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Nep, E. I. "Grewia polysaccharide gum as a pharmaceutical excipient." Thesis, Aston University, 2010. http://publications.aston.ac.uk/10310/.
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Grewia gum is obtained from the inner stem bark of the edible plant Grewia mollis Juss (Fam. Tiliaceae) which grows widely in the middle belt region of Nigeria, and is also cultivated. The dried and pulverised inner stem bark is used as a thickening agent in some food delicacies in that region of the country. This ability of the material to increase solution viscosity has generated a lot of interest and is the catalysing momentum for this research. Such materials have been used as stabilizers or suspending agents in cosmetics, foods and liquid medications, and as mucoadhesives and controlled release polymeric matrices in solid dosage forms. The physicochemical characterization of candidate excipients forms an essential step towards establishing suitability for pharmaceutical application. For natural gums, this usually requires isolation of the gum from the storage site by extraction processes. Grewia polysaccharide gum was extracted and dried using techniques such as air-drying, freeze-drying or spray-drying. Component analysis of the gum showed that it contains five neutral sugars: glucose, galactose, rhamnose, arabinose and xylose. The gum contains traces of elements such as zinc, magnesium, calcium and phosphorus. At low substance weight, the gum hydrates in aqueous medium swelling and dispersing to give a highly viscous dispersion with pseudoplasmic flow behaviour. The method by which drying is achieved can have significant effect on some physicochemical properties of the gum. Consequently, the intrinsic viscosity and molecular weight, and parameters of powder flow were shown to differ with the method of drying. The gum has good thermal stability. In comparison with established excipients, grewia gum may be preferable to gum Arabic or sodium carboxymethylcellulose as a suspending agent in ibuprofen suspension formulations. The release retardant property of the gum was superior to guar and Metolose® in ibuprofen matrices. Similarly, carboxy methylcellulose, Methocel®, gum Arabic or Metolose® may not be preferable to grewia gum when controlled release of a soluble drug like cimetidine is indicated. The mucoadhesive performance of the gum compared favourably with excellent mucoadhesives such as hydroxypropyl methylcellulose, carboxymethylcellulose, guar and carbopol 971 P.
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Mackin, L. A. "The effects of moisture on triboelectrification of selected pharmaceutical excipient powders." Thesis, University of Sunderland, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245985.
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The literature contains conflicting reports on the effect of moisture on triboelectrification, indeed experiments have shown moisture to increase, decrease or have no effect at all on the charging of solids. The research programme investigated the role of moisture in the triboelectrification of a range of pharmaceutical excipients. Selection of excipients was made on the basis of a) moisture sorption capacity (the starch group) and b) potential use in dry powder inhaler formulations (the sugar and sorbitol group). The following excipients were selected for preliminary investigations:- a-lactose monohydrate, dextrose monohydrate, sorbitol spray dried (SSD), sorbitol powder, sucrose, maize and potato starch and Primojel™.
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Camargo, Jhon Jairo Rojas. "Assessment of co-processing of cellulose II and silicon dioxide as a platform to enhance excipient functionality." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2763.
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This thesis project studied microcrystalline cellulose II (CII), a polymorphic form of cellulose, which has lower mechanical properties, less plastic deformation, higher elastic recovery and faster disintegration properties than microcrystalline cellulose I (CI). Also, the effects of processing and silicification on CII materials were investigated. Particle modification through spray drying, wet granulation and spheronization was employed to improve CII performance. Spray-drying (SDCII) and wet granulation (WGCII) produced materials with no difference in mechanical or disintegration properties from unprocessed CII, but did show an increase in density and particle flow. Conversely, spheronization (SPCII) showed the poorest mechanical properties compared to CII. Further, SDCII showed better dilution potential than CII. Thus the advantages of SDCII were apparent when it was mixed with a poorly compressible drug (acetaminophen) because fibrous CII was converted to spheroidal particles through spray drying. The rapid disintegration of SDCII and CII compacts was due to water wicking through capillaries followed by compact bursting. Compacts of ibuprofen mixed with SDCII and Avicel® PH-102 had comparable disintegration rates and release profiles compared to ibuprofen formulated with commercial disintegrants and Avicel® PH-102, especially at levels 10% w/w. Adding fumed silica into CII particles through spray drying, wet granulation (WGCII) and spheronization (SPCII) at 2-20% w/w was also studied. Silicification increased physical properties such as true density, Hausner ratio, porosity, ejection force and specific surface area of SDCII and WGCII. Other properties such as bulk and tap densities were reduced due to the amorphous and light character of fumed silica. Spheronized CII showed no change in these properties with silicification. Silicification diminished lubricant sensitivity with magnesium stearate due to the competition of SiO2 with magnesium stearate to coat CII particles. Silicification also decreased the affinity of CII for water only at the 20% w/w level due to the few silanol groups available for water interaction compared to surface hydroxyl groups on CII alone. Particle size modification of CII was process-dependent rather than silicification-dependent. Additionally, silicification decreased the apparent plasticity and elastic recovery of SDCII and WGCII when compacted. The former effect along with increased powder porosity increased surface area and compressibility of SDCII and WGCII. Compact tensile strength of silicified CII materials was in the order: spray-dried > wet granulated > spheronized. This order was due to the combined effect of particle morphology and how fumed silica was incorporated and distributed within CII particles. Silicification did not affect the rapid disintegration properties of CII. Thus, diphenhydramine HCl and griseofulvin tablets prepared with silicified CII had faster disintegration and release than those prepared with commercial silicified CI (Prosolv®). Moreover, CII beads containing diphenhydramine HCl or griseofulvin had faster release profiles compared to beads prepared with Prosolv® SMCC 50 or Avicel® PH-101. This behavior showed that rapid disintegration is an intrinsic property of CII. Compact tensile strength decreased more for unsilicified CI and CII compacts stored at 75% RH, while silicified CI and CII compacts lost less tensile strength under the same conditions. Reprocessed CI materials containing acetaminophen (1:1mixtures) lost 35-72% of their original strength compared to silicified CII materials (15-25% loss) indicating more particle interaction upon recompression.
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Tant, Martin Ray. "Biopharmaceutic and Pharmacokinetic Studies of Sucrose Acetate Isobutyrate as an Excipient for Oral Drug Delivery." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1345.
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Sucrose acetate isobutyrate (SAIB), a randomly substituted sucrose approximating sucrose diacetate hexaisobutyrate, is produced by Eastman Chemical Company for a variety of applications. SAIB is widely used in the food industry as a weighting agent to disperse flavoring oils in primarily citrus-based soft drink beverages. Additionally, SAIB is currently being marketed by another company as a parenteral drug delivery system. The studies reported here focused on investigating SAIB as an excipient, or delivery vehicle, for use in oral delivery of several drugs, including ibuprofen, saquinavir, and clarithromycin. Dissolution experiments were conducted using both ibuprofen and caffeine, and results suggest that SAIB can be used in dosage forms to control release rate. Pharmacokinetic studies in which laboratory rats were dosed with formulations containing drugs such as ibuprofen, saquinavir, and clarithromycin suggest that SAIB may act to reduce animal-to-animal variability in drug concentration profiles in some cases, and that it may also enhance gastroretention of the dosage forms. Finally, dosage form imaging studies suggest but do not reliably confirm that SAIB may aid in promoting gastric retention, which would make its use in dosage form formulation beneficial for administration of drugs whose action is intended to occur in the stomach.
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Tinmanee, Radaduen. "The role of pharmaceutical excipients in the solid-state degradation of Gabapentin." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1919.
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Drug instability in solid dosage forms includes chemical or physical processes involving covalent or polymorphic transformations wherein different polymorphs possess crystal structure differences. Gabapentin chemically degrades by intramolecular cyclization to gabapentin-lactam (lactam) in the solid-state. Additionally, gabapentin undergoes polymorphic solid-state transformations. A kinetic model was developed to describe the environmental and excipient effects on chemical and physical instability associated with milling induced stress and subsequent storage under controlled temperature and humidity conditions.
Reaction mixtures were generated by co-milling gabapentin Form II with various excipients. The effects of environmental conditions were studied by storing reaction mixtures at 40-60 ºC and 5-50 %RH. The chemical and polymorphic compositions of the reaction mixtures were measured as a function of time using a combination of chromatographic method, 13C ssNMR and XRPD. Degradation models that describe the relationship between polymorphs and degradation product in a series of sequential or parallel steps were devised based on analysis of the resultant concentration time profiles. Model parameters were estimated using non-linear regression and Bayesian methods and evaluated in terms of their quantitative relationship to compositional and conditional variations.
In reaction mixtures composed of co-milled gabapentin and excipients, gabapentin was found to exist in three forms: anhydrous polymorph II and III and gabapentin-lactam. A fourth form (II*) was observed based on initial degradation kinetics and was hypothesized to be a crystal-disordered form generated by mechanical stress. The effect of environment moisture was to decrease the net rate of lactam formation by facilitating polymorphic transformation kinetics and crystal annealing. However, excipient blocked the catalytic moisture effect on polymorphic transformations. The key features of our model are first-order physical state transitions of II* and III to II, first-order degradation of II* to lactam and autocatalytic lactamization of II and III. For chemical transitions, no humidity effect was present but the catalytic effects of excipients on the conversion of II and III → lactam were observed. For physical transitions, excipient primarily influenced the physical state transitions of II*and III → II through its ability to interact with humidity and the degree of contact between excipient and substrate.
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Gupta, Patel Salin. "MECHANISMS AND THERMODYNAMICS OF THE INFLUENCE OF SOLUTION-STATE INTERACTIONS BETWEEN HPMC AND SURFACTANTS ON MIXED ADSORPTION ONTO MODEL NANOPARTICLES." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacy_etds/103.
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Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known.
The goals of this dissertation work were (a) to determine the energetics of interactions between HPMC and model surfactants and the extent to which these solution-state interactions modulate the adsorption of these excipients onto solid surfaces, (b) to determine and characterize the structures of various aggregate species formed by the interaction between hydroxypropyl methylcellulose (HPMC) and model surfactants (nonionic and ionic) in solution-state, and (c) to extend these quantitative relationships to interpret probable mechanisms of mixed adsorption of excipients onto the model NDDS surface.
A unique approach utilizing fluorescence, solution calorimetry and adsorption isotherms was applied to tease apart the effect of solution state interactions of polymer and surfactant on the extent of simultaneous adsorption of the two excipients on a model surface. The onset of aggregation and changes in aggregate structures were quantified by a fluorescence probe approach with successive addition of surfactant. In the presence of HPMC, the structures of the aggregates formed were much smaller with an aggregation number (Nagg) of 34 as compared to micelles (Nagg ~ 68) formed in the absence of HPMC. The strength of polymer-surfactant interactions was determined to be a function of ionic strength and hydrophobicity of surfactant. The nature of these structures was characterized using their solubilization power for a hydrophobic probe molecule. This was determined to be approximately 35% higher in the polymer-surfactant aggregates as compared to micelles alone and was attributed to a significant increase in the number of aggregates formed and the increased hydrophobic microenvironment within these aggregates at a given concentration of surfactant.
The energetics of the adsorption of SDS, HPMC, and SDS-HPMC aggregate onto nanosuspensions of silica, which is the model solid surface were quantified. A strong adsorption enthalpy of 1.25 kJ/mol was determined for SDS adsorption onto silica in the presence of HPMC as compared to the negligible adsorption enthalpy of 0.1 kJ/mol for SDS alone on the silica surface. The solution depletion and HPMC/ELSD methods showed a marked increase in the adsorption of SDS onto silica in the presence of HPMC. However, at high SDS concentrations, a significant decrease in the adsorbed amount of HPMC onto silica was determined. This was further corroborated by the adsorption enthalpy that showed that the silica-HPMC-SDS aggregation process became less endothermic upon addition of SDS. This suggested that the decrease in adsorption of HPMC onto silica at high SDS concentrations was due to competitive adsorption of SDS-HPMC aggregates wherein SDS is displaced/desorbed from silica in the presence of HPMC. At low SDS concentrations, an increase in adsorption of SDS was due to cooperative adsorption wherein SDS is preferentially adsorbed onto silica in the presence of HPMC. This adsorption behavior confirmed the hypothesis that the solution-state interactions between pharmaceutical excipients such as polymers and surfactants would significantly impact the affinity and capacity of adsorption of these excipients on NDDS surfaces.
