Prediction of the tabletting behavior of powdered drugs is of great importance in the pharmaceutical industry. An instrumented hydraulic press and punch and die assembly were used to study compaction behavior of 5 widely used pharmaceutical materials, Avicel, Emcompress, spray-dried lactose, crystalline acetaminophen USP and acetaminophen DC granules. The hydraulic press was able to compress the above materials at compaction speeds comparable to those of rotary tablet presses. The compression cycle of the Betapress could not be duplicated by the hydraulic press since, with the hydraulic press, the displacement was not constant at peak pressure. The compaction parameters measured by the hydraulic press were elastic recovery (ER), punch travel distance beyond peak pressure (D), punch travel time beyond peak pressure (PTT) decrease in the force during punch travel beyond peak pressure (F). The strength of the tablets was measured with a CT40 tablet hardness tester. D and PTT appeared to be measures of flow and bonding and to be useful parameters for the tabletting behavior of the above materials. In general, materials that displayed relatively long D and PTT values formed coherent tablets regardless of their elastic recovery. Avicel which displayed the longest D and PTT values (and the largest recovery) formed the strongest tablets while crystalline acetaminophen USP displayed the shortest D and PTT values and did not form coherent compacts. Thus for particulate materials that were able to flow and bond, elastic recovery did not appear to play an important role in the tabletting process. Avicel and spray-dried lactose displayed similar D and PTT values (ie. similar extent of flow and deformation) and Avicel's elastic recovery was about 3 times as much as of that of spray-dried lactose, but Avicel formed tablets that were about 5 times stronger than those of spray-dried lactose. Therefore the nature and number of bonds that are formed between the particles (which are related to the inherent property of the materials) appeared to be the most important factor in tablet formation. The effects of peak pressure (Pmax) and average compression rate (ACR) were examined on the above parameters. Generally peak pressure influenced the elastic recovery, D, PTT and hence the strength of the tablets more than the average compression rate. / Pharmaceutical Sciences, Faculty of / Graduate

Thesis (Ph.D. (Clinical Tropical Medicine))--Mahidol University, 2003.

Thesis (Ph. D.)--University of Chicago, Dept. of Chemistry, June 2000. / Includes bibliographical references. Also available on the Internet.

No / Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.

No / Caffeine/oxalic acid 2:1 cocrystal exhibited superior stability to humidity over caffeine, but compressional behavior is not studied yet. To compare compressional properties of caffeine/oxalic acid 2:1 cocrystal obtained by different cocrystallization techniques. Cocrystal was obtained by solvent precipitation and ultrasound assisted solution cocrystallization (USSC) and characterized by X-ray powder diffraction and scanning electron microscopy. Compaction study was carried out at different compaction forces. Compact crushing strength, thickness and elastic recovery were determined. Compaction was in order, caffeine > solvent precipitation cocrystal > USSC cocrystal. Caffeine exhibited sticking and lamination, where solvent precipitation compacts showed advantage. Caffeine and solvent precipitation compacts showed sudden drop in compactability, higher elastic recovery with severe lamination at 20,000 N. This was due to overcompaction. Crystal habit of two cocrystal products was same, but USSC cocrystals were difficult to compact. Uniform needle shaped USSC cocrystals must be difficult to orient in different direction and fracture during compression. Elastic recovery of USSC cocrystals was also more compared to other powders indicating less fracture and poor bonding between particles resulting in poor compaction. Cocrystal formation did not improve compressional property of caffeine. Cocrystals exposed to different crystallization environments in two techniques may have resulted in generation of different surface properties presenting different compressional properties.

Thesis Univ. College London, 2006. / Includes bibliographical references and indexes.

