chitin's Functionality as a Novel Disintegrant: Benchmarking Against Commonly Used Disintegrants in Different Physicochemical Environments.

PubMed

Chaheen, Mohammad; Soulairol, Ian; Bataille, Bernard; Yassine, Ahmad; Belamie, Emmanuel; Sharkawi, Tahmer

2017-07-01

Disintegrants are used as excipients to ensure rapid disintegration of pharmaceutical tablets and further ensure proper dissolution of the active pharmaceutical ingredient. This study investigates disintegration mechanisms of chitin and common disintegrants. Swelling assessment (swelling force and swelling ratio) in different media, and compaction behavior (pure or mixed with other excipients) tabletability, deformation (Heckel modeling), and compact disintegration times were investigated on the tested disintegrants (alginic acid calcium salt, crospovidone, sodium starch glycolate, croscarmellose sodium, and chitin). Results show that the physicochemical properties of the disintegration medium such as pH and ionic strength, as well as other formulation ingredients, affect the disintegrant functionalities. Heckel analysis using the mean yield pressure "Py" shows that alginic acid calcium salt is the most brittle among the studied disintegrants, while crospovidone has the most plastic deformation mechanism, followed by chitin. Chitin showed good tabletability and disintegration properties that were not influenced by the physicochemical formulation environment. Chitin is largely available and easily modifiable and thus a promising material that could be used as a multifunctional excipient in tablet formulation. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Self-emulsifying excipient platform for improving technological properties of alginate-hydroxypropylcellulose pellets.

PubMed

Mannina, Paolo; Segale, Lorena; Giovannelli, Lorella; Bonda, Andrea Foglio; Pattarino, Franco

2016-02-29

In this work, alginate, alginate-pectin and alginate-hydroxypropylcellulose pellets were produced by ionotropic gelation and characterized. Ibuprofen was selected as model drug; it was suspended in the polymeric solution in crystalline form or dissolved in a self-emulsifying phase and then dispersed into the polymeric solution. The self-emulsifying excipient platform composed of Labrasol (PEG-8 caprylic/capric glycerides) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), able to solubilize the drug was used to improve the technological and biopharmaceutical properties of the alginate pellets. The pellets had diameters between 1317 and 2026 μm and a high drug content (>51%). DSC analysis showed the amorphous state of drug in the pellets containing the self-emulsifying phase. All the systems restricted drug release in conditions simulating the gastric environment and made the drug completely available at a pH value typical for the intestine. Only alginate-HPC systems containing the drug solubilized into the self-emulsifying phase showed the ability to partially control the release of ibuprofen at neutral pH. The self-emulsifying excipient platform is a useful tool to improve technological and biopharmaceutical properties of alginate-HPC pellets. Copyright © 2015 Elsevier B.V. All rights reserved.

Advances in high throughput DNA sequence data compression.

PubMed

Sardaraz, Muhammad; Tahir, Muhammad; Ikram, Ataul Aziz

2016-06-01

Advances in high throughput sequencing technologies and reduction in cost of sequencing have led to exponential growth in high throughput DNA sequence data. This growth has posed challenges such as storage, retrieval, and transmission of sequencing data. Data compression is used to cope with these challenges. Various methods have been developed to compress genomic and sequencing data. In this article, we present a comprehensive review of compression methods for genome and reads compression. Algorithms are categorized as referential or reference free. Experimental results and comparative analysis of various methods for data compression are presented. Finally, key challenges and research directions in DNA sequence data compression are highlighted.

Active intestinal drug absorption and the solubility-permeability interplay.

PubMed

Porat, Daniel; Dahan, Arik

2018-02-15

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Cosmological Particle Data Compression in Practice

NASA Astrophysics Data System (ADS)

Zeyen, M.; Ahrens, J.; Hagen, H.; Heitmann, K.; Habib, S.

2017-12-01

In cosmological simulations trillions of particles are handled and several terabytes of unstructured particle data are generated in each time step. Transferring this data directly from memory to disk in an uncompressed way results in a massive load on I/O and storage systems. Hence, one goal of domain scientists is to compress the data before storing it to disk while minimizing the loss of information. To prevent reading back uncompressed data from disk, this can be done in an in-situ process. Since the simulation continuously generates data, the available time for the compression of one time step is limited. Therefore, the evaluation of compression techniques has shifted from only focusing on compression rates to include run-times and scalability.In recent years several compression techniques for cosmological data have become available. These techniques can be either lossy or lossless, depending on the technique. For both cases, this study aims to evaluate and compare the state of the art compression techniques for unstructured particle data. This study focuses on the techniques available in the Blosc framework with its multi-threading support, the XZ Utils toolkit with the LZMA algorithm that achieves high compression rates, and the widespread FPZIP and ZFP methods for lossy compressions.For the investigated compression techniques, quantitative performance indicators such as compression rates, run-time/throughput, and reconstruction errors are measured. Based on these factors, this study offers a comprehensive analysis of the individual techniques and discusses their applicability for in-situ compression. In addition, domain specific measures are evaluated on the reconstructed data sets, and the relative error rates and statistical properties are analyzed and compared. Based on this study future challenges and directions in the compression of unstructured cosmological particle data were identified.

Studies on morphology of Langmuir-Blodgett films of stearic acid deposited with different orientation of substrates with respect to compression

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

Choudhary, Keerti; Manjuladevi, V.; Gupta, R. K., E-mail: raj@pilani.bits-pilani.ac.in

2016-05-06

The Langmuir monolayer at an air-water interface shows remarkably different surface pressure – area isotherm, when measured with the surface normal of a Wilhemly plate parallel or perpendicular to the direction of compression of the monolayer. Such difference arises due to difference in stress exerted by the monolayer on the plate in different direction. In this article, we report the effect of changing the direction of substrate normal with respect to the compression of the monolayer during Langmuir-Blodgett (LB) film deposition on the morphology of the films. The morphology of the LB film of stearic acid was studied using anmore » atomic force microscope (AFM). The morphology of the LB films was found to be different due to difference in the stress in different directions.« less

Quality of Cardiopulmonary Resuscitation When Directing the Area of maximal Compression by Transesophageal Echocardiography During Cardiac Arrest in Swine (Sus scrofa)

DTIC Science & Technology

2013-12-30

E7(/(3+21(180%(5 ,QFOXGHDUHDFRGH 18-02-2014 Final Mar 2012 - Jan 2014 Quality of cardiopulmonary resuscitation when directing the area of...1. Protocol Number: FWH20110158A 2. Type of Research: Animal Research 3. Title: Quality of cardiopulmonary resuscitation when directing...Compressions over the Left Ventricle During Cardiopulmonary Resuscitation Increases Coronary Perfusion Pressure and Return of Spontaneous Circulation

Direct-reading design charts for 75S-T6 aluminum-alloy flat compression panels having longitudinal extruded Z-section stiffeners

NASA Technical Reports Server (NTRS)

Hickman, William A; Dow, Norris F

1951-01-01

Direct-reading design charts are presented for 75S-T6 aluminum-alloy flat compression panels having longitudinal extruded Z-section stiffeners. These charts, which cover a wide range of proportions, make possible the direct determination of the stress and all panel dimensions required to carry a given intensity of loading with a given skin thickness and effective length of panel.

Influence of compression parameters on mechanical behavior of mozzarella cheese.

PubMed

Fogaça, Davi Novaes Ladeia; da Silva, William Soares; Rodrigues, Luciano Brito

2017-10-01

Studies on the interaction between direction and degree of compression in the Texture Profile Analysis (TPA) of cheeses are limited. For this reason the present study aimed to evaluate the mechanical properties of Mozzarella cheese by TPA at different compression degrees (65, 75, and 85%) and directions (axes X, Y, and Z). Data obtained were compared in order to identify possible interaction between both factors. Compression direction did not affect any mechanical variable, or rather, the cheese had an isotropic behavior for TPA. Compression degree had a significant influence (p < 0.05) on TPA responses, excepting for chewiness TPA (N), which remained constant. Data from texture profile were adjusted to models to explain the mechanical behavior according to the compression degree used in the test. The isotropic behavior observed may be result of differences in production method of Mozzarella cheese especially on stretching of cheese mass. Texture Profile Analysis (TPA) is a technique largely used to assess the mechanical properties of food, particularly cheese. The precise choice of the instrumental test configuration is essential for achieving results that represent the material analyzed. The method of manufacturing is another factor that may directly influence the mechanical properties of food. This can be seen, for instance, in stretched curd cheese, such as Mozzarella. Knowledge on such mechanical properties is highly relevant for food industries due to the mechanical resistance in piling, pressing, manufacture of packages, and food transport, or to melting features presented by the food at high temperatures in preparation of several foods, such as pizzas, snacks, sandwiches, and appetizers. © 2016 Wiley Periodicals, Inc.