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El, Sanadi Caroline Elizabeth. "THE VALUE OF A FUNCTIONAL EXCIPIENT ADDITIVE TO HUMAN INSULIN THERAPIES: FROM MANUFACTURE TO HUMAN CLINICAL TRIAL." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1450286879.
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Elgaied-Lamouchi, Dhouha. "Découverte de nouveaux excipients pharmaceutiques à base d'amidons modifiés pour une libération prolongée d'une substance active." Thesis, Lille, 2020. https://pepite-depot.univ-lille.fr/.
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Les comprimés matriciels hydrophiles sont fréquemment utilisés pour contrôler la libération d’actif dans les formes galéniques à usage oral. Les amidons représentent un choix intéressant pour cette application. En effet, ce sont des matériaux biocompatibles, biodégradables et disponibles à partir de différentes sources végétales. En plus des amidons natifs, les amidons modifiés (AM) ont été beaucoup étudiés pour la formulation des comprimés matriciels à libération prolongée. Les modifications physico-chimiques peuvent être ajustées de manière à correspondre aux propriétés souhaitées pour une application pharmaceutique spécifique. De nombreux scientifiques ont rapportés l'utilisation de ces amidons pour les comprimés à libération contrôlée. Ils ont obtenu des résultats prometteurs montrant la capacité de ces excipients à retarder la libération d’actif dans. Cependant, la plupart des amidons utilisés dans ces études sont généralement produits à l'échelle laboratoire, et peuvent donc présenter des propriétés différentes des AM produits à l’échelle industrielle. Par conséquent, il pourrait être très difficile de transposer la production de ces amidons à l’échelle industrielle sans altérer leurs propriétés caractéristiques. L'objectif principal de ce travail était d'identifier un nouvel excipient à base d'amidon pour contrôler la libération d’actif à partir de comprimés. Ainsi, dans un premier temps, un grand criblage a permis d'étudier différents types d'amidons pour préparer des comprimés de diprohylline par compression directe. L'impact de l'origine botanique des amidons, de la méthode de pré-gélatinisation, du degré et de la nature de réticulation, ainsi que la substitution chimique ont été étudiées et les cinétiques de libération d’actif ont été mesurées. Pour avoir une meilleure compréhension de ces résultats, l’analyse de texture de l’hydrogel formé au contact du milieu de libération, la microscopie optique et électronique à balayage (MEB) ainsi que l’analyse par diffraction des rayons X ont été réalisées. De plus, un « test rapide » a été mis en place pour évaluer le potentiel d'un d'amidon donné à prolonger libération d’actif. Les résultats obtenus sur l'importance du type d'amidon et leur impact sur les cinétiques de libération d’actif des comprimés matriciels peuvent aider à mieux assimiler et optimiser ces systèmes avancés d'administration de médicaments. Dans une deuxième partie, le potentiel du (PREGEFLO® PI10) a été évalué comme agent matriciel pour les comprimés à libération prolongée. Pour ce faire, différents types de comprimés chargés d’actifs ayant une solubilité différente ont été préparés par compression directe. La robustesse de cette matrice a été étudiée dans des milieux de libération très variés. Plusieurs appareils de dissolution ont été utilisés séparément ou combinés avec d'autres machines pour simuler le stress hydrodynamique subi par les comprimés lors de leur passage à travers le tractus gastro-intestinal. Les résultats obtenus ont montré que les profils de libération d’actif à partir du PREGEFLO® PI10 n'étaient pas affectés par toutes les conditions étudiées. Ainsi, le PREGEFLO® PI10 se positionne comme un bon candidat comme polymère de libération prolongée pour la voie orale. Enfin, pour caractériser la distribution d’actif au sein du système matriciel, en particulier dans les régions «sèches» et gonflés après dissolution du comprimé, et examiner comment les distributions spatiales changent au cours du temps, l'imagerie Raman, la MEB, la spectroscopie de rayons X à dispersion d'énergie (EDX) et la cristallographie aux rayons X ont été utilisées sur des comprimés avant et après exposition au tampon. Les cartographies Raman ont confirmé que l’actif est bien piégé dans le noyau du comprimé «sec». Ces observations ont mis en évidence la différence de morphologie entre la région centrale « sèche » et la région dans laquelle la matrice du comprimé a subi un gonflement importantHydrophilic matrix tablets are frequently used to control the drug release from oral dosage forms. Starch-based polymers are interesting matrix former in this respect, due to their biocompatibility, biodegradability, and availability from different plant sources. In addition to native starches, modified starches have been frequently used with various physiochemical modifications, which could be tailored to provide desired properties for a specific pharmaceutical application. Many scientists have reported the use of modified starches as matrix formers for oral controlled release tablets. Numerous starch-based extended release polymers have successfully retarded drug releases. However, most of the starch batches used in those studies are generally produced at a laboratory scale and may therefore present different properties compared to modified starches obtained with industrial scale. Hence, it could be very difficult to scale up the production of these excipients without changing their key features. The major goal of this work was to identify a new excipient, based on starch to control the drug release from direct compressible matrix tablets. Therefore, in a first instance, a large screening allowed to study different types of starches to prepare diprophylline matrix tablets. The effect of the botanical origin of starches, the type of pre-gelatinization method as well as of the degree and type of cross-linking and chemical substitution have been investigated, and the resulting drug release rates from diprophylline-loaded matrix tablets were measured. For a better understanding of these results, texture analysis of the gel-layer, created upon contact with the release medium, optical and scanning electron microscopy (SEM) as well as X- ray powder diffraction analysis were applied. Moreover, a “quick test” has been proposed to evaluate the potential of a particular type of starch to sustain the drug release rate. The obtained results on the importance of the starch type and their influence on the resulting drug release rates from matrix tablets can help for a better understanding and optimization of this type of advanced drug delivery systems. In a second phase, the potential of (PREGEFLO® PI10), has been evaluated as a matrix former for controlled release tablets. Hence, various types of matrix tablets loaded with drugs having different solubility were prepared by direct compression. The robustness of this cross-linked pregelatinized potato starch matrix was investigated in a variety of release media. In addition to that, several types of experimental USP apparatuses were used separately or combined with other devices to simulate the mechanical stress the tablets are exposed to during transpassage of the gastrointestinal tract. The obtained results showed that the drug release rates from PREGEFLO® PI10 matrix were not impacted by all the conditions studied. Therefore, the explored starch excipient offers an interesting potential as matrix former in controlled release tablets. Finally, to characterize the drug distribution throughout the matrix system, in particular in the “dry” and swollen tablet regions after hydration and the way the spatial distribution patterns change with time, the tablets were investigated using Raman imaging, SEM and Energy Dispersive X-ray Spectroscopy (EDX) before and after exposure to phosphate buffer. The Raman images confirmed that the drug is effectively trapped within the “dry” tablet core. The internal structure of the vacuum-dried tablets was visualized using SEM analysis. These observations highlighted the difference in the morphology between the “dry” core region and the region in which the tablet matrix underwent substantial swelling. The polysaccharide formed a continuous hydrogel in which the drug dissolved. SEM and EDX images have rendered visible the interface “dry “core-swollen gel and the spatial distribution of the drug in both regions. The diprophylline content is predictably much highe
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Velásquez, Armijo Cristián Jesús. "Aplicação de métodos termo-analíticos e espectroscóspicos na avaliação do comportamento do fármaco isoniazida frente a adjuvantes tecnológicos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2003. http://hdl.handle.net/10183/144233.
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Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética.Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.
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Mansa, Rola. "Preparation and Characterization of Novel Montmorillonite Nanocomposites." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20207.
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Clay minerals have historically played a consequential role in human health. While the beginnings were rooted in geophagy, a primitive act of consuming earth, the health-related uses of clay minerals have evolved and diversified over time.
As excipients in pharmaceutical formulations, clay minerals can attribute novel properties onto intercalated compounds. Intercalating oxybenzone, a UV filter, within the interlamellar space of montmorillonite is desirable in order to minimize direct contact with skin. Intercalating resveratrol, a compound known for attributing beneficial effects onto human health, may be advantageous since this compound is susceptible to cis-trans isomerisation. The strategy of using alkylammonium–modified clay was undertaken and proved successful for the intercalation of oxybenzone.
The field of biopolymer/layered silicate nanocomposites is heavily researched for use in a multitude of applications. Novel montmorillonite nanocomposites were prepared with neutral guar gum and cationic guar gum, using an environmentally friendly process and are fully characterized.
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Yu, Shen. "Roll compaction of pharmaceutical excipients." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4137/.
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Roll compaction is commonly used as a dry granulation technique in the pharmaceutical industry to produce tablets for formulations sensitive to heat and moisture. This thesis reports systematic studies on the behavior of pharmaceutical excipients in associated unit operations (i.e. roll compaction, milling, tabletting), as well as their correlations. Roll compaction experiments were carried out using an instrumented roll compactor with a gravity feeding system. The influence of the process parameters, material properties and powder conditioning were investigated Ribbons produced in roll compaction were granulated using an oscillating mill to investigate the milling process. A first order kinetics equation was introduced to describe the mass throughput of the granules. Using positron emission particle tracking technique, which provided a measurement of instantaneous velocity and the location of the ribbons, two milling regions (i.e. impact and abrasion) involving distinct fracture mechanisms were identified. Tabletting of the granules was performed using a universal test machine. A reduction in the compressibility and compactibility of the granules compared to the feed powders, due to work hardening, was also observed. A method was introduced to determine the optimized process conditions for roll compaction and milling through a close examination of the correlation between the unit operations.
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Ashiru, Diane A. I. "Modulating Intestinal Absorption Using Pharmaceutical Excipients." Thesis, University College London (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509950.
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Buggins, Talia Rae. "Effects of pharmaceutical excipients on drug disposition." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/55658/.
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This thesis investigates the potential of some commonly used pharmaceutical excipients to alter drug pharmacokinetics. In breath test studies, 3.2ml/kg DMSO prolonged the half-life of 14C-aminopyrine, -erythromycin and -NDMA, indicating in vivo inhibition of metabolism by CYP3A (erythromycin), CYP2E1 (NDMA) and the variety of enzymes that metabolise aminopyrine (CYP 2C11, 2C12, 2B1 and 2B2). However, no effects were apparent at doses typically used in pre-clinical formulations. Aminopyrine and erythromycin breath tests were not affected by propylene glycol (PG) or Solutol HS15, however PG did significantly increase 14C02 exhalation half- life in the NDMA breath test, suggesting a specific effect on metabolism by CYP2E1. While two 2ml/kg doses of DMSO increased plasma ai-AGP levels, none of the excipients tested consistently affected plasma ai-AGP at doses commonly used in pre-clinical formulations, suggesting that they are unlikely to increase protein binding by this mechanism. Transport studies in MDCK-MDR1 cells demonstrated an inhibitory effect of 0.1% Tween 80 and Solutol HS15 on P-Gp. In vivo, Tween inhibited the biliary elimination of 99mTc-MIBI but not 99mTc-HIDA, indicating inhibition of P-Gp, while Solutol inhibited the biliary elimination of both radiopharmaceuticals, suggesting inhibition of MRP and possibly P-Gp. Pre-treatment with 4ml/kg DMSO substantially impaired the renal elimination of 99mTc-DTPA. In contrast, 20% 1.8ml/kg DMSO significantly increased 99mTc-DTPA uptake into the kidneys, suggesting an increase in GFR. Both Tween and Solutol delayed 99mTc-DTPA elimination from the kidneys in some rats, without affecting GFR. However, Solutol did not significantly affect the pharmacokinetics of OAT or OCT substrates, suggesting it did not affect active renal secretion by these transporters. These results demonstrate that excipients can influence drug pharmacokinetics in vivo, after a single acute dose at levels commonly used in pre clinical studies.
