Thesis (M.S.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xiv, 159 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 118-122).

Pulmonary and oral drug administrations are usually the preferred methods of delivery of active pharmaceutical ingredients.Generally,pulmonary drug formulations are more attractive compared to oral formulations since they consist of micron-sized powders with high surface area thus having faster onset of action,as well as minimizing the drug dosage and side effects.Oral insulin formulations,if achievable,would provide an alternative to injectable insulin,as the common drawbacks of injectable insulin are the multiple daily injections and the possibility of skin infections at the injection site. In this study,the feasibility of using dense gas particle processing techniques known as the Aerosol Solvent Extraction System (ASES),Gas Anti-Solvent (GAS)and High-Pressure Media Milling (HPMM)for pharmaceutical processing was assessed.The ASEStechnique,utilizing dense ethane,was employed to prepare insulin-lactose formulations for pulmonary administration whilst the GAS and ASES techniques,utilizing dense CO2,were employed to prepare microencapsulated formulations containing insulin and Eudragit?? S100 for oral administration.Furthermore,the HPMM technique,utilizing dense hydrofluocarbon (HFC)134a/227ea,was employed to prepare suspension Metered Dose Inhaler (MDI)formulations containing budesonide and various surfactants. The Fine Particle Fraction (FPF)of processed insulin without the presence of lactose was found to be 44%.In other words,44% of processed insulin delivered to the impactor stages (excluding the throat and neck)has aerodynamic diameter of less than 5??m.With the addition of lactose as carrier,the FPFof the insulin-lactose (1:1w/w)formulation increased to 64%.The increase in FPFwas attributed to the lower density of lactose particles compared to that of insulin particles to produce an intimate mixture with enhanced powder flowability and aerodynamic performance. Proteins for oral delivery should ideally be formulated with acid-resistant polymer as a protective coating to protect against enzymatic degradation in the stomach.Eudragit?? S100,which is insoluble or almost impermeable at pH 1-4and soluble at pH 5-7,was used to prepare oral insulin formulations.The insulin release at pH 3was sustained by the Eudragit?? S100coating and the encapsulation efficiency of insulin??Eudragit?? S100formulations varied between 6% and 24% depending on the initial drug to polymer ratio. One of the major therapies utilizing metered dose inhaler formulations in the treatment of asthma has been studied using the HPMM process.The HPMM process has been demonstrated to be an efficient milling process for the enhancement of the physical stability and aerodynamic performance of budesonide in HFC-134a/227ea propellant formulations.No significant change in physical stability was observed in the formulations for 2 weeks.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 245-274). Available also in a digital version from Dissertation Abstracts.

Made available in DSpace on 2015-06-17T19:34:39Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-04-07. Added 1 bitstream(s) on 2015-06-18T12:48:28Z : No. of bitstreams: 1 000832114_20161231.pdf: 131914 bytes, checksum: 5b041ff5485011bef210d7c59bec7870 (MD5) Bitstreams deleted on 2017-01-02T15:03:52Z: 000832114_20161231.pdf,. Added 1 bitstream(s) on 2017-01-02T15:05:09Z : No. of bitstreams: 1 000832114.pdf: 2763768 bytes, checksum: 9c4b8c5a4e689e302cf1a5f9de0a829f (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O trabalho objetivou a formação do complexo darunavir:β-ciclodextrina e o estudo das consequências desta complexação, além do desenvolvimento e validação de métodos analíticos para determinação qualitativa e quantitativa do darunavir em comprimidos (livre) e complexado à β-ciclodextrina. darunavir livre. Durante todo o tempo de pesquisa a forma etanolato do darunavir foi controlada para garantir o uso do mesmo polimorfo e não haver diferenças analíticas. As análises qualitativas foram realizadas por cromatografia em camada delgada (CCD), espectrofotometria no ultravioleta (UV), espectrofotometria no infravermelho (IV), cromatografia líquida (CL) e eletroforese capilar (EC) possibilitando a identificação do darunavir etanolato em comprimidos. Métodos mais dinâmicos e ecologicamente corretos foram validados para a quantificação do darunavir etanolato na forma farmacêutica utilizando o IV e a EC. Os resultados das validações foram analisados comparativamente e as técnicas mostraram-se equivalentes sendo, portanto, intercambiáveis. darunavir:β-ciclodextrina. O darunavir foi complexado à β-ciclodextrina e confirmado através de técnicas térmicas e estudado por métodos espectroscópicos. Suas propriedades foram comparadas às do fármaco livre quanto à solubilidade e o complexo de inclusão mostrou ser 28 vezes mais solúvel que o darunavir quando utilizada a solução tamponante acetato 0,05 M pH 4,5. Este avanço da tecnologia farmacêutica abrange a resolução Best medicines for children discutida na Assembleia Mundial da Saúde, a qual lançou a campanha global Make medicines child size. Um método para quantificação de darunavir no complexo foi validado através da CL acoplada à espectrometria de massas (CL-EM), nele foram identificados seis produtos de degradação sendo dois provenientes da degradação em meio ácido, um da degradação em meio básico e três em meio oxidativo. Uma técnica ... / The work aimed the formation of complex darunavir:β-cyclodextrin and the study of the consequences of complexation, as well as development and validation of analytical methods for qualitative and quantitative determination of darunavir in tablet (free) and complexed to β-cyclodextrin. darunavir free. The form of darunavir ethanolate was monitored throughout research time to ensure use of the same polymorph and no analytical differences. Qualitative analysis was performed by thin layer chromatography (TLC), ultraviolet spectrophotometry (UV), infrared spectroscopy (IR), liquid chromatography (LC) and capillary electrophoresis (CE) allowing the identification of darunavir ethanolate in tablets. More dynamic and environmentally friendly methods were validated for the quantification of darunavir ethanolate in pharmaceutical form using the IV and CE. The results of the validations were comparatively analyzed and techniques were equivalent and are therefore interchangeable. darunavir:β-ciclodextrina. Darunavir was complexed with β- cyclodextrin and confirmed by thermal techniques and studied by spectroscopic methods. Its properties were compared to the free drug as to solubility of inclusion complex and it is 28 times more soluble than darunavir when using buffer solution of 0.05 M acetate pH 4.5. This advance of pharmaceutical technology covers the resolution Best medicines for children discussed in the World Health Assembly, which launched the global campaign Make medicines child size. A method for quantification of darunavir in the complex was validated by LC coupled with mass spectrometry (LC-MS), with him were identified six degradation products, two from acid degradation, one from basic degradation and three from oxidative degradation. A developed TLC technique was adequate for visualizing all degradation products of complex darunavir:β-cyclodextrin observed in the CL method, being achieved faster and cheaper. Complex ... / FAPESP: 2012/02749-6 / CNPq: 142080/2012-8 / CAPES: 11114-12-6