Submitted by Priscila Nascimento (pnascimento@icict.fiocruz.br) on 2012-12-19T13:13:26Z No. of bitstreams: 1 rodrigo-bretas.pdf: 958446 bytes, checksum: 4ccfe67d11ec271c6829c819b4c75292 (MD5) / Made available in DSpace on 2012-12-19T13:13:26Z (GMT). No. of bitstreams: 1 rodrigo-bretas.pdf: 958446 bytes, checksum: 4ccfe67d11ec271c6829c819b4c75292 (MD5) Previous issue date: 2011 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil. / A cultura de células animais tem sido usada como ferramenta em diversas áreas das ciências biológicas, desde a pesquisa básica até asaplicações em medicina. Como plataforma tecnológica, substratos celulares são úteis, em especial quando armazenados na forma de bancos, para a produção de inúmeros produtos biológicos, dentre os quais figuram as proteínas recombinantes de interesse terapêutico e vacinas virais para uso humano. A caracterização ou certificação de tais bancos está baseada na determinação de seus aspectos de identidade, pureza e estabilidade. O presente trabalho teve por objetivo avaliar a capacidade instalada no país para o estabelecimento e certificação de células animais, em especial as de mamíferos, visando à produção de medicamentos biológicos. Para tal, foram investigados os centros nacionais que atuam com pesquisa, desenvolvimento, controle e produção usando bancos de células. Cientistas de tais centros foram procurados para preencher um questionário a fim de estabelecer o perfil e capacidades presentes no país. Paralelamente, foi realizado levantamento e análise de toda regulamentação, nacional e internacional, relacionada à geração e certificação de substratos celulares usados com fins industriais. A comparação entre o cenário nacional e o internacional revelou que a maioria dos centros no país atua na pesquisa e desenvolvimento de biológicos; alguns desenvolvem atividades de testes de controle; e apenas dois produzem biofármacos ou vacinas. Os centros buscam adequação a regulações para que suas atividades sejam reconhecidamente aderentes a um sistema de qualidade; vários destes são potenciais parceiros para Bio-Manguinhos. Em contraste, a maioria das empresas identificadas no exterior já desenvolve bancos de células animais em conformidade às Boas Práticas de Fabricação. Foi identificada uma lacuna regulatória nacional com relação aos temas específicos levantados na pesquisa. Neste sentido, o trabalho culmina com uma proposta inicial de guia para orientar o setor produtivo quanto ao estabelecimento e certificação de bancos de células. A geração dos substratos celulares deve ser realizada em conformidade às Boas Práticas de Fabricação, em especial no que tange a aspectos como classificação de salas limpas, validações e qualificações; tal adesão deve ser verificada por inspeção por parte de Autoridade Sanitária. De forma similar, os testes para determinação do perfil de segurança devem seguir métodos validados, quando aplicável, realizados por laboratórios aderentes a um sistema de qualidade; tal fato deve ser verificado pelo cumprimento das Boas Práticas de Laboratório ou acreditação por uma Autoridade Nacional. A geração de bancos de células em condições certificadas, bem como sua caracterização por métodos válidos e aceitos, confere os atributosde autenticidade, pureza e estabilidade a esses substratos, o que irá implicar na produção demedicamentos biológicos de qualidade, eficazes e seguros. / Animal cell culture has been used as a tool in several fields within biology, from basic research to medical applications. As a technological platform, cell substrates are useful, especially when stored as banks, for the productionof many biologicals such as recombinant proteins of therapeutic interest and viral vaccinesfor human use. The characterization or certification of such banks is based on the determination of their identity, purity and stability features. The present work aimed to assess the installed capacity in the country for establishing and certifying animal cells, especially the ones from mammals, for the production of biologicals. Thus, national centers dealing with research, development, control and production were investigated. Their scientists were requested to fill in a questionnaire in order to draw the profile and capacities present in the country. In parallel, all regulation, national and international, was searched and analyzed, regardinggeneration and certification of cell substrates used for industrial purposes. The comparison between national and international scenarios showed that most national centers are involved with biologicals research and development; some act in testing and control; and only two produce biomedicines or vaccines. Centers seek adequacy to regulations so that their activities be acknowledged as compliant to a quality system; several of such centers are potential partners to Bio-Manguinhos. In contrast, most international companies identified already develop animal cell banks according to Good Manufacturing Practices. A national regulatory gap was identified regarding specific topics raised in the research. This way, the work culminates with an initial draftversion of a guideline to orient the productive sector in establishing and certifying cell banks. Such banks must be generated in conformity to Good Manufacturing Practices, especially in aspects as classification of clean rooms, validations and qualifications; such compliance must be verified by the Health Authority. Similarly, tests to determine the safetyprofile must follow validated methods, when applicable, performed by laboratories which comply to a quality system; this must be verified by fulfillment of Good Laboratory Practices or accreditation by a National Authority. Generation of cell banks under certified conditions, as well as their characterization by valid and accepted methods, grants the attributes of authenticity, purity and stability to these substrates, which will implicate in the production of biologicals with quality, efficacy and safety.

No / The purpose of this work was to explore NIR spectroscopy as a PAT tool to monitor the formation of ibuprofen and nicotinamide cocrystals during extrusion based solvent free continuous cocrystallization (SFCC). Drug and co-former were gravimetrically fed into a heated co-rotating twin screw extruder to form cocrystals. Real-time process monitoring was performed using a high temperature NIR probe in the extruder die to assess cocrystal content and subsequently compared to off-line powder X-ray diffraction measurements. The effect of processing variables, such as temperature and mixing intensity, on the extent of cocrystal formation was investigated. NIR spectroscopy was sensitive to cocrystal formation with the appearance of new peaks and peak shifts, particularly in the 4800-5200 cm(-1) wave-number region. PXRD confirmed an increased conversion of the mixture into cocrystal with increase in barrel temperature and screw mixing intensity. A decrease in screw rotation speed also provided improved cocrystal yield due to the material experiencing longer residence times within the process. A partial least squares analysis in this region of NIR spectrum correlated well with PXRD data, providing a best fit with cocrystal conversion when a limited range of process conditions were considered, for example a single set temperature. The study suggests that NIR spectroscopy could be used to monitor cocrystal purity on an industrial scale using this continuous, solvent-free process.

No / OBJECTIVES: To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), by hot-melt extrusion (HME) and spray drying. METHODS: Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40 degrees C/75% RH) over 8 weeks. KEY FINDINGS: Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. CONCLUSIONS: Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations.

No / A systematic identification of the degradation products of hydroxypropyl methylcellulose phthalate (HPMCP) during hot melt extrusion (HME) has been performed. A reverse phase HPLC method was developed for the extrudates of both hydroxypropyl methylcellulose acetate succinate (HPMCAS) and HPMCP polymers to quantify their thermal hydrolytic products: acetic acid (AA), succinic acid (SA) for HPMCAS and phthalic acid (PA) for HPMCP, without hydrolysing the polymers in strong alkaline solutions. The polymers were extruded in the temperature range of 160-190 degrees C at different screw rotation speeds and hydrolytic impurities were analysed. Investigation of extruded HPMCP showed an additional thermal degradation product, who is structural elucidation revealed to be phthalic anhydride (PAH). Moreover, two environmental analytical impurities, dimethyl phthalate and methyl benzoate formed in situ were recorded on GC-MS and their origin was found to be associated with PAH derivatization. Using the experimental data gathered during this study, a degradation mechanism for HPMCP is proposed.