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Dogbe, Selasi Cudjoe. "Predictive milling of active pharmaceutical ingredients and excipients." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/17937/.
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Spiral jet milling is a size reduction process used in various industries, ranging from paints to food and pharmaceuticals. It has great benefit in the pharmaceutical industry due to its ability to reduce particulate solids to micron sizes and narrow size distributions. Despite its heavy usage, the underlying size reduction mechanism of the mill is not well understood. However it is generally known that the milling behaviour is dependent on the grinding conditions of the mill, as well as the materials physical and mechanical properties. The system is also very energy inefficient. In this work the milling behaviour of active pharmaceutical ingredients and excipients in the spiral jet mill has been analysed based on their mechanical properties, as established from the Ghadiri and Zhang semi-brittle breakage model. Using the Single Particle Impact Test Rig, the breakability index (αH/KC2) of three pharmaceutical materials (paracetamol, aspirin, and α-lactose monohydrate) is determined. It is shown that the order of breakability is paracetamol > aspirin > α-lactose monohydrate. For milling studies the Hosokawa Alpine Aeroplex Spiral Jet Mill 50AS is used. The change in specific surface area (ΔSSA) due to milling is quantified by size analysis and related to the breakability indices. The order of ΔSSA is α-lactose monohydrate > paracetamol > aspirin at high grinding pressure conditions. The loading of particles in the grinding chamber of the mill is found to be an important characteristic for the classification of milled materials in addition to the effects of centrifugal and drag forces. Numerical simulations have been carried out and used to analyse the behaviour of the spiral jet mill. Using Computational Fluid Dynamics, the mechanics of internal particle classification by size of the 50AS has been analysed. Particles of 2 µm and less are shown to be classified. The Discrete Element Method is coupled with Computational Fluid Dynamics to investigate the effect of grinding conditions and particle properties on the particle motion and fluid-particle energy transfer, including gas pressure, the number of particles and the particle size distribution. A very small amount of energy is transferred to the particles from the fluid, highlighting the energy inefficiency of the system. Interparticle interactions are found to have a greater amount of dissipated energy compared to particle-wall interactions, which suggests interparticle collisions are the primary source of particle breakage. The majority of the stress exerted on the particles is close to the wall of the mill, with the normal stress being greater than the shear stress. A very low proportion of particles are found to be in contact at a given time, indicating particle breakage occurs from instantaneous collisions rather than particles shearing against each other. Finally the potential for scale-up of the spiral jet mill is investigated based on the fluid power input to the system. There is a good comparison of the ΔSSA of α-lactose monohydrate milled in four different mills at similar fluid power input conditions. Two of the mills are the 50AS and the Hosokawa Alpine Piconizer (33 AS), and the other two are of different design but with internal diameters of 2 inches and 4 inches, i.e. roughly similar size to the Hosokawa mills. The latter two mills had a greater fluid power as the grinding nozzle diameters are larger than the Hosokawa mills.
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Doherty, C. "Microenvironmental role of pharmaceutical excipients in drug dissolution control." Thesis, University of Bradford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374915.
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Mai, Yang. "Sex-specific modulation of drug bioavailability with pharmaceutical excipients." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044027/.
Full textAbstract:
The biopharmaceutics classification system (BCS) is a framework for classifying drug substances based on their aqueous solubility and permeability across a biological membrane. It is possible for individuals to request a waiver of in vivo bioequivalence (BE) studies for immediate-release solid oral dosage forms. Nowadays, the Food and Drug Administration allows the biowaiver for BCS Class I and Class III drugs. However, the findings in this thesis call attention to the unearthed loopholes in this regulation, given that formerly considered “inert” pharmaceutical excipients have shown unexpected impacts on the absorption of co-formulated drugs. By virtue of our studies, it has been exposed that a number of excipients used to aid tablet manufacturing or formulation development are able to enhance therapeutic efficacy of the drug by the modulation of transporter activity and expression. This, therefore, could characterize the excipient to have two applications; in manufacturing and drug formulation. Furthermore, the thesis outlines the modifications of the overall function of transporters, simply due to the sex of the organism. As a result, the work reported here emphasizes that the selection of excipients during formulation development is integral in preventing differences in therapeutic efficacy and side effect profiles between males and females.
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Gaisford, Simon. "Kinetic and thermodynamic investigation of a series of pharmaceutical excipients." Thesis, University of Kent, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242881.
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Mansa, Rachel Fran. "Roll compaction of pharmaceutical excipients and prediction using intelligent software." Thesis, University of Birmingham, 2007. http://etheses.bham.ac.uk//id/eprint/5406/.
Full textAbstract:
Roll compaction is a dry granulation method. In the pharmaceutical industry it assists in binding tablet ingredients together to form a larger mass. This is conducted to ease subsequent processing, decrease dust, improve flowability, improve material distribution, more suitable for moisture and heat sensitive materials than wet granulation methods, minimises operating space and suited for a continuous manufacturing set-up. In pharmaceutical roll compaction various types of powder material mixtures are compacted into ribbon that are subsequently milled and tableted. The aim of this research is to investigate the use of intelligent software (FormRules and INForm software) for predicting the effects of the roll compaction process and formulation characteristics on final ribbon quality. Firstly, the tablet formulations were characterised in terms of their particle size distribution, densities, compressibility, compactibility, effective angle of friction and angle of wall friction. These tablet formulations were then roll compacted. The tablet formulation characteristics and roll compaction results formed 64 datasets, which were then used in FormRules and INForm software training. FormRules software highlighted the key input variables (i.e. tablet formulations, characteristics and roll compaction process parameters). Next these key input variables were used as input variables in the model development training of INForm. The INForm software produced models which were successful in predicting experimental results. The predicted nip angle values of the INForm models were found to be within 5%, which was more accurate to those derived from Johanson’s model prediction. The Johanson’s model was not successful in predicting nip angle above the roll speed of 1 rpm due to air entrainment. It also over-predicted the experimental nip angle of DCPA and MCC by 200%, while the approximation using Johanson’s pressure profile under-predicted the experimental nip angle of DCPA by 5-20% and MCC by 20%.
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Garr, Joseph Sunday Mola. "Compaction characteristics of direct compression tableting excipients." Thesis, Liverpool John Moores University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261399.
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Lucero, Borja Diego Sebastián. "Solubility and Dissolution Rate of Active Pharmaceutical Ingredients: Dissolution Media and Effect of Enhancers." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/671762.
Full textAbstract:
The present doctoral thesis is focused on the effect of pH, enhancers and biorelevant media in the Solubility and the Dissolution Rates of some selected acidic active pharmaceutical ingredients (API). Because of the effect of these physicochemical parameters in the bioavailability of drugs and their pharmacological action, deepen the knowledge on the factors affecting the dissolution properties is of paramount importance in the drug development process.
Solubility and dissolution rates are examined in different aqueous solutions and buffering systems, accounting for the pH values of main interest in the gastrointestinal tract (2.0, 5.8 and 6.5), together with dissolution media that simulate intestinal fluids in fasted (FaSSIF) and fed states (FeSSIF). It is also determined in these media and discussed the effect of some excipients intended as dissolution enhancers, such as cyclodextrins, polyvinylpyrrolidones and hydroxypropylcellulose. Finally, differential scanning calorimetry was used to identify solid-solid interactions between excipients and APIs. As a complementary investigation, this thesis also presents a comparative study of the reference shake-flask and potentiometric CheqSol methods for the determination of solubility, including APIs with different acid/base properties (acidic, amphoteric and basic).
The study confirms that solubility is pH dependent, and an accurate pKa determination of the drugs is needed to detect the presence of concurrent aggregation or complexation reactions affecting the amount of compound dissolved. As expected, the addition of excipients increases the solubility of APIs, but in different degrees depending on the drug, excipient, and pH conditions. Solubility in simulated intestinal fluids is generally improved, and the addition of excipients might increase, diminish or even cancel the enhancement, depending on the matrix formed. Interestingly, the factors improving the solubility of an API do not necessarily enhance its dissolution rate. The release of the drug from its compressed solid form (tablet) is a complex process, involving an aqueous boundary layer between the solid and the bulk solution.
The results of this thesis point out the need of systematic and detailed dissolution studies in the step of pharmaceutical formulation, as long as the enhancement produced by a particular excipient in a singular dissolution medium can be characteristic of an individual API, and these results cannot be uncritically extended to other drugs.La presente tesis doctoral se enfoca en el efecto del pH, excipientes y medios biorelevantes sobre la solubilidad y velocidad de disolución de algunos principios activos (PA). Dado el efecto de estos parámetros fisicoquímicos en la biodisponibilidad de los fármacos y su acción farmacológica, el profundizar en el conocimiento de los factores que afectan estas propiedades de disolución es de suma importancia en el desarrollo de medicamentos. La solubilidad y velocidad de disolución se examinan en diferentes soluciones y sistemas tamponadores, de acuerdo a valores de pH de interés del tracto gastrointestinal, junto a medios de disolución que simulan fluidos intestinales. También se determina el efecto que puedan tener en estos medios, sustancias como excipientes que aumenten la disolución, tales como ciclodextrinas, polivinilpirrolidonas e hidroxipropilcelulosa. Calorimetría diferencial de barrido fue utilizada para identificar interacciones sólido-sólido entre excipientes y PA. Complementariamente, en esta tesis también se presenta un estudio comparativo entre el método de referencia de equilibrio de fases y el método potenciométrico CheqSol para la determinación de solubilidad, incluyendo PA de diferentes propiedades fisicoquímicas. El estudio confirma la dependencia entre pH y solubilidad, una medición exacta del pKa de los fármacos es necesaria para detectar la presencia de agregados o complejos que afecten la cantidad de muestra disuelta. Como se esperaba, la adición de excipientes incrementa la solubilidad pero en diferente grado dependiendo del compuesto, el excipiente y las condiciones de pH. La solubilidad generalmente es mejorada cuando se usan medios biorelevantes, mientras que el uso de excipientes en estos medios podría incrementar, disminuir o cancelar el efecto de solubilización, dependiendo de la matriz formada. Sorpresivamente, los factores que incrementan la solubilidad no necesariamente lo hacen en la velocidad de disolución. La liberación del compuesto desde la superficie de la tableta es un proceso complejo, relacionado con la capa acuosa intermedia entre la tableta y la solución. Los resultados de esta tesis señalan la necesidad de estudios sistemáticos y detallados en el paso previo de formulación farmacéutica, pues la mejora producida por un excipiente en particular en condiciones singulares del medio, puede ser característica para un PA específico, y estos resultados no deben ser extrapolados sin criterio a otros fármacos.
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Cote, Marie. "Solubility and phase behaviour of selected pharmaceutical excipients in 2h, 3h-perfluoropentane." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/54770/.