Orientador : Hérida Regina Nunes Salgado / Banca: Maximiliano da Silva Sangoi / Banca: Norberto Peporine Lopes / Banca: Marlus Chorilli / Banca: Silvia Stanisçuaski Guterres / Resumo: O trabalho objetivou a formação do complexo darunavir:β-ciclodextrina e o estudo das consequências desta complexação, além do desenvolvimento e validação de métodos analíticos para determinação qualitativa e quantitativa do darunavir em comprimidos (livre) e complexado à β-ciclodextrina. darunavir livre. Durante todo o tempo de pesquisa a forma etanolato do darunavir foi controlada para garantir o uso do mesmo polimorfo e não haver diferenças analíticas. As análises qualitativas foram realizadas por cromatografia em camada delgada (CCD), espectrofotometria no ultravioleta (UV), espectrofotometria no infravermelho (IV), cromatografia líquida (CL) e eletroforese capilar (EC) possibilitando a identificação do darunavir etanolato em comprimidos. Métodos mais dinâmicos e ecologicamente corretos foram validados para a quantificação do darunavir etanolato na forma farmacêutica utilizando o IV e a EC. Os resultados das validações foram analisados comparativamente e as técnicas mostraram-se equivalentes sendo, portanto, intercambiáveis. darunavir:β-ciclodextrina. O darunavir foi complexado à β-ciclodextrina e confirmado através de técnicas térmicas e estudado por métodos espectroscópicos. Suas propriedades foram comparadas às do fármaco livre quanto à solubilidade e o complexo de inclusão mostrou ser 28 vezes mais solúvel que o darunavir quando utilizada a solução tamponante acetato 0,05 M pH 4,5. Este avanço da tecnologia farmacêutica abrange a resolução "Best medicines for children" discutida na Assembleia Mundial da Saúde, a qual lançou a campanha global "Make medicines child size". Um método para quantificação de darunavir no complexo foi validado através da CL acoplada à espectrometria de massas (CL-EM), nele foram identificados seis produtos de degradação sendo dois provenientes da degradação em meio ácido, um da degradação em meio básico e três em meio oxidativo. Uma técnica ... / Abstract: The work aimed the formation of complex darunavir:β-cyclodextrin and the study of the consequences of complexation, as well as development and validation of analytical methods for qualitative and quantitative determination of darunavir in tablet (free) and complexed to β-cyclodextrin. darunavir free. The form of darunavir ethanolate was monitored throughout research time to ensure use of the same polymorph and no analytical differences. Qualitative analysis was performed by thin layer chromatography (TLC), ultraviolet spectrophotometry (UV), infrared spectroscopy (IR), liquid chromatography (LC) and capillary electrophoresis (CE) allowing the identification of darunavir ethanolate in tablets. More dynamic and environmentally friendly methods were validated for the quantification of darunavir ethanolate in pharmaceutical form using the IV and CE. The results of the validations were comparatively analyzed and techniques were equivalent and are therefore interchangeable. darunavir:β-ciclodextrina. Darunavir was complexed with β- cyclodextrin and confirmed by thermal techniques and studied by spectroscopic methods. Its properties were compared to the free drug as to solubility of inclusion complex and it is 28 times more soluble than darunavir when using buffer solution of 0.05 M acetate pH 4.5. This advance of pharmaceutical technology covers the resolution "Best medicines for children" discussed in the World Health Assembly, which launched the global campaign "Make medicines child size". A method for quantification of darunavir in the complex was validated by LC coupled with mass spectrometry (LC-MS), with him were identified six degradation products, two from acid degradation, one from basic degradation and three from oxidative degradation. A developed TLC technique was adequate for visualizing all degradation products of complex darunavir:β-cyclodextrin observed in the CL method, being achieved faster and cheaper. Complex ... / Doutor