Thermal Aging Study of a Dow Corning SE 1700 Porous Structure Made by Direct Ink Writing: 1-Year Results and Long-Term Predictions

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

Small, Ward; Pearson, Mark A.; Maiti, Amitesh

Dow Corning SE 1700 (reinforced polydimethylsiloxane) porous structures were made by direct ink writing (DIW). The specimens (~50% porosity) were subjected to various compressive strains (15, 30, 45%) and temperatures (room temperature, 35, 50, 70°C) in a nitrogen atmosphere (active purge) for 1 year. Compression set and load retention of the aged specimens were measured periodically during the study. Compression set increased with strain and temperature. After 1 year, specimens aged at room temperature, 35, and 50°C showed ~10% compression set (relative to the applied compressive deflection), while those aged at 70°C showed 20-40%. Due to the increasing compression set,more » load retention decreased with temperature, ranging from ~90% at room temperature to ~60-80% at 70°C. Long-term compression set and load retention at room temperature were predicted by applying time-temperature superposition (TTS). The predictions show compression set relative to the compressive deflection will be ~10-15% with ~70-90% load retention after 50 years at 15-45% strain, suggesting the material will continue to be mechanically functional. Comparison of the results to previously acquired data for cellular (M97*, M9760, M9763) and RTV (S5370) silicone foams suggests that the SE 1700 DIW porous specimens are on par with, or outperform, the legacy foams.« less

Compressive strain induced enhancement in thermoelectric-power-factor in monolayer MoS2 nanosheet

NASA Astrophysics Data System (ADS)

Dimple; Jena, Nityasagar; De Sarkar, Abir

2017-06-01

Strain and temperature induced tunability in the thermoelectric properties in monolayer MoS2 (ML-MoS2) has been demonstrated using density functional theory coupled to semi-classical Boltzmann transport theory. Compressive strain, in general and uniaxial compressive strain (along the zig-zag direction), in particular, is found to be most effective in enhancing the thermoelectric power factor, owing to the higher electronic mobility and its sensitivity to lattice compression along this direction. Variation in the Seebeck coefficient and electronic band gap with strain is found to follow the Goldsmid-Sharp relation. n-type doping is found to raise the relaxation time-scaled thermoelectric power factor higher than p-type doping and this divide widens with increasing temperature. The relaxation time-scaled thermoelectric power factor in optimally n-doped ML-MoS2 is found to undergo maximal enhancement under the application of 3% uniaxial compressive strain along the zig-zag direction, when both the (direct) electronic band gap and the Seebeck coefficient reach their maximum, while the electron mobility drops down drastically from 73.08 to 44.15 cm2 V-1 s-1. Such strain sensitive thermoelectric responses in ML-MoS2 could open doorways for a variety of applications in emerging areas in 2D-thermoelectrics, such as on-chip thermoelectric power generation and waste thermal energy harvesting.

Mechanical Properties Experimental Study of Engineering Vehicle Refurbished Tire

NASA Astrophysics Data System (ADS)

Qiang, Wang; Xiaojie, Qi; Zhao, Yang; Yunlong, Wang; Guotian, Wang; Degang, Lv

2018-05-01

The vehicle refurbished tire test system was constructed, got load-deformation, load-stiffness, and load-compression ratio property laws of engineering vehicle refurbished tire under the working condition of static state and ground contact, and built radial direction loading deformation mathematics model of 26.5R25 engineering vehicle refurbished tire. The test results show that radial-direction and side-direction deformation value is a little less than that of the new tire. The radial-direction stiffness and compression ratio of engineering vehicle refurbished tire were greatly influenced by radial-direction load and air inflation pressure. When load was certain, radial-direction stiffness would increase with air inflation pressure increasing. When air inflation pressure was certain, compression ratio of engineering vehicle refurbished tire would enlarge with radial-direction load increasing, which was a little less than that of the new and the same type tire. Aging degree of old car-case would exert a great influence on deformation property of engineering vehicle refurbished tire, thus engineering vehicle refurbished tires are suitable to the working condition of low tire pressure and less load.

Uniaxial compressive behavior of micro-pillars of dental enamel characterized in multiple directions.

PubMed

Yilmaz, Ezgi D; Jelitto, Hans; Schneider, Gerold A

2015-04-01

In this work, the compressive elastic modulus and failure strength values of bovine enamel at the first hierarchical level formed by hydroxyapatite (HA) nanofibers and organic matter are identified in longitudinal, transverse and oblique direction with the uniaxial micro-compression method. The elastic modulus values (∼70 GPa) measured here are within the range of results reported in the literature but these values were found surprisingly uniform in all orientations as opposed to the previous nanoindentation findings revealing anisotropic elastic properties in enamel. Failure strengths were recorded up to ∼1.7 GPa and different failure modes (such as shear, microbuckling, fiber fracture) governed by the orientation of the HA nanofibers were visualized. Structural irregularities leading to mineral contacts between the nanofibers are postulated as the main reason for the high compressive strength and direction-independent elastic behavior on enamels first hierarchical level. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Indexing and retrieval of MPEG compressed video

NASA Astrophysics Data System (ADS)

Kobla, Vikrant; Doermann, David S.

1998-04-01

To keep pace with the increased popularity of digital video as an archival medium, the development of techniques for fast and efficient analysis of ideo streams is essential. In particular, solutions to the problems of storing, indexing, browsing, and retrieving video data from large multimedia databases are necessary to a low access to these collections. Given that video is often stored efficiently in a compressed format, the costly overhead of decompression can be reduced by analyzing the compressed representation directly. In earlier work, we presented compressed domain parsing techniques which identified shots, subshots, and scenes. In this article, we present efficient key frame selection, feature extraction, indexing, and retrieval techniques that are directly applicable to MPEG compressed video. We develop a frame type independent representation which normalizes spatial and temporal features including frame type, frame size, macroblock encoding, and motion compensation vectors. Features for indexing are derived directly from this representation and mapped to a low- dimensional space where they can be accessed using standard database techniques. Spatial information is used as primary index into the database and temporal information is used to rank retrieved clips and enhance the robustness of the system. The techniques presented enable efficient indexing, querying, and retrieval of compressed video as demonstrated by our system which typically takes a fraction of a second to retrieve similar video scenes from a database, with over 95 percent recall.

A Novel Range Compression Algorithm for Resolution Enhancement in GNSS-SARs.

PubMed

Zheng, Yu; Yang, Yang; Chen, Wu

2017-06-25

In this paper, a novel range compression algorithm for enhancing range resolutions of a passive Global Navigation Satellite System-based Synthetic Aperture Radar (GNSS-SAR) is proposed. In the proposed algorithm, within each azimuth bin, firstly range compression is carried out by correlating a reflected GNSS intermediate frequency (IF) signal with a synchronized direct GNSS base-band signal in the range domain. Thereafter, spectrum equalization is applied to the compressed results for suppressing side lobes to obtain a final range-compressed signal. Both theoretical analysis and simulation results have demonstrated that significant range resolution improvement in GNSS-SAR images can be achieved by the proposed range compression algorithm, compared to the conventional range compression algorithm.

Creating Drug Solubilization Compartments via Phase Separation in Multicomponent Buccal Patches Prepared by Direct Hot Melt Extrusion-Injection Molding.

PubMed

Alhijjaj, Muqdad; Bouman, Jacob; Wellner, Nikolaus; Belton, Peter; Qi, Sheng

2015-12-07

Creating in situ phase separation in solid dispersion based formulations to allow enhanced functionality of the dosage form, such as improving dissolution of poorly soluble model drug as well as being mucoadhesive, can significantly maximize the in vitro and in vivo performance of the dosage form. This formulation strategy can benefit a wide range of solid dosage forms for oral and alternative routes of delivery. This study using buccal patches as an example created separated phases in situ of the buccal patches by selecting the excipients with different miscibility with each other and the model drug. The quaternary dispersion based buccal patches containing PEG, PEO, Tween 80, and felodipine were prepared by direct hot melt extrusion-injection molding (HME-IM). The partial miscibility between Tween 80 and semicrystalline PEG-PEO led to the phase separation after extrusion. The Tween phases acted as drug solubilization compartments, and the PEG-PEO phase had the primary function of providing mucoadhesion and carrier controlled dissolution. As felodipine was preferably solubilized in the amorphous regions of PEG-PEO, the high crystallinity of PEG-PEO resulted in an overall low drug solubilizing capacity. Tween 80 was added to improve the solubilization capacity of the system as the model drug showed good solubility in Tween. Increasing the drug loading led to the supersaturation of drug in Tween compartments and crystalline drug dispersed in PEG-PEO phases. The spatial distribution of these phase-separated compartments was mapped using X-ray micro-CT, which revealed that the domain size and heterogeneity of the phase separation increased with increasing the drug loading. The outcome of this study provides new insights into the applicability of in situ formed phase separation as a formulation strategy for the delivery of poorly soluble drugs and demonstrated the basic principle of excipient selection for such technology.

The Influence of GI and GII on the Compression After Impact Strength of Carbon Fiber/Epoxy Laminates and Sandwich Structure

NASA Technical Reports Server (NTRS)

Nettles, A. T.; Scharber, L. L.

2017-01-01

This study measured the compression after impact strength of IM7 carbon fiber laminates made from epoxy resins with various mode I and mode II toughness values to observe the effects of these toughness values on the resistance to damage formation and subsequent residual compression strength-carrying capabilities. Both monolithic laminates and sandwich structure were evaluated. A total of seven different epoxy resin systems were used ranging in approximate GI values of 245-665 J/sq m and approximate GII values of 840-2275 J/sq m. The results for resistance to impact damage formation showed that there was a direct correlation between GII and the planar size of damage, as measured by thermography. Subsequent residual compression strength testing suggested that GI had no influence on the measured values and most of the difference in compression strength was directly related to the size of damage. Thus, delamination growth assumed as an opening type of failure mechanism does not appear to be responsible for loss of compression strength in the specimens examined in this study.

Natural Gas Propulsion Options for Short Sea Shipping Routes

DTIC Science & Technology

2010-08-01

that are involved with gas and the relevant systems, along with personal protection issues that come into effect when handling both compressed and...a compressed air system for engine starting, which is stored in compressed air storage cylinders . The system leads compressed air through a valve...directly into the cylinder heads at 30bar to begin the rotation of the engine. After this rotation occurs, the engine is supplied with diesel fuel

Microstructure of directionally solidified Ti-Fe eutectic alloy with low interstitial and high mechanical strength

NASA Astrophysics Data System (ADS)

Contieri, R. J.; Lopes, E. S. N.; Taquire de La Cruz, M.; Costa, A. M.; Afonso, C. R. M.; Caram, R.