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The behaviour of pharmaceutical excipients was studied in 2H, 3H-perfluoropentane (HPFP), a partially fluorinated liquid considered as a highly suitable model propellant for medicinal pressurized metered-dose inhalers (pMDIs) used in drug delivery to the lungs. The additives chosen belonged to three main categories: ethylene oxide oligomers and derivatives, chosen for their wide range of applications in pharmaceutical formulations, their harmlessness and low cost a hydrophobically modified cyclodextrin that shows potential for controlled release via host-guest interactions and some interesting solubility pattern in HPFP a family of tetrahydroxy diesters that act as unprecedented organogelators for mixtures of HPFP and a partially fluorinated alcohol co-solvent. By studying ethylene oxide oligomers and derivatives in HPFP and fully fluorinated analogue PFP, it was found that the solubility of the oligomers could be tuned by varying the nature of their end-group and the polarity of the fluorinated liquids employed. Methyl groups, either placed at the extremities, thus blocking the hydroxyl end-groups of dihydroxyl end-capped polyethylene glycols, or directly added on the polymer backbone, clearly enhanced their solubility. The Lower Critical Solution Temperature initially observed was either displaced or removed via the presence of the additional methyl groups. On the other hand, such phase separation could also be induced by the subsequent addition of PFP it is shown that such behaviours are dominated by end-group/solvent interactions. This study was published in two papers, Journal of Pharmacy and Pharmacology, 2008, 60: p. 593-599 and International Journal of Pharmaceutics, 2008, 362: p. 147-152. As an attractive formulation means, the hydrophobic triacetylated-P-cyclodextrin (TAjJCD) was chosen amongst others for its partial solubility in model propellant HPFP. The observation that various batches of the same chemical entity lead to highly different solubility profiles in HPFP resulted in the full characterisation of two existing polymorphs for this compound. The monitored conversion of one form into the other was achieved, and the amorphous form could be fully recrystallysed into the higher energy form via a limited seeding process. HPFP acted as a discriminator of the two crystalline forms. More details may be found in Journal of Physical Chemistry C, 2008,112: p. 14570-15578. The monitoring of the solubility via solvent properties, as seen in the first part, was also used in the formation of self-assembled supramolecular organogels. The addition of non-solvent HPFP to an initially stable sol composed of a small tetrahydroxy diesters in the fluoroalcohol 1H, 1H-heptafluorobutanol initiated their coming out of solution. However, instead of simply precipitating, the tetrahydroxy diester molecules self-assemble into long cylindrical fibres that form a 3-dimensional network capable of entrapping the fluorinated liquids, leading to a system that is both solid-like macroscopically and liquid-like microscopically. Such gels are thermoreversible and can be obtained at gelator concentrations as low as 0.1 wt%, thus, surface tension and capillary action are thought to be the principal forces behind these structures, along with hydrogen-bonding between the gelators molecules, rather than a specific gelator-solvent interaction. This work is the reference for both Chemical Communications, 2005,31: p. 3998-4000 and a manuscript to be submitted.
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Schulze, Julia. "The in vivo effects of pharmaceutical excipients on gastrointestinal transit and drug absorption." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406724.
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Donnelly, Conor Michael. "Rationalising the selection of pharmaceutical excipients for the formulation of amorphous solid dispersions." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680168.
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Lerdkanchanaporn, Supaporn. "Application of thermal analysis to ibuprofen and associated formulation excipients." Thesis, University of Hertfordshire, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302281.
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Mohlala, Mangaabane Gorden. "The effect of pharmaceutical excipients on rifampicin release from chitosan beads / Mangaabane Gorden Mohlala." Thesis, North-West University, 2004. http://hdl.handle.net/10394/484.
Full textAbstract:
Controlled release systems aim at achieving a predictable and reproducible drug
release over a desired time period. These systems allow reduced dosing frequency,
constant drug levels in the blood, increased patient compliance and decreased adverse
effects. In a recent study, Chitosan beads, containing N-trimethyl Chitosan chloride,
have shown a potential in the delivery of rifampicin. However, because of inadequate
amounts of rifampicin released over 24 hours, incorporation of other pharmaceutical
excipients to increase the swelling behaviour of the beads to improve drug release,
was considered in this study.
Chitosan beads were prepared through ionotropic gelation with tripolyphosphate
(TPP) as a crosslinking agent. To increase the porosity if the Chitosan beads
Explotab®, Ac-Di-Sol® and vitamin C were added individually to Chitosan solutions
at concentrations of 0.1, 0.25 and 0.5 % w/v before adding the mixture to the TPP
solution. Swelling and morphology studies were used in the evaluation of the different
formulations. The swelling and morphology results were then used to select a set of
combination and concentrations of two excipients sand then prepare and characterise
beads containing two combinations. The combination formulations and formulations
containing single excipients were then loaded with rifampicin. Pure chitosan beads
exhibited a higher drug loading capacity (67.49 %) compared to the lowest loading
capacity of 41.61 % exhibited by chitosan beads containing a combination of
Explotab®, Ac-Di-Sol®.For all the other formulations the drug loading capacity
ranged within 48 and 63 %.
These formulations were used for dissolution studies over a period of 6 hours at pH
5.60 and 7.40. The dissolution results showed that no chitosan has dissolved at both
pH values. A significant amount of rifampicin was, however, released from the beads,
especially at pH 7.40. chitosan beads containing vitamin C also exhibited high
rifampicin release (48.34 ± 1.00) %) at pH 5.60 compared to the other formulations
and this makes vitamin C a potential excipient for enhanced drug release over a wide
pH range (both acidic and alkalinic). However, further studies are necessary to
optimise the preparation method to minimise drug loss during loading and to improve
the drug loading capacity of the beads.Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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Van, Rensburg Andries Gideon. "The effect of pharmaceutical excipients on isoniazid release from chitosan beads / Deon van Rensburg." Thesis, North-West University, 2007. http://hdl.handle.net/10394/1248.
Full textAbstract:
In controlled release applications a drug is molecularly dispersed in a polymer phase. In
the presence of a thermodynamically compatible solvent, swelling occurs and the
polymer releases its content to the surrounding medium. The rate of the drug release can
be controlled by interfering with the swelling rate of the beads or by influencing diffusion
through the viscosity of the polymer.
Beads that contain chitosan were prepared through the ionotropic gelation method where
tripolyphosphate (TPP) was used as the crosslinking agent. Beads that consisted of 3%
w/v isoniazid (lNH) and 5% w/v chitosan were prepared in a 5% w/v TPP solution (pH
8.7) as the primary beads. To improve the drug loading of chitosan isoniazid beads (ClB)
the TPP concentration, pH of the TPP solution and the INH concentrations were altered
for maximum drug loading. To increase the porosity of the beads of chitosan beads
Explotab® (EXPL), Ac-Di-Sol® (ADS) and Vitamin C (VC) were added individually to
chitosan solutions at concentrations of 0.1, 0.25 and 0.5% w/v before adding the mixture
to the TPP solution. Morphology, swelling and drug loading studies were used to
evaluate the different formulations. After these excipients were added individually they
were also added in combinations of two excipients respectively and characterised. From
the results of the drug loading studies the beads that contained only chitosan and
isoniazid showed a percentage drug loading of (43.92%) which is the best of all the beads
that were analyzed. The multi excipient combination of Ac-Di-Sol® and Explotab®
showed the best swelling capability at both pH levels.
Dissolution studies were conducted on all the formu lations over a period of 6 hours (360
minutes) at pH 5.6 and pH 7.4. From the dissolution results it were clear that no chitosan
dissolved at both pH values. The dissolution of single pharmaceutical excipient (SPE)
and multi pharmaceutical excipient (MPE) formulations can be arranged in the following
order: VC/ADS < VC < ADS/EXPL < ADS < VC/EXPL < CIB < EXPL. Explotab® is a
potential excipient for enhanced drug release over a wide pH range.Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.
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Yang, Xue. "Evaluation of Cucurbit[7]uril and its derivative for their use as pharmaceutical excipients." Thesis, University of Macau, 2017. http://umaclib3.umac.mo/record=b3690845.
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Darkwah, Joseph. "Protein stability : impact of formulation excipients and manufacturing processes in protein-based pharmaceuticals." Thesis, De Montfort University, 2017. http://hdl.handle.net/2086/16284.
Full textAbstract:
Presently, over 300 proteins or peptide based therapeutic medicines have been approved by the FDA owing to advances in protein engineering and technology. However, majority of these protein-based medications are unstable or have limited shelf life when in aqueous form. During pre-formulation and manufacturing, various technological processes including mixing, dissolving, filling (through pipes) can produce strong mechanical stresses on proteins. These stresses may cause the protein molecule to unfold, denature or aggregate. To improve stability upon formulation, they may be manufactured as freeze dried cakes that requires reconstitution with a buffer or water prior to administration. Although it has been successful in improving the stability of protein-based formulations, the freeze drying process itself also contributes to protein aggregation. This process introduces other stresses such as freezing, thawing and drying. In addition to these stresses, the agitation processes used during reconstitution may also destabilize the protein’s native structure. Two key processes used in preparation of protein based formulations were studied in this work; mechanical agitation and freeze drying. The aim of this project was to explore the aggregation of proteins that occur due to the various technological processes typical in the production of protein based formulations. The project has two parts that relates to liquid and solid formulations. In the first part, the effect of different methods of mechanical agitations on BSA protein was investigated. In the second part, the focus was on the effect of formulation (i.e. the application of amino acids) on aggregation of protein (BSA) in freeze dried formulations. Arginine and lysine were added individually into protein-based freeze-dried formulation to study their potential of improving the stability of the proteins during manufacturing, storage and reconstitution. In the formulation development, additional excipients were added to prevent moisture uptake due to the hygroscopic properties of the amino acids and to provide lyo- and cryo- protection for the protein molecule during freeze drying. Without further purification, BSA solutions prepared by using sonication, low shear rotor mixer or high shear tube/pipe mixing were studied using dynamic light scattering (DLS). Thioflavin T assay and turbidimetry analysis were used as complementary studies. In protein-based freeze dried formulations, at accelerated storage conditions, the presence of aggregates were studied in samples containing arginine or lysine using ThT assay and turbidimetry analysis. Characterisation of the freeze dried cakes was performed relative to their moisture sorption, cake shrinkage, mechanical properties and morphology using various analytical techniques. iv In the BSA solution studies, particle size analysis indicated two distributions for non-agitated BSA solution that corresponds to the average particle sizes of BSA molecules and their aggregates. Under mechanical stresses (all types), the intensity of distribution centered ≈ 7.8 nm reduces and broadens as the agitation time increases, indicating a reduction in the amount of “free” BSA macromolecules. The second distribution, as a result of increasing agitation time or shear intensity, reveals a significant shift towards larger sizes, or even splits into two particle size populations. These particle size growths reflect the formation of aggregates due to intensive collisions and, as a result, partial unfolding followed by hydrophobic interactions of exposed non-polar amino acids. UV spectra showed that aggregation in both low shear and mechanical vibration agitations were lower compared to the high shear stress. When compared to non-agitated BSA solution, ThT assay recorded ≈15 times higher fluorescence emission from the high shear samples, ≈2 times fluorescence emission from low shear and ≈6 times fluorescence emission from mechanical vibrations. Thus all the three agitation methods showed a good correlation between the results. The second part of this project was performed in three stages. In the initial 2 stages, 2- and 3-excipients component system were investigated to develop an optimal preliminary formulations which will be used in the final protein based 4-components formulations. From the 1st stage (ArgHCl/LysHCl + sugar/polyol), among 4 tested excipients (polyol and sugar), mannitol was observed to have resisted moisture uptake by the highly hygroscopic ArgHCl/LysHCl amino acids. However, mannitol is considered a good cryoprotector but has poor lyoprotection properties. Therefore, in the following stage, a 3rd excipient (in a 3-excipients component system) sucrose or trehalose, was introduced into the formulation. The formulation was made up of 20% ArgHCl (LysHCl), and various ratios of mannitol and sugar were explored. The criteria for selecting the best systems were based on ideal physicochemical properties i.e. moisture uptake, shrinkage, mechanical properties, matrix structure and appearance, and thermal properties. The final stage was the formulation of a 4-components system comprising the three excipients and combinations selected from the stage 2 studies, and the addition of BSA as the model protein. To study aggregation in this system, a freeze dried 4-components excipient/protein system was reconstituted and incubated at accelerated storage conditions over time. Fluorescence spectroscopy and turbidimetry were used to study aggregation of proteins, moisture uptake kinetics with gravimetric balance, and thermal analytical techniques were used to characterise the freeze dried cakes with and without BSA protein. This study represented a systematic analysis of aggregation of proteins in both liquid and solid formulations. Some of the novel aspects of this study include: v 1. The new experimental results obtained for aggregation of proteins in solution subjected to mechanical agitations. The high shear stress created by syringe agitation, simulated the real situation in post manufacturing process during filling through narrow pipes, and has been shown here to strongly affect the aggregation of protein macromolecules. 2. The development of a methodical approach for optimization of multi component (up to 4 excipients) protein based formulations. 3. The unexpected non-linear behavior of the physicochemical properties of the 3-excipients component system as a function of composition. To the best of my knowledge, this novel aspect has not been previously reported in literature. 4. Application of amino acid in protein based formulations has shown the inhibition of aggregation of BSA, with the highest effect observed with ArgHCl. The results of this study coincide with the conclusions published previously for aggregation of proteins in solution.