2011-10-01

The performance of Ti alloys can be considerably enhanced by combining Ti and other elements, causing an eutectic transformation and thereby producing composites in situ from the liquid phase. This paper reports on the processing and characterization of a directionally solidified Ti-Fe eutectic alloy. Directional solidification at different growth rates was carried out in a setup that employs a water-cooled copper crucible combined with a voltaic electric arc moving through the sample. The results obtained show that a regular fiber-like eutectic structure was produced and the interphase spacing was found to be a function of the growth rate. Mechanical properties were measured using compression, microindentation and nanoindentation tests to determine the Vickers hardness, compressive strength and elastic modulus. Directionally solidified eutectic samples presented high values of compressive strength in the range of 1844-3000 MPa and ductility between 21.6 and 25.2%.

3D Printed Silicones with Shape Memory

DOE PAGES

Wu, Amanda S.; Small IV, Ward; Bryson, Taylor M.; ...

2017-07-05

Direct ink writing enables the layer-by-layer manufacture of ordered, porous structures whose mechanical behavior is driven by architecture and material properties. Here, we incorporate two different gas filled microsphere pore formers to evaluate the effect of shell stiffness and T g on compressive behavior and compression set in siloxane matrix printed structures. The lower T g microsphere structures exhibit substantial compression set when heated near and above T g, with full structural recovery upon reheating without constraint. By contrast, the higher T g microsphere structures exhibit reduced compression set with no recovery upon reheating. Aside from their role in tuningmore » the mechanical behavior of direct ink write structures, polymer microspheres are good candidates for shape memory elastomers requiring structural complexity, with potential applications toward tandem shape memory polymers.« less

3D Printed Silicones with Shape Memory

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

Wu, Amanda S.; Small IV, Ward; Bryson, Taylor M.

Direct ink writing enables the layer-by-layer manufacture of ordered, porous structures whose mechanical behavior is driven by architecture and material properties. Here, we incorporate two different gas filled microsphere pore formers to evaluate the effect of shell stiffness and T g on compressive behavior and compression set in siloxane matrix printed structures. The lower T g microsphere structures exhibit substantial compression set when heated near and above T g, with full structural recovery upon reheating without constraint. By contrast, the higher T g microsphere structures exhibit reduced compression set with no recovery upon reheating. Aside from their role in tuningmore » the mechanical behavior of direct ink write structures, polymer microspheres are good candidates for shape memory elastomers requiring structural complexity, with potential applications toward tandem shape memory polymers.« less

Dynamic alteration of regional cerebral blood flow during carotid compression and proof of reversibility.

PubMed

Asahi, Kouichi; Hori, M; Hamasaki, N; Sato, S; Nakanishi, H; Kuwatsuru, R; Sasai, K; Aoki, S

2012-01-01

It is difficult to non-invasively visualize changes in regional cerebral blood flow caused by manual compression of the carotid artery. To visualize dynamic changes in regional cerebral blood flow during and after manual compression of the carotid artery. Two healthy volunteers were recruited. Anatomic features and flow directions in the circle of Willis were evaluated with time-of-flight magnetic resonance angiography (MRA) and two-dimensional phase-contrast (2DPC) MRA, respectively. Regional cerebral blood flow was visualized with territorial arterial spin-labeling magnetic resonance imaging (TASL-MRI). TASL-MRI and 2DPC-MRA were performed in three states: at rest, during manual compression of the right carotid artery, and after decompression. In one volunteer, time-space labeling inversion pulse (Time-SLIP) MRA was performed to confirm collateral flow. During manual carotid compression, in one volunteer, the right thalamus changed to be fed only by the vertebrobasilar system, and the right basal ganglia changed to be fed by the left internal carotid artery. In the other volunteer, the right basal ganglia changed to be fed by the vertebrobasilar system. 2DPC-MRA showed that the flow direction changed in the right A1 segment of the anterior cerebral artery and the right posterior communicating artery. Perfusion patterns and flow directions recovered after decompression. Time-SLIP MRA showed pial vessels and dural collateral circulation when the right carotid artery was manually compressed. Use of TASL-MRI and 2DPC-MRA was successful for non-invasive visualization of the dynamic changes in regional cerebral blood flow during and after manual carotid compression.

Valeriana officinalis Dry Plant Extract for Direct Compression: Preparation and Characterization

PubMed Central

Gallo, Loreana; Ramírez-Rigo, María Veronica; Piña, Juliana; Palma, Santiago; Allemandi, Daniel; Bucalá, Verónica

2012-01-01

Valeriana officinalis L. (Valerianaceae) is one of the most widely used plants for the treatment of anxiety and insomnia. Usually dry plant extracts, including V. officinalis, are hygroscopic materials with poor physico-mechanical properties that can be directly compressed. A V. officinalis dry extract with moderate hygroscocity is suitable for direct compression, and was obtained by using a simple and economical technique. The V. officinalis fluid extract was oven-dried with colloidal silicon dioxide as a drying adjuvant. The addition of colloidal silicon dioxide resulted in a dry plant extract with good physico-mechanical properties for direct compression and lower hygroscopicity than the dry extract without the carrier. The dry plant extract glass transition temperature was considerably above room temperature (about 72 °C). The colloidal silicon dioxide also produced an antiplasticizing effect, improving the powder’s physical stability. The pharmaceutical performance of the prepared V. officinalis dry extract was studied through the design of tablets. The manufactured tablets showed good compactability, friability, hardness, and disintegration time. Those containing a disintegrant (Avicel PH 101) exhibited the best pharmaceutical performance, having the lowest disintegration time of around 40 seconds. PMID:23264947

Frequency shift measurement in shock-compressed materials

DOEpatents

Moore, David S.; Schmidt, Stephen C.

1985-01-01

A method for determining molecular vibrational frequencies in shock-compressed transparent materials. A single laser beam pulse is directed into a sample material while the material is shock-compressed from a direction opposite that of the incident laser beam. A Stokes beam produced by stimulated Raman scattering is emitted back along the path of the incident laser beam, that is, in the opposite direction to that of the incident laser beam. The Stokes beam is separated from the incident beam and its frequency measured. The difference in frequency between the Stokes beam and the incident beam is representative of the characteristic frequency of the Raman active mode of the sample. Both the incident beam and the Stokes beam pass perpendicularly through the shock front advancing through the sample, thereby minimizing adverse effects of refraction.

Frequency shift measurement in shock-compressed materials

DOEpatents

Moore, D.S.; Schmidt, S.C.

1984-02-21

A method is disclosed for determining molecular vibrational frequencies in shock-compressed transparent materials. A single laser beam pulse is directed into a sample material while the material is shock-compressed from a direction opposite that of the incident laser beam. A Stokes beam produced by stimulated Raman scattering is emitted back along the path of the incident laser beam, that is, in the opposite direction to that of the incident laser beam. The Stokes beam is separated from the incident beam and its frequency measured. The difference in frequency between the Stokes beam and the incident beam is representative of the characteristic frequency of the Raman active mode of the sample. Both the incident beam and the Stokes beam pass perpendicularly through the stock front advancing through the sample, thereby minimizing adverse effects of refraction.

High bit depth infrared image compression via low bit depth codecs

NASA Astrophysics Data System (ADS)

Belyaev, Evgeny; Mantel, Claire; Forchhammer, Søren

2017-08-01

Future infrared remote sensing systems, such as monitoring of the Earth's environment by satellites, infrastructure inspection by unmanned airborne vehicles etc., will require 16 bit depth infrared images to be compressed and stored or transmitted for further analysis. Such systems are equipped with low power embedded platforms where image or video data is compressed by a hardware block called the video processing unit (VPU). However, in many cases using two 8-bit VPUs can provide advantages compared with using higher bit depth image compression directly. We propose to compress 16 bit depth images via 8 bit depth codecs in the following way. First, an input 16 bit depth image is mapped into 8 bit depth images, e.g., the first image contains only the most significant bytes (MSB image) and the second one contains only the least significant bytes (LSB image). Then each image is compressed by an image or video codec with 8 bits per pixel input format. We analyze how the compression parameters for both MSB and LSB images should be chosen to provide the maximum objective quality for a given compression ratio. Finally, we apply the proposed infrared image compression method utilizing JPEG and H.264/AVC codecs, which are usually available in efficient implementations, and compare their rate-distortion performance with JPEG2000, JPEG-XT and H.265/HEVC codecs supporting direct compression of infrared images in 16 bit depth format. A preliminary result shows that two 8 bit H.264/AVC codecs can achieve similar result as 16 bit HEVC codec.

Choice of excipients for gelly-like pulp prepared ex tempore "on a spoon"- "placebo" and with sartans.

PubMed

Wolska, Eliza; Kluk, Anna; Zarazińska, Magda; Boniecka, Magdalena; Sznitowska, Małgorzata

2016-01-01

To ensure safe oral administration, pediatric patients require an appropriate dosage form to be swallowed without relevant difficulties. Ex tempore hydrated powders, forming viscous pulp "on a spoon", have recently gained much interest as pediatric formulations. The aim of this study was to evaluate the viscosity-increasing substances and disintegrants, alone or in mixtures, as excipients suitable for preparing such formulations, with candesartan and valsartan chosen as model active substances. The mixtures of excipients were prepared in the form of powders, granules or lyophilizates, which were evaluated in terms of their ability to form a homogenous mass after hydration with a small amount of water. The best compositions were tested with candesartan cilexetil and valsartan (2% and 10% w/w, respectively). Performed studies include macroscopic, organoleptic and microscopic observations, as well as a textural analysis, determination of gelation time and rheological measurements. Mixtures of guar gum, lactose and one of the disintegrants (F-Melt M, Prosolv 50, Prosolv Easy, Lycatab, Pharmaburst, Pearlitol) demonstrated the best properties. With regard to drug-incorporating formulations, granules were evaluated as the most satisfying form, while the functional properties of lyophilized formulations were poor. Granules with candesartan cilexetil (2%) were found to be the most promising for further development.

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.

Elucidating the weak protein-protein interaction mechanisms behind the liquid-liquid phase separation of a mAb solution by different types of additives.

PubMed

Wu, Guoliang; Wang, Shujing; Tian, Zhou; Zhang, Ning; Sheng, Han; Dai, Weiguo; Qian, Feng

2017-11-01

Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering. The LLPS of JM2 was confirmed to be a thermodynamic equilibrium process with no structural changes or irreversible aggregation of proteins. Phase diagrams of various JM2 formulations were constructed, suggesting that the phase behavior of JM2 was dependent on the solution pH, ionic strength and the presence of other excipients such as glycine, alanine, sorbitol and sucrose. Furthermore, we demonstrated that for this mAb, the interaction parameter (k D ) determined at low protein concentration appeared to be a good predictor for the occurrence of LLPS at high concentration. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets.

PubMed

Patel, Himanshu; Stalcup, Apryll; Dansereau, Richard; Sakr, Adel

2003-10-02

Levothyroxine tablets, 50 microg, have been marketed for many decades but have had numerous recalls due to degradation and failure to meet potency. These experiments were devised to study the effects of various excipients on the stability of levothyroxine sodium pentahydrate in aqueous slurries and in formulated tablets. The active alone was found to be stable in the solid state for 6 months at 40 degrees C/75% RH whether stored in open or closed containers, and was found to be non-hygroscopic under normal processing conditions (>30% RH). In aqueous slurries with an excipient, the stability of the active improved as the pH of the slurry was increased from pH 3 to 11. Tablets manufactured with lactose anhydrous, starch, or microcrystalline cellulose failed to meet USP assay requirements at 3 months at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate or mannitol met USP assay requirements at 3, but not 6 months when stored at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate and a basic pH modifier, such as sodium carbonate, sodium bicarbonate, or magnesium oxide, met the USP assay requirements at both 3 and 6 months. Thus, the use of basic pH modifiers is a potential technique for improving the stability of levothyroxine sodium pentahydrate tablets.

Carboxymethyl starch and lecithin complex as matrix for targeted drug delivery: I. Monolithic mesalamine forms for colon delivery.

PubMed

Mihaela Friciu, Maria; Canh Le, Tien; Ispas-Szabo, Pompilia; Mateescu, Mircea Alexandru

2013-11-01

For drugs expected to act locally in the colon, and for successful treatment, a delivery device is necessary, in order to limit the systemic absorption which decreases effectiveness and causes important side effects. Various delayed release systems are currently commercialized; most of them based on pH-dependent release which is sensitive to gastrointestinal pH variation. This study proposes a novel excipient for colon delivery. This new preparation consists in the complexation between carboxymethyl starch (CMS) and Lecithin (L). As opposed to existing excipients, the new complex is pH-independent, inexpensive, and easy to manufacture and allows a high drug loading. FTIR, X-ray, and SEM structural analysis all support the hypothesis of the formation of a complex. By minor variation of the excipient content within the tablet, it is possible to modulate the release time and delivery at specific sites of the gastrointestinal tract. This study opens the door to a new pH-independent delivery system for mesalamine targeted administration. Our novel formulation fits well with the posology of mesalamine, used in the treatment of Inflammatory Bowel Disease (IBD), which requires repeated administrations (1g orally four times a day) to maintain a good quality of life. Copyright © 2013 Elsevier B.V. All rights reserved.

Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets.

PubMed

Monajjemzadeh, Farnaz; Hassanzadeh, Davoud; Valizadeh, Hadi; Siahi-Shadbad, Mohammad R; Mojarrad, Javid Shahbazi; Robertson, Thomas A; Roberts, Michael S

2009-11-01

This study documents drug-excipient incompatibility studies of acyclovir in physical mixtures with lactose and in different tablet brands. Differential scanning calorimetry (DSC) was initially used to assess compatibility of mixtures. The Fourier-transform infrared (FTIR) spectrum was also compared with the spectra of pure drug and excipient. Although DSC results indicated incompatibility with lactose, FTIR spectra were mostly unmodified due to overlapping peaks. Samples of isothermally stressed physical mixture were stored at 95 degrees C for 24 h. The residual drug was monitored using a validated high-performance liquid chromatography (HPLC) assay and data fitting to solid-state kinetic models was performed. The drug loss kinetics followed a diffusion model. The aqueous mixture of drug and excipient was heated in order to prepare an adduct mixture. HPLC analysis revealed one extra peak that was fractionated and subsequently injected into the liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) system. The MRM (Multiple Reaction Monitoring) chromatograms characterized the peak with molecular mass corresponding to an acyclovir-lactose Maillard reaction product. The presence of lactose in commercial tablets was checked using a new TLC method. Overall, the incompatibility of acyclovir with lactose was successfully evaluated using a combination of thermal methods and LC-MS/MS.

Influence of Excipients and Spray Drying on the Physical and Chemical Properties of Nutraceutical Capsules Containing Phytochemicals from Black Bean Extract.

PubMed

Guajardo-Flores, Daniel; Rempel, Curtis; Gutiérrez-Uribe, Janet A; Serna-Saldívar, Sergio O

2015-12-03

Black beans (Phaseolus vulgaris L.) are a rich source of flavonoids and saponins with proven health benefits. Spray dried black bean extract powders were used in different formulations for the production of nutraceutical capsules with reduced batch-to-batch weight variability. Factorial designs were used to find an adequate maltodextrin-extract ratio for the spray-drying process to produce black bean extract powders. Several flowability properties were used to determine composite flow index of produced powders. Powder containing 6% maltodextrin had the highest yield (78.6%) and the best recovery of flavonoids and saponins (>56% and >73%, respectively). The new complexes formed by the interaction of black bean powder with maltodextrin, microcrystalline cellulose 50 and starch exhibited not only bigger particles, but also a rougher structure than using only maltodextrin and starch as excipients. A drying process prior to capsule production improved powder flowability, increasing capsule weight and reducing variability. The formulation containing 25.0% of maltodextrin, 24.1% of microcrystalline cellulose 50, 50% of starch and 0.9% of magnesium stearate produced capsules with less than 2.5% weight variability. The spray drying technique is a feasible technique to produce good flow extract powders containing valuable phytochemicals and low cost excipients to reduce the end-product variability.

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.

Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol, medium chain glycerides and PEG esters.

PubMed

Fernandez, Sylvie; Jannin, Vincent; Rodier, Jean-David; Ritter, Nicolas; Mahler, Bruno; Carrière, Frédéric

2007-05-01

Labrasol is a lipid-based self-emulsifying excipient used in the preparation of lipophilic drugs intended for oral delivery. It is mainly composed of PEG esters and glycerides with medium acyl chains, which are potential substrates for digestive lipases. The hydrolysis of Labrasol by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases was investigated in the present study. Classical human pancreatic lipase (HPL) and porcine pancreatic lipase, which are the main lipases involved in the digestion of dietary triglycerides, showed very low levels of activity on the entire Labrasol excipient as well as on separated fractions of glycerides and PEG esters. On the other hand, gastric lipase, pancreatic lipase-related protein 2 (PLRP2) and carboxyl ester hydrolase (CEH) showed high specific activities on Labrasol. These lipases were found to hydrolyze the main components of Labrasol (PEG esters and monoglycerides) used as individual substrates, whereas these esters were found to be poor substrates for HPL. The lipolytic activity of pancreatic extracts and human pancreatic juice on Labrasol(R) is therefore mainly due to the combined action of CEH and PLRP2. These two pancreatic enzymes, together with gastric lipase, are probably the main enzymes involved in the in vivo lipolysis of Labrasol taken orally.

In vitro gastrointestinal lipolysis of four formulations of piroxicam and cinnarizine with the self emulsifying excipients Labrasol and Gelucire 44/14.

PubMed

Fernandez, Sylvie; Chevrier, Stéphanie; Ritter, Nicolas; Mahler, Bruno; Demarne, Frédéric; Carrière, Frédéric; Jannin, Vincent

2009-08-01

Labrasol and Gelucire 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases. We investigated their in vitro gastrointestinal lipolysis to understand which compounds are, after digestion, responsible for keeping poorly water-soluble drugs in solution. The precipitation of piroxicam and cinnarizine formulated in these excipients during the gastrointestinal lipolysis was also studied. Monoacylglycerols and PEG monoesters are the largest compounds present at the end of gastric phase whereas PEG-monoesters are the largest compounds after the duodenal phase. The precipitation of piroxicam is mainly due to the gastric lipolysis. In the control experiments performed without digestive lipases, cinnarizine formulated in Labrasol was found to precipitate upon dilution of the gastric medium to form the solution mimicking the duodenal medium. In the presence of gastric lipase, Labrasol was hydrolyzed and the precipitation of cinnarizine was not observed in this case. When the cinnarizine was formulated with Gelucire 44/14 the precipitation was only due to the dilution of the gastric medium. Our study highlights the importance of the gastrointestinal lipolysis and the associated phenomena such as the dilution of chyme by biliary and pancreatic secretions in vivo, on the solubilisation of poorly water-soluble drugs formulated with lipid-based excipients.