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Havinga, Riana. "The effect of pharmaceutical excipients on the release of indomethacin from chitosan beads / Riana Havinga." Thesis, North-West University, 2006. http://hdl.handle.net/10394/4.
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Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin CThesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.
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Bisharat, Lorina Milad Nae’m. "An investigation into the use of zein proteins as pharmaceutical excipients for modified drug release applications." Thesis, University of East Anglia, 2012. https://ueaeprints.uea.ac.uk/39448/.
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Mi, Yanli. "Protection Mechanisms of Excipients on Lactate Dehydrogenase during Freeze-Thawing and Lyophilization." View the abstract Download the full-text PDF version, 2002. http://etd.utmem.edu/WORLDACCESS/ymi/default.htm.
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Ali, H. R. H. "Vibrational spectroscopic techniques (Raman, FT-IR and FT-NIR spectroscopy) as a means for the solid-state structural analysis of pharmaceuticals." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/3343.
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The aim of this work was to assess the suitability of vibrational spectroscopic techniques (Raman, FT-IR and FT-NIR spectroscopy) as a means for the solid-state structural analysis of pharmaceuticals. Budesonide, fluticasone propionate, salbutamol hemisulfate, terbutaline hemisulfate, ipratropium bromide, polymorphic forms of salmeterol xinafoate and two polymorphic forms of sulfathiazole were selected since they are used in the management of certain respiratory disorders and from different chemical and pharmacological entities along with some pharmaceutical excipients. Conventional visual examination is not sufficient to identify and differentiate spectra between different pharmaceuticals. To confirm the assignment of key molecular vibrational band signatures, quantum chemical calculations of the vibrational spectra were employed for better understanding of the first five selected drugs. The nondestructive nature of the vibrational spectroscopic techniques and the success of quantum chemical calculations demonstrated in this work have indeed offered a new dimension for the rapid identification and characterisation of pharmaceuticals and essentially warrant further research. The application of simultaneous in situ Raman spectroscopy and differential scanning calorimetry for the preliminary investigation of the polymorphic transformation of salmeterol xinafoate polymorphs and two polymorphic forms of sulfathiazole has also been explored in this work leading to the development of a new method for the solid-state estimation of the transition temperature of entantiotropically related pharmaceutical polymorphs which represents the first analytical record of the use of this approach for pharmaceutical polymorphs.
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Setiawan, Nico. "UNDERSTANDING THE THERMODYNAMICS AND ORAL ABSORPTION POTENTIAL OF PHARMACEUTICAL AMORPHOUS SOLID DISPERSIONS." UKnowledge, 2018. https://uknowledge.uky.edu/pharmacy_etds/85.
Full textAbstract:
Supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs), have been used extensively to elevate the apparent solubility and oral bioavailability of poorly water-soluble drugs. However, despite the numerous examples of success in increasing solubility and oral bioavailability using ASDs, physical stability challenges remain as formulators seek to employ high drug loading for cost reduction and improved patient compliance. Therefore, stability in both the solid and solution state must be considered for ASDs to be successful. In the solid state, the drug must remain amorphous in the solid matrix throughout the shelf life of the product. Although excipients, such as polymers, have been known to stabilize the amorphous drug in the solid state, stresses encountered during manufacturing and fluctuations in storage conditions may have a detrimental impact on the physical stability of ASDs. Numerous studies have been performed on the impact of each process on ASD stability, yet the relative quantitative impact of each process with respect to the overall energetics landscape is not well understood.
Further, ASDs must dissolve after administration and maintain the intended supersaturation in the gastrointestinal (GI) tract during the GI transit time to achieve maximum oral absorption. In solution, the energetics advantage of the amorphous over the crystalline material is a “double-edged sword,” in that it produces not only a high absorption driving force but also an undesirable high crystallization potential. An approach to quantitatively measure the thermodynamic activity of amorphous materials is, thus, desirable. However, it is difficult to measure thermodynamic activity quantitatively, especially due to the speciation process induced by formulation excipients and endogenous materials. Hence, it is often difficult to assess the true enhancement in the absorption for a given ASD and to measure its crystallization tendency in solution. Overall, this dissertation aims to address the following:
1. The relative thermodynamics magnitude of various processes with respect to the crystallization energy associated with amorphous drugs
2. The development of a practical tool to measure the thermodynamic activity of amorphous materials over its crystalline counterpart in solution to assess the enhancement in absorption in the presence of excipients
3. The impact of measured thermodynamic activity on drug crystallization energetics in the presence of excipients
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Hillgren, Anna. "Investigation of the Freeze-Thawing Process for Pharmaceutical Formulations of a Model Protein." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5304-X/.
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Xia, Xin. "Dissolving the Rocks : Solubility Enhancement of Active Pharmaceutical Ingredients using Mesoporous Silica." Doctoral thesis, Stockholms universitet, Institutionen för material- och miljökemi (MMK), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-103190.
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Poor aqueous solubility is one of the greatest barriers for new drug candidates to enter toxicology studies, let alone clinical trials. This thesis focuses on contributing to solving this problem, evaluating the oral toxicity of mesoporous silica particles, and enhancing the apparent solubility and bioavailability of active pharmaceutical ingredients in vitro and in vivo using mesoporous silica particles. Toxicological studies in rats showed that two types of mesoporous silica particles given by oral administration were well tolerated without showing clinical signs of toxicity. Solubility enhancement, including in vivo bioavailability and in vitro intracellular activity, has been evaluated for selected drug compounds. Mesoporous silica was shown to effectively increase drug solubility by stabilizing the amorphous state of APIs, such as itraconazole (anti-fungal), dasatinib (anti-cancer), atazanavir (anti-HIV) and PA-824 (anti-tuberculosis). Itraconazole was successfully loaded into a variety of porous silica materials showing a distinct improvement in the dissolution properties in comparison to non-porous silica materials (and the free drug). Microporosity in SBA-15 particles has advantages in stabilizing the supersaturation state of dasatinib. Small pore sizes show better confinement of atazanavir, contributing to a higher dissolution of the drug compound. In the in vivo animal studies, NFM-1 loaded with atazanavir shows a four-fold increase in bioavailability compared to free crystalline atazanavir. PA-824 has a higher dissolution rate and solubility after loading into AMS-6 mesoporous particles. The loaded particles show similar antibacterial activity as the free PA-824. This thesis aims at highlighting some of the important factors enabling the selection of adequate mesoporous structures to enhance the pharmacokinetic profile of poorly water-soluble compounds, and preparing the scientific framework for uncovering the effects of drug confinement within mesopores of varying structural properties.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 5: Submitted.
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Ilko, David [Verfasser], Ulrike [Gutachter] Holzgrabe, and Petra [Gutachter] Högger. "The use of charged aerosol detection for the analysis of excipients and active pharmaceutical ingredients / David Ilko. Gutachter: Ulrike Holzgrabe ; Petra Högger." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1112943218/34.
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Nyman, Olof. "Är generiska bröstcancerläkemedel likvärdiga ur alla kliniskt betydelsefulla aspekter?" Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-34144.
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Bröstcancer är den vanligaste cancerformen hos kvinnor. I ca 80 % av fallen är cancern hormonpositiv. Förutom operation och cytostatika används läkemedel som antingen förhindrar att östrogen kan binda till sina receptorer eller minskar bildningen av östrogen. Denna typ av behandling är förknippad med en rad biverkningar. Vissa biverkningar kan kopplas till östrogenets minskade effekter i kroppen. Andra biverkningar är mer svårförklarliga. Det är dessutom inte helt ovanligt att patienter upplever starkare biverkningar av vissa generiska preparat, trots att de anses likvärdiga. För att läkemedel ska anses likvärdiga ska de bl.a. innehålla samma mängd aktiva substans. Det som oftast skiljer dem åt är vilka hjälpämnen som, förutom den aktiva substansen, ingår i formuleringen. Det finns med andra ord starka misstankar om att dessa hjälpämnen kan påverka läkemedlens biverkningsprofil i större utsträckning än man tidigare trott. Syftet med denna litteraturstudie var att ta reda på varför generiska bröstcancerläkemedel som anses likvärdiga ändå ger olika biverkningar. Detta gjordes genom att söka vetenskapliga artiklar om vad som finns skrivet om de olika hjälpämnena. De vetenskapliga artiklarna hämtades från PubMed för att sedan sammanfattas i en resultatdel. Vissa av hjälpämnena, som polysorbat 80 och kollodial kiseldioxid har visat sig ge allergiska reaktioner. Andra hjälpämnen har visat sig kontaminera aktiva substanser medan vissa hjälpämnen kan påverka CYP3A4-enzymen som metaboliserar bröstcancerpreparat. Slutsatsen är alltså att det finns en mängd potentiella sätt som generiska preparat kan skilja sig åt.
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Lagercrantz, Forss Louise. "Adhesive mixtures for dry powder inhalation." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447786.
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When it comes to dry powder inhalation (DPI), adhesive mixtures are the most widely used formulation type. Various techniques have been developed to generate inhaled drug particles and improve the delivery efficiency of DPI formulations. For dry powder inhaler formulations (DPIs), micronized drug powders are usually mixed with lactose carriers to improve powder handling during manufacturing and powder aerosol delivery during patient use. The performance of DPI systems is strongly dependent on several formulation factors, the construction of the delivery device and the inhalation technique. There is a growing interest in DPI in new medical areas such as vaccines and antibiotics which requires further development and challenges to ensure physical and aerosolization stability of DPI. This project aims to discuss the development of inhalation therapy, the challenges during formulation processes, the mixing process and the use of excipients in pulmonary drug delivery in DPIs. Further, the project is covered by experiments based on the literature overview and performed at the Department of Pharmaceutical Biosciences at Uppsala University. Bulk density was measured on three series of adhesive mixtures with increasing amounts of fine particles. In two series, small amounts of Magnesium Stearate, 0,1% and 0,01% were added.
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Urlaub, Jonas [Verfasser], Ulrike [Gutachter] Holzgrabe, and Ann-Christin [Gutachter] Pöppler. "Development of analytical methods for the quality assessment of mineral oil based excipients and mechanochemically stressed active pharmaceutical ingredients / Jonas Urlaub ; Gutachter: Ulrike Holzgrabe, Ann-Christin Pöppler." Würzburg : Universität Würzburg, 2021. http://d-nb.info/1240148011/34.
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Junior, Alcidesio Sales de Souza. "Estudo retrospectivo sobre o uso de medicamentos em neonatos internados em uma Unidade de Terapia Intensiva Neonatal em BrasÃlia-DF." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=13058.