An in vitro analysis model for investigating the staining effect of various chlorhexidine-based mouthwashes.

PubMed

Kouadio, Alain-Ayepa; Struillou, Xavier; Bories, Céline; Bouler, Jean-Michel; Badran, Zahi; Soueidan, Assem

2017-03-01

There are different mouthwashes containing chlorhexidine in different concentrations, as well as various excipients. Chlorhexidine induce stains or discoloration in teeth and mucous membranes. The aim of this work was to design a model to reproduce in vitro staining associated with the use of different mouthwashes containing chlorhexidine. We used as substrates of natural teeth and elephant ivory slices. Different incubation baths were conducted over 21 days in culture dishes at 37°C. At the beginning of experiment before incubation (D0) and after 21 days (D21) of incubation with different mouthwashes, pictures of substrates were taken in a standardized manner and an image analysis software was used to analyse and quantify the staining under the various conditions by using the 3 main colours (Red, Green, Blue, RGB). The results of this work demonstrate a very good reproducibility of the protocol, and secondly, a different expression statistically significant of the primary blue colour. We suggest that for a given concentration of chlorhexidine, the staining effects may vary depending on the excipients used. This replicable model, easy to implement over a relatively short duration, can be used for evaluation of existing mouthwashes, and to test the excipients anti discoloration proposed by manufacturers. Key words: In vitro, chlorhexidine, mouthwashes, dental stain, tooth discoloration.

Characterization of Propylene Glycol-Mitigated Freeze/Thaw Agglomeration of a Frozen Liquid nOMV Vaccine Formulation by Static Light Scattering and Micro-Flow Imaging.

PubMed

Mensch, Christopher D; Davis, Harrison B; Blue, Jeffrey T

2015-01-01

The purpose of this work was to investigate the susceptibility of an aluminum adjuvant and an aluminum-adjuvanted native outer membrane vesicle (nOMV) vaccine formulation to freeze/thaw-induced agglomeration using static light scattering and micro-flow Imaging analysis; and to evaluate the use of propylene glycol as a vaccine formulation excipient by which freeze/thaw-induced agglomeration of a nOMV vaccine formulation could be mitigated. Our results indicate that including 7% v/v propylene glycol in an nOMV containing aluminum adjuvanted vaccine formulation, mitigates freeze/thaw-induced agglomeration. We evaluated the effect of freeze-thawing on an aluminum adjuvant and an aluminum adjuvanted native outer membrane vesicle (nOMV) vaccine formulation. Specifically, we characterized the freeze/thaw-induced agglomeration through the use of static light scattering, micro-flow imaging, and cryo-electron microscopy analysis. Further, we evaluated the use of 0-9% v/v propylene glycol as an excipient which could be included in the formulation for the purpose of mitigating the agglomeration induced by freeze/thaw. The results indicate that using 7% v/v propylene glycol as a formulation excipient is effective at mitigating agglomeration of the nOMV vaccine formulation, otherwise induced by freeze-thawing. © PDA, Inc. 2015.

Propylene Glycol-Related Delirium After Esmolol Infusion.

PubMed

Kapitein, Berber S; Biesmans, Renee S C G; van der Sijs, Heleen S I; de Wildt, Saskia S N

2014-07-01

Excipients used in oral or intravenous preparations may cause serious adverse events. We present the case of a 15-year-old boy with hypertrophic cardiomyopathy. In the pediatric intensive care unit, he received high doses of continuous intravenous esmolol (range = 20-400 µg/kg/min) for cardiac rhythm control. After a few days he developed a delirium not responding to high doses of antipsychotics or discontinuation of benzodiazepines. We eventually realized that the IV esmolol formulation contained high doses of propylene glycol and ethanol, which may accumulate after prolonged infusion and cause intoxication. Intoxication with propylene glycolcan cause neuropsychiatric symptoms. The boy's propylene glycol plasma concentration was approximately 4 g/L, whereas clinical symptoms arise at concentrations above 1 to 1.44 g/L. Application of the Naranjo adverse drug reaction probability scale suggested a probable relationship (score 6) between the propylene glycol infusion and the delirium. After discontinuation of esmolol, the delirium disappeared spontaneously. This is the first case describing excipient toxicity of esmolol, with an objective causality assessment revealing a probable relationship for the adverse event-namely, delirium-and esmolol. Although excipient toxicity is a well-known adverse drug reaction, this case stresses the importance for easily available information for and education of physicians. © The Author(s) 2014.

Thermodynamics of water-solid interactions in crystalline and amorphous pharmaceutical materials.

PubMed

Sacchetti, Mark

2014-09-01

Pharmaceutical materials, crystalline and amorphous, sorb water from the atmosphere, which affects critical factors in the development of drugs, such as the selection of drug substance crystal form, compatibility with excipients, dosage form selection, packaging, and product shelf-life. It is common practice to quantify the amount of water that a material sorbs at a given relative humidity (RH), but the results alone provide minimal to no physicochemical insight into water-solid interactions, without which pharmaceutical scientists cannot develop an understanding of their materials, so as to anticipate and circumvent potential problems. This research was conducted to advance the science of pharmaceutical materials by examining the thermodynamics of solids with sorbed water. The compounds studied include nonhygroscopic drugs, a channel hydrate drug, a stoichiometric hydrate excipient, and an amorphous excipient. The water sorption isotherms were measured over a range of temperature to extract the partial molar enthalpy and entropy of sorbed water as well as the same quantities for some of the solids. It was found that water-solid interactions spanned a range of energy and entropy as a function of RH, which was unique to the solid, and which could be valuable in identifying batch-to-batch differences and effects of processing in material performance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

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.

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.

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.

A Novel Range Compression Algorithm for Resolution Enhancement in GNSS-SARs

PubMed Central

Zheng, Yu; Yang, Yang; Chen, Wu

2017-01-01

In this paper, a novel range compression algorithm for enhancing range resolutions of a passive Global Navigation Satellite System-based Synthetic Aperture Radar (GNSS-SAR) is proposed. In the proposed algorithm, within each azimuth bin, firstly range compression is carried out by correlating a reflected GNSS intermediate frequency (IF) signal with a synchronized direct GNSS base-band signal in the range domain. Thereafter, spectrum equalization is applied to the compressed results for suppressing side lobes to obtain a final range-compressed signal. Both theoretical analysis and simulation results have demonstrated that significant range resolution improvement in GNSS-SAR images can be achieved by the proposed range compression algorithm, compared to the conventional range compression algorithm. PMID:28672830

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

Computational Simulation of Breast Compression Based on Segmented Breast and Fibroglandular Tissues on Magnetic Resonance Images

PubMed Central

Shih, Tzu-Ching; Chen, Jeon-Hor; Liu, Dongxu; Nie, Ke; Sun, Lizhi; Lin, Muqing; Chang, Daniel; Nalcioglu, Orhan; Su, Min-Ying

2010-01-01

This study presents a finite element based computational model to simulate the three-dimensional deformation of the breast and the fibroglandular tissues under compression. The simulation was based on 3D MR images of the breast, and the craniocaudal and mediolateral oblique compression as used in mammography was applied. The geometry of whole breast and the segmented fibroglandular tissues within the breast were reconstructed using triangular meshes by using the Avizo® 6.0 software package. Due to the large deformation in breast compression, a finite element model was used to simulate the non-linear elastic tissue deformation under compression, using the MSC.Marc® software package. The model was tested in 4 cases. The results showed a higher displacement along the compression direction compared to the other two directions. The compressed breast thickness in these 4 cases at 60% compression ratio was in the range of 5-7 cm, which is the typical range of thickness in mammography. The projection of the fibroglandular tissue mesh at 60% compression ratio was compared to the corresponding mammograms of two women, and they demonstrated spatially matched distributions. However, since the compression was based on MRI, which has much coarser spatial resolution than the in-plane resolution of mammography, this method is unlikely to generate a synthetic mammogram close to the clinical quality. Whether this model may be used to understand the technical factors that may impact the variations in breast density measurements needs further investigation. Since this method can be applied to simulate compression of the breast at different views and different compression levels, another possible application is to provide a tool for comparing breast images acquired using different imaging modalities – such as MRI, mammography, whole breast ultrasound, and molecular imaging – that are performed using different body positions and different compression conditions. PMID:20601773

Computational simulation of breast compression based on segmented breast and fibroglandular tissues on magnetic resonance images.

PubMed

Shih, Tzu-Ching; Chen, Jeon-Hor; Liu, Dongxu; Nie, Ke; Sun, Lizhi; Lin, Muqing; Chang, Daniel; Nalcioglu, Orhan; Su, Min-Ying

2010-07-21

This study presents a finite element-based computational model to simulate the three-dimensional deformation of a breast and fibroglandular tissues under compression. The simulation was based on 3D MR images of the breast, and craniocaudal and mediolateral oblique compression, as used in mammography, was applied. The geometry of the whole breast and the segmented fibroglandular tissues within the breast were reconstructed using triangular meshes by using the Avizo 6.0 software package. Due to the large deformation in breast compression, a finite element model was used to simulate the nonlinear elastic tissue deformation under compression, using the MSC.Marc software package. The model was tested in four cases. The results showed a higher displacement along the compression direction compared to the other two directions. The compressed breast thickness in these four cases at a compression ratio of 60% was in the range of 5-7 cm, which is a typical range of thickness in mammography. The projection of the fibroglandular tissue mesh at a compression ratio of 60% was compared to the corresponding mammograms of two women, and they demonstrated spatially matched distributions. However, since the compression was based on magnetic resonance imaging (MRI), which has much coarser spatial resolution than the in-plane resolution of mammography, this method is unlikely to generate a synthetic mammogram close to the clinical quality. Whether this model may be used to understand the technical factors that may impact the variations in breast density needs further investigation. Since this method can be applied to simulate compression of the breast at different views and different compression levels, another possible application is to provide a tool for comparing breast images acquired using different imaging modalities--such as MRI, mammography, whole breast ultrasound and molecular imaging--that are performed using different body positions and under different compression conditions.