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nÃo hÃNeonatos internados em unidade de terapia intensiva neonatal (UTIN) sÃo expostos a uma grande variedade de medicamentos, a maioria sem dados de seguranÃa e eficÃcia. Descrever o perfil de uso de medicamentos em neonatos em UTIN de um hospital pÃblico no Brasil de acordo com dados de registro do medicamento e potencial nocivo destes, foi o objetivo do trabalho. Trata-se de um estudo descritivo retrospectivo sobre uso de medicamentos em UTIN, envolvendo neonatos internados por mais de 24 horas e dados de prescriÃÃo coletados em prontuÃrio eletrÃnico durante o perÃodo de janeiro a junho do ano de 2012. InformaÃÃes sobre os medicamentos, com base nas bulas, foram comparadas com o British National Formulary for Children 2012-2013 e a base de dados Thomson Micromedex. O potencial nocivo de medicamentos e excipientes foi avaliado conforme a literatura. Neonatos foram categorizados em grupos de idade gestacional (IG). Os dados foram submetidos à anÃlise descritiva e testes de distribuiÃÃo (ANOVA, Teste U de Mann-Whitney, Kruskal-Wallis, qui-quadrado de Pearson) por IG com o nÃvel de significÃncia de p < 0,05. IncluÃram-se 192 neonatos, a maioria prÃ-termo, com mediana de 33 semanas de IG, totalizando 3.617 neonatos-dia. Registraram-se 3.290 prescriÃÃes, mÃdia 17,1 prescriÃÃes/neonato (DP  17,9) e 8,8 medicamentos/neonato (DP  5,9), maiores em neonatos mais imaturos (p < 0,05). Anti-infecciosos de uso sistÃmico, medicamentos para o sangue e ÃrgÃos formadores do sangue, trato alimentar e metabolismo apresentaram maior utilizaÃÃo, variando conforme a IG. Neonatos apresentaram maior exposiÃÃo a gentamicina seguido por ampicilina, heparina e fitomenadiona. A maioria dos neonatos (99,5%) foi exposta a medicamentos nÃo licenciados (NL) e de uso nÃo padronizado (NP), mais frequentes em neonatos com IG < 28 semanas (p < 0,05). Mais de 70% dos RN estiveram expostos a algum medicamento potencialmente perigoso (MPP), com maior frequÃncia em neonatos com IG < 31 semanas (p < 0,05). Praticamente todos os neonatos estiveram expostos a excipientes nocivos (EN) e potencialmente nocivos, sendo maior o nÃmero de formulaÃÃes prescritas a neonatos mais imaturos. Metilparabeno, propilparabeno e polissorbato 80 foram os EN aos quais os neonatos estiveram mais expostos, principalmente nas formulaÃÃes de domperidona soluÃÃo oral, polivitamÃnicos soluÃÃo oral e fentanila soluÃÃo injetÃvel. Neonatos em UTIN no Brasil, tal como em outras realidades, estÃo expostos a uma variedade de medicamentos NL, NP e com potencial nocivo, uma situaÃÃo preocupante. Alternativas seguras e estudos sÃo necessÃrios sobre esse tema.
Neonates admitted to neonatal intensive care unit (NICU) are exposed to a wide variety of drugs most without data on safety and efficacy. To describe the drug use profile of neonates in NICU of a public hospital in Brazil according to the drugs records and harmful potential of drugs and pharmaceutical excipients. Descriptive and retrospective study of drug use in NICU, with neonate inpatients for over 24 hours and prescription data from electronic medical records over the period from January to June, 2012. Drug information found in the package leaflets were compared with information in the British National Formulary for Children 2012-2013 and in the Thomson Micromedex database. The drug and excipients harmful potential was evaluated according to the literature. Neonates were categorized into groups of gestational age (GA). The data were analyzed using descriptive analysis and Distribution tests tests (ANOVA Mann-Whitney U, Kruskal-Wallis and Pearson's chi-squared) by GA, with a significance level of p <0.05. Were included 192 neonates, most preterm with median 33 weeks of GA and a total of 3.617 neonates-day. Were registered 3,290 prescriptions, average 17.1 prescriptions/neonate (SD Â 17.9) and 8.8 drugs/neonate (SD Â 5.9), higher in most immature neonates (p < 0.05). The anti-infectives for systemic use, blood and blood forming organs, alimentary tract and metabolism drugs groups showed increased use among the neonates, varying according to the GA. Neonates had higher exposure to gentamicin followed by ampicillin, heparin and phytomenadione. Most neonates (99.5%) were exposed to unlicensed drugs (UL) and off label use (OL), more frequently those with GA < 28 weeks (p < 0.05). More than 70% of the neonates were exposed to any high-alert medications, with higher frequency among neonates with GA < 31 weeks (p < 0.05). Almost all neonates were exposed to harmful and potentially harmful excipients, being greater the number of formulations prescribed to more immature neonates. Gentamicin (sulfate) injectable Solution 10 mg/mL (1 mL), fentanyl solution injectable 0.05 mg/mL (10 mL) and sodium heparin injectable solution were the containing harmful excipients formulations to which neonates were most exposed. Neonates in Brazilian NICU, as in other settings, are exposed to a variety of OL, UL and potentially harmful drugs and harmful excipients, an alarming situation. Safety alternatives and more studies are needed on this topic.
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Boc, Susan. "Aerosolized Surfactants: Formulation Development and Evaluation of Aerosol Drug Delivery to the Lungs of Infants." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5577.
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The overall aim of this research project was to develop surfactant dry powder formulations and devices for efficient delivery of aerosol formulations to infants using the excipient enhanced growth (EEG) approach. Use of novel formulations and inline delivery devices would allow for more efficient treatment of infants suffering from neonatal respiratory distress syndrome and bronchiolitis.
A dry powder aerosol formulation has been developed using the commercial product, Survanta ® (beractant) and EEG technology to produce micrometer-sized hygroscopic particles. Spray drying and formulation parameters were initially determined with dipalmitoylphosphatidylcholine (DPPC, the dominant phospholipid in pulmonary surfactant), which produced primary particles 1 um in size with a mass median aerodynamic diameter of 1-2 um.
Investigation of dry powder dispersion enhancers and alcohol concentration on the effect of powder aerosol characteristics were performed with the Survanta-EEG formulation. The optimal formulation consisted of Survanta ® , mannitol and sodium chloride as hygroscopic excipients, and leucine as the dry powder dispersion enhancer, prepared in 20% v/v ethanol/water. The powders produced primary particles of 1 um with >50% of the particles less than 1 um. The presence of surfactant proteins and surface activity were demonstrated with the Survanta-EEG formulation following processing.
A novel containment unit dry powder inhaler (DPI) was designed for delivery of the surfactant-EEG formulation using a low volume of dispersion air. Studies explored optimization of air entrainment pathway, inlet hole pattern, delivery tube internal diameter and length. With 3- 10 mg fill masses of spray dried surfactant powder, the DPI enabled delivery of >2 mg using one 3-mL actuation of dispersion air. Overall, it was possible to deliver >85% of the loaded fill mass using three actuations.
Nebulized aerosol formulations are characterized with low delivered doses. Using a novel mixer-heater delivery system, the highest estimated percent lung dose achieved during realistic in vitro testing of a Survanta-EEG formulation aerosolized with a commercial mesh nebulizer was when nebulization was synchronized with inhalation of the breathing profile. Design changes to the mixer-heater system eliminated the need for synchronization, achieving an estimated percent lung dose of 31% of the nominal, an improvement compared with existing systems that achieve approximately <2% lung dose.
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Busignies, Virginie. "Recherche de lois de mélange sur des propriétés mécaniques de systèmes granulaires compactés." Phd thesis, Université Paris Sud - Paris XI, 2005. http://tel.archives-ouvertes.fr/tel-00012167.
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Les matériaux granulaires sont utilisés dans de nombreux domaines tels que la pharmacie, la chimie, la métallurgie, l'agroalimentaire. Ils font l'objet de nombreuses recherches théoriques et expérimentales. La compression en matrice fermée est un procédé économique et facile à automatiser, ce qui explique qu'elle soit très répandue dans les industries qui utilisent des milieux granulaires. Dans le domaine pharmaceutique, le comprimé reste la forme la plus présente sur le marché. Bien que simple en apparence, la compression est un processus dynamique irréversible d'une grande complexité. Dans le cas d'un comprimé pharmaceutique, il faut garder à l'esprit que celui ci doit répondre à la fois à des contraintes technologiques, à des contraintes thérapeutiques et à des contraintes réglementaires très strictes. Pour répondre à ces différentes contraintes, les comprimés pharmaceutiques sont obtenus par la compression de mélanges souvent complexes d'excipients et d'une substance active. Bien que des progrès aient été fait dans la quantification des propriétés mécaniques des systèmes simples, le comportement mécanique des systèmes de poudres plus complexes a été moins étudié. L'idéal pour le formulateur serait de disposer des propriétés de chaque constituant du mélange et de sa contribution au comportement de l'ensemble du système pour pouvoir prédire le comportement des constituants en mélange. L'expérience semble montrer que ce n'est pas aussi simple. Or, comprendre le comportement d'un mélange en fonction des propriétés de ces constituants de base, c'est non seulement pouvoir prédire le comportement du mélange, mais également pouvoir développer de nouvelles formules.L'objectif de ce travail de recherche est d'évaluer les propriétés de mélanges granulaires compactés. Etant donnée la complexité du problème et la difficulté d'interprétation lorsque l'on s'intéresse à des mélanges d'excipients, les études doivent être réalisées sur des systèmes simples (mélanges binaires faisant intervenir des systèmes monodisperses). Il a donc été nécessaire d'étudier de la façon la plus complète possible les systèmes simples choisis avant de pouvoir passer à l'étude de leurs mélanges binaires.
Les excipients étudiés (A TAB®, Fast Flo®, Vivapur 12®) sont représentatifs des excipients utilisés dans le domaine pharmaceutique. Les données de la littérature ont également mis en évidence des comportements en compression très différenciés.
Le premier objectif de ce travail a donc été de caractériser de la manière la plus exhaustive possible le comportement sous pression des trois excipients ainsi que les propriétés mécaniques de ces systèmes compactés.
Les résultats obtenus sur la compressibilité des trois excipients (énergies mises en jeu au cours de la compression, consommation de la porosité, modélisation de Heckel et seuil moyen d'écoulement plastique) ont confirmé des aptitudes à la compression très différentes.
En complément, la technique de microtomographie X a été utilisée pour caractériser la fraction solide des comprimés de Vivapur 12®. Cette technique est une technique émergente dans l'étude des comprimés pharmaceutiques. Il a donc été nécessaire au préalable de la valider dans le domaine d'application dans lequel nous voulions la mettre en oeuvre (vérification de la loi de Beer-Lambert). Après une étape de calibration, une hétérogénéité au niveau de la répartition de la masse volumique a été mise en évidence au sein des comprimés, avec une différence importante entre la surface (surdensifiée) et le centre du comprimé. A la vue de ces observations, il apparaît donc que la différence entre les propriétés du volume (résistance à la rupture, module de Young, ...) et les propriétés de surface (dureté en indentation, ...) doit être faite.
Concernant les propriétés mécaniques des systèmes simples compactés (résistance à la rupture, module de Young, ténacité, dureté Brinell), des différences ont été observées entre les trois excipients pour une même propriété. De plus, pour un même excipient, des variations marquées entre les propriétés mécaniques caractéristiques du volume du compact et les propriétés mécaniques caractéristiques de la surface ont été mises en évidence.
Le modèle de la percolation qui est de plus en plus rencontré dans le domaine de la compression de composés pharmaceutiques a été appliqué aux trois systèmes étudiés. Les résultats de nos essais de modélisation semble montrer que ce modèle présente des limites. L'exposant critique ne semble pas universel pour une propriété donnée et les seuils de densité critique obtenus restent difficile à interpréter.
La deuxième partie de ce travail est consacrée à l'étude des mélanges binaires formés à partir des trois excipients étudiés dans la première partie.
Le suivi de l'évolution de la porosité des mélanges (à une contrainte de compression donnée) en fonction de la composition massique du mélange a permis de mettre en évidence une relation linéaire Porosité/Composition. Cette relation permet de déterminer la porosité d'un mélange compacté sous une pression donnée à partir des données recueillies au cours de l'étude des systèmes simples. Par contre, le seuil moyen d'écoulement plastique des mélanges n'évolue pas linéairement avec la composition massique du mélange. Mais en raison de la relation précédemment obtenue, une méthode de calcul indirect du seuil moyen d'écoulement plastique est possible. Cette méthode prédictive permet une bonne approximation des propriétés de densification et de déformation d'un mélange binaire quelle que soit sa composition.
Pour toutes les propriétés mécaniques étudiées, les lois de proportionnalités simples classiquement utilisées en mécanique ne sont pas applicables. Dans la majorité des cas, une déviation négative est même observée par rapport à ces lois simples.
Dans le cas particulier des propriétés mécaniques qui caractérisent la surface des compacts, il est apparu qu'elles étaient régies par le composé le plus plastique du mélange dès que sa proportion massique est égale à environ 30 à 20 %.
Pour s'inscrire dans une optique d'aide à la formulation, un modèle a été proposé pour décrire l'évolution du module de Young et de la résistance à la rupture en fonction de la composition du mélange. Après ajustement, une approche basée sur des interactions triangulaires et sur la probabilité de présence de ces interactions semble la plus adaptée.
Pour compléter l'étude des systèmes binaires, des essais de microtomographie X ont également été menés sur des mélanges Vivapur 12®/A TAB® compactés. Les représentations obtenues ont permis de mettre en évidence le Vivapur 12® au niveau des surfaces des compacts qui ont été en contact avec les pièces mécaniques. Ces observations confirment les résultats obtenus en microindentation sur ce mélange. Les seuils de percolation des deux excipients ont également été mis en évidence.
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Chitu, Toma-Mihai. "Granulation humide des poudres cohésives : rhéologie, mécanismes de croissance et tenue mécanique des granules." Thesis, Toulouse, INPT, 2009. http://www.theses.fr/2009INPT040G/document.
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Cette étude est dédiée à la compréhension du processus de granulation humide en mélangeurs à haut taux de cisaillement. Une étude systémique et méthodologique a été menée permettant l'investigation de l'influence des paramètres opératoires, de la technologie employée et des propriétés physico-chimiques des matières premières. Cette investigation est réalisé a travers des techniques de caractérisation morphologiques, rhéologiques et mécaniques. En reliant les courbes de couple enregistrés lors de la granulation humide à la cinétique de croissance des granules, aux caractérisations microscopiques et aux propriétés mécaniques des granules la prédiction du comportement lors de la granulation devient possible. La caractérisation des propriétés mécaniques des granules a été étudié à deux échelles: à l'échelle du milieu humide la consistance a été caractérisé par un rheometre à torque et à l'échelle de l'agglomérat sec la résistance mécanique a été caractérisé par des mesures de compression directe des grains individuelles. Cette approche permet d'avoir des informations complémentaires permettant de mieux décrire l'évolution des courbes de couple dépendantes de propriétés de la masse humide et la compétition entre les forces interfaciales et visqueuses conditionnant la qualité des grains secs résultés. Les paramètres investigués par cette approche sont l'effet du taux de remplissage du réacteur, l'effet de la vitesse d'agitation, de la présence et de la conception de l'émotteur, de la conception du réacteur employé, des propriétés physico-chimiques de la solution liante et des propriétés des mélanges binaires des poudres hydro-solubles / hydro-insolublesThis study is dedicated to the understanding of the wet granulation process in high shear mixers. A systematic study has been carried out that allows the investigation of the influence of operating conditions, technology and physico-chemical properties of the starting materials. This investigation is achieved by morphological, rheological and mechanical characterization methods. By linking recorded torque curves during the granulation process to granule growth kinetics, microscope characterizations and to the end-granule properties granulation outcome prediction becomes possible. The characterization of the mechanical properties has been done at two scales: at the granule bed scale the bulk wet mass consistency has been determined on a mixer torque rheometer, at the granule scale single dry granule direct compression tests were carried out. This approach gives complementary information allowing better description of the torque curves directly related to the wet mass properties and the competition between static and viscous forces conditioning the dry end granule quality. The factors investigated in this study are: the effect of fill ratio, impeller speed, chopper presence and design, mixer design, binder physico-chemical properties and formulation properties for binary water-soluble / water insoluble powder mixtures
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Navarro, Marco Vin?cius Monteiro. "Emprego de redes neurais artificiais supervisionadas e n?o supervisionadas no estudo de par?metros reol?gicos de excipientes farmac?uticos s?lidos." Universidade Federal do Rio Grande do Norte, 2014. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13866.
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Previous issue date: 2014-02-05In this paper artificial neural network (ANN) based on supervised and unsupervised algorithms were investigated for use in the study of rheological parameters of solid pharmaceutical excipients, in order to develop computational tools for manufacturing solid dosage forms. Among four supervised neural networks investigated, the best learning performance was achieved by a feedfoward multilayer perceptron whose architectures was composed by eight neurons in the input layer, sixteen neurons in the hidden layer and one neuron in the output layer. Learning and predictive performance relative to repose angle was poor while to Carr index and Hausner ratio (CI and HR, respectively) showed very good fitting capacity and learning, therefore HR and CI were considered suitable descriptors for the next stage of development of supervised ANNs. Clustering capacity was evaluated for five unsupervised strategies. Network based on purely unsupervised competitive strategies, classic "Winner-Take-All", "Frequency-Sensitive Competitive Learning" and "Rival-Penalize Competitive Learning" (WTA, FSCL and RPCL, respectively) were able to perform clustering from database, however this classification was very poor, showing severe classification errors by grouping data with conflicting properties into the same cluster or even the same neuron. On the other hand it could not be established what was the criteria adopted by the neural network for those clustering. Self-Organizing Maps (SOM) and Neural Gas (NG) networks showed better clustering capacity. Both have recognized the two major groupings of data corresponding to lactose (LAC) and cellulose (CEL). However, SOM showed some errors in classify data from minority excipients, magnesium stearate (EMG) , talc (TLC) and attapulgite (ATP). NG network in turn performed a very consistent classification of data and solve the misclassification of SOM, being the most appropriate network for classifying data of the study. The use of NG network in pharmaceutical technology was still unpublished. NG therefore has great potential for use in the development of software for use in automated classification systems of pharmaceutical powders and as a new tool for mining and clustering data in drug development
Neste trabalho foram estudadas redes neurais artificiais (RNAs) baseadas em algoritmos supervisionados e n?o supervisionados para emprego no estudo de par?metros reol?gicos de excipientes farmac?uticos s?lidos, visando desenvolver ferramentas computacionais para o desenvolvimento de formas farmac?uticas s?lidas. Foram estudadas quatro redes neurais artificiais supervisionadas e cinco n?o supervisionadas. Todas as RNAs supervisionadas foram baseadas em arquitetura de rede perceptron multicamada alimentada ? frente (feedfoward MLP). Das cinco RNAs n?o supervisionadas, tr?s foram baseadas em estrat?gias puramente competitivas, "Winner-Take- All" cl?ssica, "Frequency-Sensitive Competitive Learning" e "Rival-Penalize Competitive Learning" (WTA, FSCL e RPCL, respectivamente). As outras duas redes n?o supervisionadas, Self- Organizing Map e Neural Gas (SOM e NG) foram baseadas estrat?gias competitivo-cooperativas. O emprego da rede NG em tecnologia farmac?utica ? ainda in?dito e pretende-se avaliar seu potencial de emprego como nova ferramenta de minera??o e classifica??o de dados no desenvolvimento de medicamentos. Entre os prot?tipos de RNAs supervisionadas o melhor desempenho foi conseguido com uma rede de arquitetura composta por 8 neur?nios de entrada, 16 neur?nios escondidos e 1 neur?nio de sa?da. O aprendizado de rede e a capacidade preditiva em rela??o ao ?ngulo de repouso (α) foi deficiente, e muito boa para o ?ndice de Carr e fator de Hausner (IC, FH). Por esse motivo IC e FH foram considerados bons descritores para uma pr?xima etapa de desenvolvimento das RNAs supervisionadas. As redes, WTA, RPCL e FSCL, foram capazes de estabelecer agrupamentos dentro da massa de dados, por?m apresentaram erros grosseiros de classifica??o caracterizados pelo agrupamento de dados com propriedades conflitantes, e tamb?m n?o foi poss?vel estabelecer qual o crit?rio de classifica??o adotado. Tais resultados demonstraram a inviabilidade pr?tica dessas redes para os sistemas estudados sob nossas condi??es experimentais. As redes SOM e NG mostraram uma capacidade de classifica??o muito superior ?s RNAs puramente competitivas. Ambas as redes reconheceram os dois agrupamentos principais de dados correspondentes ? lactose (LAC) e celulose (CEL). Entretanto a rede som demonstrou defici?ncia na classifica??o de dados relativos aos excipientes minorit?rios, estearato de magn?sio (EMG), talco (TLC) e atapulgita (ATP). A rede NG, por sua vez, estabeleceu uma classifica??o muito consistente dos dados e resolveu o erro de classifica??o apresentados pela rede SOM, mostrando-se a rede mais adequada para a classifica??o dos dado do presente estudo. A rede Neural Gas, portanto, mostrou- se promissora para o desenvolvimento de softwares para uso na classifica??o automatizada de sistemas pulverulentos farmac?uticos
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Bai, Shujun. "Understanding physicochemical stability of proteins in solution and development of new analytical methods for freeze-dried protein formulations /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
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Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado Denver, 2008.Typescript. Includes bibliographical references (leaves 134-146). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
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Danielsson, Linnea. "XRF för kvalitetskontroll av farmaceutiska råvaror : - metodutveckling och utbildning av användare." Thesis, KTH, Skolan för teknikvetenskap (SCI), 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-93444.
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Detta examensarbete dokumenterar arbetet med utveckling, införande och dokumentation av en nymetod för identitetsbestämning av farmaceutiska råvaror med röntgenfluorescens. Metoden ärutvecklad för att användas på laboratorier för kvalitetskontroll på AstraZeneca i Södertälje. Syftetmed arbetet var att utveckla en robust och effektiv metod samt att utbilda användarna i dethanteringssätt som krävs för att utföra snabba och korrekta analyser. Rapporten presenterarteknologin bakom röntgenfluorescensinstrument och vilka felkällor som kan påverka resultaten samtde pedagogiska teorier som använts för att beskriva det praktiska arbete som äger rum pålaboratoriet. Metoden och de försök som föregick metoden presenteras, och resultat och beslutdiskuteras. Hur utbildningen planerades, genomfördes och utvärderades presenteras också.This master thesis is the documented work of the development, implementation and documentationof a new method for identification of pharmaceuticals excipients using X-ray fluorescence. Themethod is supposed to be used at the laboratory for quality control at AstraZeneca, Södertälje. Thepurpose of the thesis was to develop a stout and effective method and to educate the users in theskills needed to perform fast and correct analyses. This thesis presents the technology behind XRFinstruments and which sources of errors that could affect the results as well as the pedagogicaltheories used to describe the practical work that takes place at the laboratory. The method and theexperiment that preceded the method are presented, and the results and decisions are discussed.How the education was planned, performed and evaluated is also presented.
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Santos, Ana Isabel Caldeira Freitas dos. ""Dendrimers as Pharmaceutical Excipients"." Master's thesis, 2019. http://hdl.handle.net/10316/88283.