Electric power generating plant having direct-coupled steam and compressed-air cycles

DOEpatents

Drost, M.K.

1981-01-07

An electric power generating plant is provided with a Compressed Air Energy Storage (CAES) system which is directly coupled to the steam cycle of the generating plant. The CAES system is charged by the steam boiler during off peak hours, and drives a separate generator during peak load hours. The steam boiler load is thereby levelized throughout an operating day.

Electric power generating plant having direct coupled steam and compressed air cycles

DOEpatents

Drost, Monte K.

1982-01-01

An electric power generating plant is provided with a Compressed Air Energy Storage (CAES) system which is directly coupled to the steam cycle of the generating plant. The CAES system is charged by the steam boiler during off peak hours, and drives a separate generator during peak load hours. The steam boiler load is thereby levelized throughout an operating day.

Music information retrieval in compressed audio files: a survey

NASA Astrophysics Data System (ADS)

Zampoglou, Markos; Malamos, Athanasios G.

2014-07-01

In this paper, we present an organized survey of the existing literature on music information retrieval systems in which descriptor features are extracted directly from the compressed audio files, without prior decompression to pulse-code modulation format. Avoiding the decompression step and utilizing the readily available compressed-domain information can significantly lighten the computational cost of a music information retrieval system, allowing application to large-scale music databases. We identify a number of systems relying on compressed-domain information and form a systematic classification of the features they extract, the retrieval tasks they tackle and the degree in which they achieve an actual increase in the overall speed-as well as any resulting loss in accuracy. Finally, we discuss recent developments in the field, and the potential research directions they open toward ultra-fast, scalable systems.

Compliant Buckled Foam Actuators and Application in Patient-Specific Direct Cardiac Compression.

PubMed

Mac Murray, Benjamin C; Futran, Chaim C; Lee, Jeanne; O'Brien, Kevin W; Amiri Moghadam, Amir A; Mosadegh, Bobak; Silberstein, Meredith N; Min, James K; Shepherd, Robert F

2018-02-01

We introduce the use of buckled foam for soft pneumatic actuators. A moderate amount of residual compressive strain within elastomer foam increases the applied force ∼1.4 × or stroke ∼2 × compared with actuators without residual strain. The origin of these improved characteristics is explained analytically. These actuators are applied in a direct cardiac compression (DCC) device design, a type of implanted mechanical circulatory support that avoids direct blood contact, mitigating risks of clot formation and stroke. This article describes a first step toward a pneumatically powered, patient-specific DCC design by employing elastomer foam as the mechanism for cardiac compression. To form the device, a mold of a patient's heart was obtained by 3D printing a digitized X-ray computed tomography or magnetic resonance imaging scan into a solid model. From this model, a soft, robotic foam DCC device was molded. The DCC device is compliant and uses compressed air to inflate foam chambers that in turn apply compression to the exterior of a heart. The device is demonstrated on a porcine heart and is capable of assisting heart pumping at physiologically relevant durations (∼200 ms for systole and ∼400 ms for diastole) and stroke volumes (∼70 mL). Although further development is necessary to produce a fully implantable device, the material and processing insights presented here are essential to the implementation of a foam-based, patient-specific DCC design.

Instrumented roll technology for the design space development of roller compaction process.

PubMed

Nesarikar, Vishwas V; Vatsaraj, Nipa; Patel, Chandrakant; Early, William; Pandey, Preetanshu; Sprockel, Omar; Gao, Zhihui; Jerzewski, Robert; Miller, Ronald; Levin, Michael

2012-04-15

Instrumented roll technology on Alexanderwerk WP120 roller compactor was developed and utilized successfully for the measurement of normal stress on ribbon during the process. The effects of process parameters such as roll speed (4-12 rpm), feed screw speed (19-53 rpm), and hydraulic roll pressure (40-70 bar) on normal stress and ribbon density were studied using placebo and active pre-blends. The placebo blend consisted of 1:1 ratio of microcrystalline cellulose PH102 and anhydrous lactose with sodium croscarmellose, colloidal silicon dioxide, and magnesium stearate. The active pre-blends were prepared using various combinations of one active ingredient (3-17%, w/w) and lubricant (0.1-0.9%, w/w) levels with remaining excipients same as placebo. Three force transducers (load cells) were installed linearly along the width of the roll, equidistant from each other with one transducer located in the center. Normal stress values recorded by side sensors and were lower than normal stress values recorded by middle sensor and showed greater variability than middle sensor. Normal stress was found to be directly proportional to hydraulic pressure and inversely to screw to roll speed ratio. For active pre-blends, normal stress was also a function of compressibility. For placebo pre-blends, ribbon density increased as normal stress increased. For active pre-blends, in addition to normal stress, ribbon density was also a function of gap. Models developed using placebo were found to predict ribbon densities of active blends with good accuracy and the prediction error decreased as the drug concentration of active blend decreased. Effective angle of internal friction and compressibility properties of active pre blend may be used as key indicators for predicting ribbon densities of active blend using placebo ribbon density model. Feasibility of on-line prediction of ribbon density during roller compaction was demonstrated using porosity-pressure data of pre-blend and normal stress measurements. Effect of vacuum to de-aerate pre blend prior to entering the nip zone was studied. Varying levels of vacuum for de-aeration of placebo pre blend did not affect the normal stress values. However, turning off vacuum completely caused an increase in normal stress with subsequent decrease in gap. Use of instrumented roll demonstrated potential to reduce the number of DOE runs by enhancing fundamental understanding of relationship between normal stress on ribbon and process parameters. Copyright © 2012 Elsevier B.V. All rights reserved.

Hierarchical honeycomb auxetic metamaterials

NASA Astrophysics Data System (ADS)

Mousanezhad, Davood; Babaee, Sahab; Ebrahimi, Hamid; Ghosh, Ranajay; Hamouda, Abdelmagid Salem; Bertoldi, Katia; Vaziri, Ashkan

2015-12-01

Most conventional materials expand in transverse directions when they are compressed uniaxially resulting in the familiar positive Poisson’s ratio. Here we develop a new class of two dimensional (2D) metamaterials with negative Poisson’s ratio that contract in transverse directions under uniaxial compressive loads leading to auxeticity. This is achieved through mechanical instabilities (i.e., buckling) introduced by structural hierarchy and retained over a wide range of applied compression. This unusual behavior is demonstrated experimentally and analyzed computationally. The work provides new insights into the role of structural organization and hierarchy in designing 2D auxetic metamaterials, and new opportunities for developing energy absorbing materials, tunable membrane filters, and acoustic dampeners.

Peripheral Neuropathy and Nerve Compression Syndromes in Burns.

PubMed

Strong, Amy L; Agarwal, Shailesh; Cederna, Paul S; Levi, Benjamin

2017-10-01

Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury. Patients present with pain, paresthesias, or weakness along a specific nerve distribution or experience generalized peripheral neuropathy. The symptoms manifest at various times from within one week of hospitalization to many months after wound closure. Peripheral neuropathy may be caused by vascular occlusion of vasa nervorum, inflammation, neurotoxin production leading to apoptosis, and direct destruction of nerves from the burn injury. This article discusses the natural history, diagnosis, current treatments, and future directions for potential interventions for peripheral neuropathy and nerve compression syndromes related to burn injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Neogene ongoing tectonics in the Southern Ecuadorian Andes: analysis of the evolution of the stress field

NASA Astrophysics Data System (ADS)

Lavenu, A.; Noblet, C.; Winter, T. H.

1995-01-01

Microtectonic analysis of infilling deposits in South Ecuadorian Neogene basins brings to light a compressive stress field with σ1 along a NNE-SSW to NE-SW direction in the early Miocene, changing to an E-W direction in the Middle and Late Miocene. The syn-sedimentary deformations which affect the deposits of the basins suggest similar stress regimes due to a compressive ongoing tectonic system in the Miocene, for at least 15 Ma. There is a good correlation between rapid convergence in the Neogene and the time period during which the continental South Ecuadorian basins were deformed by compression (Quechua period).

Development and evaluation of Ketoprofen sustained release matrix tablet using Hibiscus rosa-sinensis leaves mucilage.