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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de FarmáciaO estágio curricular é um momento crucial de aplicação de todos os conhecimentos adquiridos, sendo também um período de grande aprendizagem. Com base nesta evidência,decidi repartir o meu estágio curricular por duas áreas diferentes (Indústria Farmacêutica e Farmácia Comunitária), de modo a contactar com várias realidades e ganhar uma nova visão sobre o mercado farmacêutico.O estágio nos Laboratórios Basi possibilitou a perceção do papel do farmacêutico no funcionamento de uma indústria farmacêutica e no ciclo do medicamento, garantindo a sua eficácia, segurança e qualidade. Relativamente ao estágio na Farmácia Coimbra, este permitiu obter experiência na organização e gestão de uma farmácia, bem como experiência profissional na dispensa de medicamentos e no contacto com o público. Os relatórios de estágio estão sob a forma de uma análise SWOT, tendo sido elaborada uma lista de pontos positivos e negativos, de âmbito quer interno, quer externo, relativo ao estágio. A monografia tem como objetivo discutir as propriedades que tornam os dendrímeros em excipientes farmacêuticos e suas possíveis aplicações nos campos farmacêutico e biomédico. Embora os dendrímeros não tenham uma monografia descrita numa farmacopeia oficial e, deste modo, não poderem ser considerados excipientes farmacêuticos, estas nanoestruturas têm recebido grande atenção por parte dos investigadores. Devido às suas propriedades únicas, tais como dimensões em nanoescala, alto grau de ramificação,polivalência, alta solubilidade em água, presença de cavidades internas e alta biocompatibilidade, os dendrímeros são candidatos ideais como excipientes farmacêuticos. Estas características permitem aumentar, eficazmente, a solubilidade de fármacos com baixa solubilidade em água. O facto de as propriedades de um dendrímero poderem ser controláveis durante a sua síntese, torna estas nanoestruturas agentes promissores para aplicações de libertação controlada de fármacos, em várias formulações farmacêuticas. Além disso, os dendrímeros podem ser usados para reduzir a toxicidade do fármaco e para o aumento da eficácia do mesmo.
The curricular internship is a crucial moment of application of all the acquiredknowledge, being also a period of great learning. Based on this evidence I decided to dividemy internship into two different areas (Pharmaceutical Industry and Community Pharmacy), inorder to contact with various realities and gain a new perspective on the pharmaceuticalmarket.The internship at Laboratórios Basi, enabled a more real perception of the pharmacist'srole on the pharmaceutical industry and the on the product’s lifecycle, ensuring itseffectiveness, safety, and quality. Regarding the internship at Farmácia Coimbra, this allowed againing of experience in the organization and management of a pharmacy, as well asprofessional experience in dispensing medicines and on contact with the public.The internship reports are written in the form of a SWOT analysis. Therefore, theyprovide a list of positive and negative aspects on the internship internal and external realm.The monograph aims to discuss the properties that turn dendrimers intopharmaceutical excipients and their potential applications in the pharmaceutical and biomedicalfields. Although dendrimers do not have a pharmacopoeia monograph and, officially, cannotbe recognized as pharmaceutical excipients, these nanostructures have received enormousattention from researchers. Due to their unique properties, like the nanoscale uniform size, ahigh degree of branching, polyvalency, aqueous solubility, internal cavities and biocompatibility,dendrimers are ideal as excipients, enhancing the solubility of poorly water-soluble drugs. Thefact that the dendrimer’s properties are controllable during their synthesis renders them aspromising agents for drug delivery applications in several pharmaceutical formulations.Additionally, dendrimers can be used for reducing the drug toxicity and for the enhancementof the drug efficacy.
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Cardoso, Sara Sofia Dias. "Generic drug product development of a modified-release oral dosage form." Master's thesis, 2018. http://hdl.handle.net/10316/84678.
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Dissertação de Mestrado em Tecnologias do Medicamento apresentada à Faculdade de FarmáciaO presente projeto visa o desenvolvimento de um medicamento genérico de libertação prolongada para administração oral, sob a forma farmacêutica de comprimidos não revestidos. O projeto foi desenvolvido na Bluepharma Indústria Farmacêutica, S.A. e foi referido como Blue055, de acordo com a política de confidencialidade da empresa.Os principais objetivos do projeto foram desenvolver uma formulação, um processo de fabrico e produzir protótipos capazes de mimetizar o comportamento in vitro do produto de referência. Especificamente, o perfil de libertação da substância ativa deverá ser semelhante ao do produto de referência. Para tal, foi avaliada a influência de diferentes variáveis quer da substância ativa quer dos excipientes na modelação da libertação da susbtância ativa, bem como dos parâmetros do processo. Adicionalmente, os parâmetros testados para obtenção da forma farmacêutica, quer de formulação quer de processo, foram adequadamente analisados e avaliados com base numa abordagem Quality by Design para uma posterior implementação à escala piloto e industrial. Durante o desenvolvimento farmacêutico foram considerados todos os requisitos das Guidelines ICH Q8 (R2), Q6A, Q2(R), Q3B, Q3C e da Guideline de Bioequivalência, requisitos da Farmacopeia dos Estados Unidos e cumprimento das cGMPs, com o objetivo de produzir um produto final com elevada qualidade, de forma a garantir o seu desempenho a nível da segurança e eficácia terapêutica.Os parâmetros da formulação estudados foram: o tamanho de partícula da substância ativa, o grau e a quantidade de diluente, o grau, quantidade, viscosidade, tamanho de partícula e teor de hidroxipropilo de hidroxipropilmetilcelulose (HPMC), quantidade de desagregante e quantidade de surfactante. Observou-se que o perfil de dissolução é afetado por estes parâmetros.Os parâmetros de processo estudados foram: granulação seca, tempo de mistura e tempo de lubrificação. Observou-se que o processo de granulação tem impacto no doseamento, na uniformidade da mistura e no perfil de dissolução do produto acabado.A implementação do conceito Quality by Design (QbD) permitiu claramente uma abordagem sistemática para projectar e desenvolver formulações farmacêuticas e processos de fabrico, de forma a garantir a qualidade do produto.
The present project aims at developing a generic extended-release drug product for oral administration in the pharmaceutical form of uncoated tablets. The project was developed at Bluepharma Indústria Farmacêutica, S.A. and is referred to as Blue055, in accordance with the company's confidentiality policy.The main objectives of the project are to develop a formulation and a manufacturing process and to produce prototypes capable of mimicking the in vitro behaviour of the reference product. Specifically, the release profile of the drug substance should be similar to that of the reference product. The influence of the drug substance and excipient variables in the modelling of the release of the drug substance was evaluated, as well as the influence of the parameters of the process. In addition, the parameters tested to obtain the pharmaceutical form, either formulation or process, were adequately analysed and evaluated following a Quality by Design approach for further implementation at pilot and industrial scale.During the pharmaceutical development, all the ICH Guidelines Q8 (R2), Q6A, Q2 (R), Q3B, Q3C and Guideline for bioequivalence, United States Pharmacopoeia and cGMPs requirements were taken into account in order to produce a high-quality final product, and to guarantee its performance in terms of safety and efficacy.The parameters of the formulation studied were drug substance particle size, diluent grade and amount of, hydroxypropylmethylcellulose (HPMC) grade, amount, viscosity, particle size and hydroxypropyl content, and disintegrant amount. All the above variables influenced dissolution behaviour.The process parameters considered for analysis included dry granulation process, blending and lubrication times. It was observed that roller gap has an impact on drug product assay, blend uniformity and dissolution profile. The application of the Quality by design (QbD) concept has clearly enabled a systematic approach to designing and developing pharmaceutical formulations and manufacturing processes to ensure product quality.
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Abrantes, Cátia Filipa Guerreiro. "Segurança dos excipientes utilizados pela indústria farmacêutica." Master's thesis, 2015. http://hdl.handle.net/10437/6355.
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Orientação: Ana Catarina ReisA parte mais importante de um Medicamento, em termos de volume total da formulação, é constituída pelos seus excipientes que têm as funções importantes de garantir a dose, a estabilidade e biodisponibilidade do princípio activo. As substâncias utilizadas como excipientes devem apresentar as características exigidas pela sua função, mas como acontece com qualquer substância administrada ao homem, devem também corresponder aos requisitos de Segurança exigidos. De facto, no passado, a importância de se avaliar os possíveis efeitos adversos dos excipientes foi subestimada, pois a sua inércia e inocuidade foram tomadas como garantidas. A toxicidade dos excipientes farmacêuticos não é simples por várias razões, entre as quais, o grande número de substâncias existentes no mercado e a diversidade dos seus perfis químicos, das suas fontes, das suas funções técnicas, e da presença de produtos secundários ou de impurezas, que podem ser as verdadeiras causas de efeitos adversos. Os excipientes são incluídos no Medicamento para auxiliar a produção deste, a administração ao doente ou a absorção do princípio activo no organismo. Apesar de serem considerados farmacologicamente inertes, os excipientes podem iniciar, propagar ou participar em interacções físicas ou químicas com as moléculas de fármaco, o que pode comprometer a Eficácia do Medicamento. Os excipientes não são perfeitamente puros, pelo que é necessário entender o contexto da sua origem e produção, de modo a identificar as possíveis interacções entre o princípio activo e as suas impurezas. As interacções químicas podem levar à degradação da substância activa, reduzindo assim a quantidade disponível para o efeito terapêutico. Por outro lado, as interacções físicas podem afectar a taxa de dissolução, a uniformidade da dose ou a facilidade de administração.
The most important part of a drug in terms of the total volume of the formulation comprises the excipients, which have the important function of ensuring the dose, stability and bioavailability of the active ingredient. Substances used as excipients must have the characteristics required for its function, but as with any substance administered to humans, must also meet the requirements of safety required. In fact, in the past, the importance of evaluating the possible adverse effects of excipients was underestimated because its inertia and safety have been taken for granted. The toxicity of pharmaceutical excipients is not simple, for several reasons, including the large number of substances on the market and the diversity of their chemical profiles, their sources, their technical functions, and the presence of side products or impurities which may be the real cause of adverse effects. The excipients are included in the medicine to help their production, to allow the drug absorption after its administration in the organism. Although considered as pharmacologically inert, excipients can start or participate in physical or chemical interactions with drug molecules, which can compromise the efficacy of the drug. Excipients are not perfectly pure, it is necessary to understand the context of its origin and production, in order to identify possible interactions between the active substance and impurities. Chemical interactions may lead to degradation of the active substance, thereby reducing the amount available of drug for the therapeutic effect. Furthermore, the physical interaction may affect the dissolution rate, dose uniformity or ease of administration.
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林任士. "Studies on Slugging and Recompression Characterisation of some Blends of three Common Pharmaceutical Excipients." Thesis, 1997. http://ndltd.ncl.edu.tw/handle/07545917256284660075.
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碩士高雄醫學大學
藥學研究所
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Slugs of Avicel PH102, Lactose fast-flo 316 and Di-tab were compressed, either on their own or in soddium chloride, captopril combinations, between 10.0mm flat faced punches on a hydraulic press at 7 different pressures. 100 tablets of each batch were compressed and the crushing strengths, the friabilities, the tensile strengths and the densities were determined. In addition, the dissolution rate of captopril was also determined. The 50 remaining slugs were screened through an hammer granulator and recompressed at the same pressure used initially. The characterisations of the final tablets were again determined. The mean yield pressures were evaluated for the slugs utilizing Heckel analysis. The results indicated that the highest tensile strength were produced using 100% Avicel PH102. The mean yield pressure values showed that on addition of sodium chloride to Avicel PH102 there is a move away from predominantly plastic deformation and to Di-tab there is a move away from deforming by fragmentation. It would seem that fragmentation of Di-tab enhances bonding on compaction and so leads to increased crushing strength after re-compressed. However, except 25% Avicel PH102 75% sodium chloride blends, for all slugged tablets containing Avicel PH102 there was a reduction in the crushing strength of the tablet after the second compression. This would indicate that the extent of plastic deformation is less when the materials are compressed twice, compared to when the materials are compacted once. It was concluded that the slugging process is therefore independent of an increase in dwell time.