PubMed

Kaleemullah, M; Jiyauddin, K; Thiban, E; Rasha, S; Al-Dhalli, S; Budiasih, S; Gamal, O E; Fadli, A; Eddy, Y

2017-07-01

Currently, the use of natural gums and mucilage is of increasing importance in pharmaceutical formulations as valuable drug excipient. Natural plant-based materials are economic, free of side effects, biocompatible and biodegradable. Therefore, Ketoprofen matrix tablets were formulated by employing Hibiscus rosa-sinensis leaves mucilage as natural polymer and HPMC (K100M) as a synthetic polymer to sustain the drug release from matrix system. Direct compression method was used to develop sustained released matrix tablets. The formulated matrix tablets were evaluated in terms of physical appearance, weight variation, thickness, diameter, hardness, friability and in vitro drug release. The difference between the natural and synthetic polymers was investigated concurrently. Matrix tablets developed from each formulation passed all standard physical evaluation tests. The dissolution studies of formulated tablets revealed sustained drug release up to 24 h compared to the reference drug Apo Keto® SR tablets. The dissolution data later were fitted into kinetic models such as zero order equation, first order equation, Higuchi equation, Hixson Crowell equation and Korsmeyer-Peppas equation to study the release of drugs from each formulation. The best formulations were selected based on the similarity factor ( f 2 ) value of 50% and more. Through the research, it is found that by increasing the polymers concentration, the rate of drug release decreased for both natural and synthetic polymers. The best formulation was found to be F3 which contained 40% Hibiscus rosa-sinensis mucilage polymer and showed comparable dissolution profile to the reference drug with f 2 value of 78.03%. The release kinetics of this formulation has shown to follow non-Fickian type which involved both diffusion and erosion mechanism. Additionally, the statistical results indicated that there was no significant difference (p > 0.05) between the F3 and reference drug in terms of MDT and T50% with p-values of 1.00 and 0.995 respectively.

Near-wall modeling of compressible turbulent flow

NASA Technical Reports Server (NTRS)

So, Ronald M. C.

1991-01-01

A near-wall two-equation model for compressible flows is proposed. The model is formulated by relaxing the assumption of dynamic field similarity between compressible and incompressible flows. A postulate is made to justify the extension of incompressible models to ammount for compressibility effects. This requires formulation the turbulent kinetic energy equation in a form similar to its incompressible counterpart. As a result, the compressible dissipation function has to be split into a solenoidal part, which is not sensitive to changes of compressibility indicators, and a dilatational part, which is directly affected by these changes. A model with an explicit dependence on the turbulent Mach number is proposed for the dilatational dissipation rate.

Optimization of poorly compactable drug tablets manufactured by direct compression using the mixture experimental design.

PubMed

Martinello, Tiago; Kaneko, Telma Mary; Velasco, Maria Valéria Robles; Taqueda, Maria Elena Santos; Consiglieri, Vladi O

2006-09-28

The poor flowability and bad compressibility characteristics of paracetamol are well known. As a result, the production of paracetamol tablets is almost exclusively by wet granulation, a disadvantageous method when compared to direct compression. The development of a new tablet formulation is still based on a large number of experiments and often relies merely on the experience of the analyst. The purpose of this study was to apply experimental design methodology (DOE) to the development and optimization of tablet formulations containing high amounts of paracetamol (more than 70%) and manufactured by direct compression. Nineteen formulations, screened by DOE methodology, were produced with different proportions of Microcel 102, Kollydon VA 64, Flowlac, Kollydon CL 30, PEG 4000, Aerosil, and magnesium stearate. Tablet properties, except friability, were in accordance with the USP 28th ed. requirements. These results were used to generate plots for optimization, mainly for friability. The physical-chemical data found from the optimized formulation were very close to those from the regression analysis, demonstrating that the mixture project is a great tool for the research and development of new formulations.

Prechamber Compression-Ignition Engine Performance

NASA Technical Reports Server (NTRS)

Moore, Charles S; Collins, John H , Jr

1938-01-01

Single-cylinder compression-ignition engine tests were made to investigate the performance characteristics of prechamber type of cylinder head. Certain fundamental variables influencing engine performance -- clearance distribution, size, shape, and direction of the passage connecting the cylinder and prechamber, shape of prechamber, cylinder clearance, compression ratio, and boosting -- were independently tested. Results of motoring and of power tests, including several typical indicator cards, are presented.

Bi-directionally draining pore fluid extraction vessel

DOEpatents

Prizio, Joseph; Ritt, Alexander; Mower, Timothy E.; Rodine, Lonn

1991-01-01

The invention is used to extract pore fluid from porous solids through a combination of mechanical compression and inert-gas injection and comprises a piston for axially compressing samples to force water out, and top and bottom drainage plates for capturing the exuded water and using inert gas to force water to exit when the limits of mechanical compression have been reached.

Lossless compression algorithm for REBL direct-write e-beam lithography system

NASA Astrophysics Data System (ADS)

Cramer, George; Liu, Hsin-I.; Zakhor, Avideh

2010-03-01

Future lithography systems must produce microchips with smaller feature sizes, while maintaining throughputs comparable to those of today's optical lithography systems. This places stringent constraints on the effective data throughput of any maskless lithography system. In recent years, we have developed a datapath architecture for direct-write lithography systems, and have shown that compression plays a key role in reducing throughput requirements of such systems. Our approach integrates a low complexity hardware-based decoder with the writers, in order to decompress a compressed data layer in real time on the fly. In doing so, we have developed a spectrum of lossless compression algorithms for integrated circuit layout data to provide a tradeoff between compression efficiency and hardware complexity, the latest of which is Block Golomb Context Copy Coding (Block GC3). In this paper, we present a modified version of Block GC3 called Block RGC3, specifically tailored to the REBL direct-write E-beam lithography system. Two characteristic features of the REBL system are a rotary stage resulting in arbitrarily-rotated layout imagery, and E-beam corrections prior to writing the data, both of which present significant challenges to lossless compression algorithms. Together, these effects reduce the effectiveness of both the copy and predict compression methods within Block GC3. Similar to Block GC3, our newly proposed technique Block RGC3, divides the image into a grid of two-dimensional "blocks" of pixels, each of which copies from a specified location in a history buffer of recently-decoded pixels. However, in Block RGC3 the number of possible copy locations is significantly increased, so as to allow repetition to be discovered along any angle of orientation, rather than horizontal or vertical. Also, by copying smaller groups of pixels at a time, repetition in layout patterns is easier to find and take advantage of. As a side effect, this increases the total number of copy locations to transmit; this is combated with an extra region-growing step, which enforces spatial coherence among neighboring copy locations, thereby improving compression efficiency. We characterize the performance of Block RGC3 in terms of compression efficiency and encoding complexity on a number of rotated Metal 1, Poly, and Via layouts at various angles, and show that Block RGC3 provides higher compression efficiency than existing lossless compression algorithms, including JPEG-LS, ZIP, BZIP2, and Block GC3.

Direct and continuous strain control of catalysts with tunable battery electrode materials

DOE PAGES

Wang, Haotian; Xu, Shicheng; Tsai, Charlie; ...

2016-11-24

We report a method for using battery electrode materials to directly and continuously control the lattice strain of platinum (Pt) catalyst and thus tune its catalytic activity for the oxygen reduction reaction (ORR). Whereas the common approach of using metal overlayers introduces ligand effects in addition to strain, by electrochemically switching between the charging and discharging status of battery electrodes the change in volume can be precisely controlled to induce either compressive or tensile strain on supported catalysts. Lattice compression and tension induced by the lithium cobalt oxide substrate of ~5% were directly observed in individual Pt nanoparticles with aberration-correctedmore » transmission electron microscopy. As a result, we observed 90% enhancement or 40% suppression in Pt ORR activity under compression or tension, respectively, which is consistent with theoretical predictions.« less

[Effects of different excipients on properties of Tongsaimai mixture and pellet molding].

PubMed

Wang, Jin; Lv, Zhiyang; Wu, Xiaoyan; Di, Liuqing; Dong, Yu; Cai, Baochang

2011-01-01

To study preliminarily on the relationship between properties of the mixture composed of Tongsaimai extract and different excipients and pellet molding. The multivariate regression analysis was used to investigate the correlation of different mixture and pellet molding by measuring the cohesion, liquid-plastic limit of mixture, and the powder properties of pellets. The weighted coefficients of the powder properties were determined by analytic hierarchy process combined with criteria importance through intercriteria correlation. The results showed that liquid-plastic limit seemed to be a major factor, which had positive correlation with pellet molding, while cohesion had negative correlation with pellet molding in the measured range. The physical properties of the mixture has marked influence on pellet molding.

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.

Handling the data management needs of high-throughput sequencing data: SpeedGene, a compression algorithm for the efficient storage of genetic data

PubMed Central

2012-01-01

Background As Next-Generation Sequencing data becomes available, existing hardware environments do not provide sufficient storage space and computational power to store and process the data due to their enormous size. This is and will be a frequent problem that is encountered everyday by researchers who are working on genetic data. There are some options available for compressing and storing such data, such as general-purpose compression software, PBAT/PLINK binary format, etc. However, these currently available methods either do not offer sufficient compression rates, or require a great amount of CPU time for decompression and loading every time the data is accessed. Results Here, we propose a novel and simple algorithm for storing such sequencing data. We show that, the compression factor of the algorithm ranges from 16 to several hundreds, which potentially allows SNP data of hundreds of Gigabytes to be stored in hundreds of Megabytes. We provide a C++ implementation of the algorithm, which supports direct loading and parallel loading of the compressed format without requiring extra time for decompression. By applying the algorithm to simulated and real datasets, we show that the algorithm gives greater compression rate than the commonly used compression methods, and the data-loading process takes less time. Also, The C++ library provides direct-data-retrieving functions, which allows the compressed information to be easily accessed by other C++ programs. Conclusions The SpeedGene algorithm enables the storage and the analysis of next generation sequencing data in current hardware environment, making system upgrades unnecessary. PMID:22591016

Application of PDF methods to compressible turbulent flows

NASA Astrophysics Data System (ADS)

Delarue, B. J.; Pope, S. B.

1997-09-01

A particle method applying the probability density function (PDF) approach to turbulent compressible flows is presented. The method is applied to several turbulent flows, including the compressible mixing layer, and good agreement is obtained with experimental data. The PDF equation is solved using a Lagrangian/Monte Carlo method. To accurately account for the effects of compressibility on the flow, the velocity PDF formulation is extended to include thermodynamic variables such as the pressure and the internal energy. The mean pressure, the determination of which has been the object of active research over the last few years, is obtained directly from the particle properties. It is therefore not necessary to link the PDF solver with a finite-volume type solver. The stochastic differential equations (SDE) which model the evolution of particle properties are based on existing second-order closures for compressible turbulence, limited in application to low turbulent Mach number flows. Tests are conducted in decaying isotropic turbulence to compare the performances of the PDF method with the Reynolds-stress closures from which it is derived, and in homogeneous shear flows, at which stage comparison with direct numerical simulation (DNS) data is conducted. The model is then applied to the plane compressible mixing layer, reproducing the well-known decrease in the spreading rate with increasing compressibility. It must be emphasized that the goal of this paper is not as much to assess the performance of models of compressibility effects, as it is to present an innovative and consistent PDF formulation designed for turbulent inhomogeneous compressible flows, with the aim of extending it further to deal with supersonic reacting flows.

Tensile and compressive creep behavior of extruded Mg–10Gd–3Y–0.5Zr (wt.%) alloy

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

Wang, H.; The State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240; Wang, Q.D., E-mail: wangqudong@sjtu.edu.cn

2015-01-15

The tensile and compressive creep behavior of an extruded Mg–10Gd–3Y–0.5Zr (wt.%) alloy was investigated at temperatures ranging from 200 °C to 300 °C and under stresses ranging from 30 MPa to 120 MPa. There existed an asymmetry in the tensile and compressive creep properties. The minimum creep rate of the alloy was slightly greater in tension than in compression. The measured values of the transient strain and initial creep rate in compression were greater than those in tension. The creep stress exponent was approximately 2.5 at low temperatures (T < 250 °C) and 3.4 at higher temperatures both in tensionmore » and in compression. The compression creep activation energy at low temperatures and high temperatures was 83.4 and 184.3 kJ/mol respectively, while one activation energy (184 kJ/mol) represented the tensile–creep behavior over the temperature range examined. Dislocation creep was suggested to be the main mechanism in tensile creep and in the high-temperature regime in compressive creep, while grain boundary sliding was suggested to dominate in the low-temperature regime in compressive creep. Precipitate free zones were observed near grain boundaries perpendicular to the loading direction in tension and parallel to the loading direction in compression. Electron backscattered diffraction analysis revealed that the texture changed slightly during creep. Non-basal slip was suggested to contribute to the deformation after basal slip was introduced. In the tensile–creep ruptured specimens, intergranular cracks were mainly observed at general high-angle boundaries. - Highlights: • Creep behavior of an extruded Mg–RE alloy was characterized by EBSD. • T5 aging treatment enhanced the tension–compression creep asymmetry. • The grains grew slightly during tensile creep, but not for compressive creep. • Precipitate free zones (PFZs) were observed at specific grain boundaries. • Intergranular fracture was dominant and cracks mainly originated at GHABs.« less

Continuous manufacturing of extended release tablets via powder mixing and direct compression.

PubMed

Ervasti, Tuomas; Simonaho, Simo-Pekka; Ketolainen, Jarkko; Forsberg, Peter; Fransson, Magnus; Wikström, Håkan; Folestad, Staffan; Lakio, Satu; Tajarobi, Pirjo; Abrahmsén-Alami, Susanna

2015-11-10

The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Optimal Surgical Therapy in a Porcine (Sus scrofa) Model of Extra-Thoracic Penetrating Trauma Resulting in Hemorrhagic Shock: ED Thoracotomy vs. Immediate Trans-Abdominal Vascular Control. A Porcine Model for Evaluating the Management of Non-Compressible Torso Hemorrhage

DTIC Science & Technology

2010-11-08

celiac aortic clamping (n=6), direct vascular control (n=6), and endovascular aortic occlusion n=6). This study presents a large animal model of class...including thoracic aortic clamping, supra- celiac aortic clamping, direct vascular control, and proximal endovascular balloon occlusion. Following vascular...subsequently underwent non-compressible hemorrhage with thoracic aortic clamping (n=6), supra- celiac aortic clamping (n=6), direct vascular control (n=6

Assessing Impact Direction in 3-point Bending of Human Femora: Incomplete Butterfly Fractures and Fracture Surfaces,.

PubMed

Isa, Mariyam I; Fenton, Todd W; Deland, Trevor; Haut, Roger C

2018-01-01

Current literature associates bending failure with butterfly fracture, in which fracture initiates transversely at the tensile surface of a bent bone and branches as it propagates toward the impact surface. The orientation of the resulting wedge fragment is often considered diagnostic of impact direction. However, experimental studies indicate bending does not always produce complete butterfly fractures or produces wedge fragments variably in tension or compression, precluding their use in interpreting directionality. This study reports results of experimental 3-point bending tests on thirteen unembalmed human femora. Complete fracture patterns varied following bending failure, but incomplete fractures and fracture surface characteristics were observed in all impacted specimens. A flat, billowy fracture surface was observed in tension, while jagged, angular peaks were observed in compression. Impact direction was accurately reconstructed using incomplete tension wedge butterfly fractures and tension and compression fracture surface criteria in all thirteen specimens. © 2017 American Academy of Forensic Sciences.

REGULATION OF EPHRIN-A EXPRESSION IN COMPRESSED RETINOCOLLICULAR MAPS

PubMed Central

Tadesse, T.; Cheng, Q.; Xu, M.; Baro, D.J.; Young, L.J.; Pallas, S.L.

2012-01-01

Retinotopic maps can undergo compression and expansion in response to changes in target size, but the mechanism underlying this compensatory process has remained a mystery. The discovery of ephrins as molecular mediators of Sperry’s chemoaffinity process allows a mechanistic approach to this important issue. In Syrian hamsters, neonatal, partial (PT) ablation of posterior superior colliculus (SC) leads to compression of the retinotopic map, independent of neural activity. Graded, repulsive EphA receptor/ephrin-A ligand interactions direct the formation of the retinocollicular map, but whether ephrins might also be involved in map compression is unknown. To examine whether map compression might be directed by changes in the ephrin expression pattern, we compared ephrin-A2 and ephrin-A5 mRNA expression between normal SC and PT SC using in situ hybridization and quantitative real-time PCR. We found that ephrin-A ligand expression in the compressed maps was low anteriorly and high posteriorly, as in normal animals. Consistent with our hypothesis, the steepness of the ephrin gradient increased in the lesioned colliculi. Interestingly, overall levels of ephrin-A2 and -A5 expression declined immediately after neonatal target damage, perhaps promoting axon outgrowth. These data establish a correlation between changes in ephrin-A gradients and map compression, and suggest that ephrin-A expression gradients may be regulated by target size. This in turn could lead to compression of the retinocollicular map onto the reduced target. These findings have important implications for mechanisms of recovery from traumatic brain injury. PMID:23008269

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.

Chapter 22: Compressed Air Evaluation Protocol. The Uniform Methods Project: Methods for Determining Energy Efficiency Savings for Specific Measures

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

Kurnik, Charles W; Benton, Nathanael; Burns, Patrick

Compressed-air systems are used widely throughout industry for many operations, including pneumatic tools, packaging and automation equipment, conveyors, and other industrial process operations. Compressed-air systems are defined as a group of subsystems composed of air compressors, air treatment equipment, controls, piping, pneumatic tools, pneumatically powered machinery, and process applications using compressed air. A compressed-air system has three primary functional subsystems: supply, distribution, and demand. Air compressors are the primary energy consumers in a compressed-air system and are the primary focus of this protocol. The two compressed-air energy efficiency measures specifically addressed in this protocol are: High-efficiency/variable speed drive (VSD) compressormore » replacing modulating, load/unload, or constant-speed compressor; and Compressed-air leak survey and repairs. This protocol provides direction on how to reliably verify savings from these two measures using a consistent approach for each.« less

Twinning behaviors of a rolled AZ31 magnesium alloy under multidirectional loading

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

Hou, Dewen

The microstructure and texture evolution of an AZ31 magnesium rolled sheet during quasi-static compression at strain rates of 10{sup −3} s{sup −1} has been investigated by in situ electron backscattered diffraction. The influence of the initial and pre-deformed texture on the predominant deformation mechanisms during compression has been examined. It has been found that extensive grain reorientation due to (10 − 12) tensile twinning appeared when compressed along transverse direction. Tensile twin variants were observed under this loading condition, and different variants will cause an effect to the following deformation. Several twinning modes occurred with continuative loading along rolling direction.more » - Highlights: •Twinning behaviors were investigated through in situ multidirectional compressive tests. •Deformation behavior was affected by the twin variants. •Four types of twinning behaviors were observed during deformation process.« less

Geometry of generalized depolarizing channels

NASA Astrophysics Data System (ADS)

Burrell, Christian K.

2009-10-01

A generalized depolarizing channel acts on an N -dimensional quantum system to compress the “Bloch ball” in N2-1 directions; it has a corresponding compression vector. We investigate the geometry of these compression vectors and prove a conjecture of Dixit and Sudarshan [Phys. Rev. A 78, 032308 (2008)], namely, that when N=2d (i.e., the system consists of d qubits), and we work in the Pauli basis then the set of all compression vectors forms a simplex. We extend this result by investigating the geometry in other bases; in particular we find precisely when the set of all compression vectors forms a simplex.