This investigation attempts to examine the influences of validation on pharmaceutical processes especially at a new manufacturing facility that has to meet international requirements, and fulfil a cost effective business strategy. At Aspen Pharmacare, a pharmaceutical organisation, there are two manufacturing facilities situated adjacent to each other, one new and one old. The new facility creates ideal opportunities to supply products to local and international markets. The investigation compares legal requirements from local and international regulatory authorities. Validation and qualification practices as well as the problems encountered during the different phases are discussed. Particular attention is given to the validation approach at the new Aspen facility. Problems and proposed solutions relating to the design review, installation, operational, and performance qualification are discussed. Validation of analytical methods for cleaning analysis, cleaning validation of equipment, and optimisation of some tablet manufacturing processes are described. Statistical evaluations of analytical results are included to find the optimum conditions for integrating new personnel with new processes and equipment. A business model reviews the cost of non-conformances of the enalapril maleate 10 mg tablets manufactured at the two manufacturing facilities. Finally the dissertation proves that validation is not only a regulatory requirement but that it also provides benefits such as adding value to the business, and ultimately reducing the cost of medicines.

No / In the pharmaceutical field, current practice in gaining process understanding by data analysis or knowledge discovery has generally focused on dealing with single experimental databases. This limits the level of knowledge extracted in the situation where data from a number of sources, so called fractured data, contain interrelated information. This situation is particularly relevant for complex processes involving a number of operating variables, such as a fluid-bed granulation. This study investigated three data mining strategies to discover and integrate knowledge "hidden" in a number of small experimental databases for a fluid-bed granulation process using neurofuzzy logic technology. Results showed that more comprehensive domain knowledge was discovered from multiple databases via an appropriate data mining strategy. This study also demonstrated that the textual information excluded in individual databases was a critical parameter and often acted as the precondition for integrating knowledge extracted from different databases. Consequently generic knowledge of the domain was discovered, leading to an improved understanding of the granulation process.

Foram produzidos comprimidos de liberação prolongada de teofilina baseados em matrizes hidrofílicas de misturas de hidroxipropilmetilcelulose e etilcelulose e polietilenoglicol. O planejamento estatístico de mistura Design Expert® foi empregado na seleção da composição do sistema de controle da liberação e, numa segunda fase, para otimização das formulações de comprimidos. Foram produzidas 26 formulações por compressão direta e as características físico-químicas dos comprimidos como peso médio, friabilidade, dureza e teor de fármaco foram determinadas. A porcentagem de teofilina liberada foi avaliada conforme o método da Farmacopéia Americana 30 ed. (2007), para cápsulas de liberação prolongada (Teste 10 - pá), por um período de 8 horas. Conforme as farmacopéicas os comprimidos produzidos apresentaram características físico-químicas de acordo com as especificações, com exceção das formulações 2 e 3, para o teste de friabilidade, cujos valores foram superiores. Entretanto, quanto ao ensaio de dissolução, a formulação 13, constituída por 30% de etilcelulose, atendeu aos valores preconizados para liberação prolongada de teofilina. As respostas obtidas dos experimentos foram introduzidas no programa Design Expert® que gerou superfícies de respostas nas quais foi possível avaliar a influência da composição nos parâmetros friabilidade e porcentagem de teofilina liberada na dissolução. Dessa forma, foi possível obter 3 formulações com etilcelulose (13,50% a 15,90%), metilcelulose tipo E4MCR (6,90% a 8,10%) e metilcelulose tipo K4MPRCR (0,30% a 0,60%), com as características desejadas empregando o planejamento estatístico de mistura, com o número mínimo de experimentos sem a necessidade de estudar todas as possíveis combinações experimentais, abreviando o trabalho com ganho de tempo. Os resultados encontrados para friabilidade e dissolução nas formulações otimizadas foram próximos dos previstos pela análise de regressão e dentro dos valores especificados na Farmacopéia Americana 30 ed. 2007. / Controlled release dosage forms of theophylline were prepared with hidrophyllic matrix using polymers as hydroxy-methyl-cellulose, hydroxy-ethyl-cellulose and polyethylenglycol. The program Design Expert® was used to select polymers composition and at the second moment, to optimized tablets formulations. It was obtained 26 formulations by direct compression that physical-chemical characteristics of tablets as weight deviation, friability, hardness and drug dosage were performed. Dissolution rate of these tablets were controlled by United States Pharmacopeia 30 ed. Test for theophylline extended-release capsules (test 10 - paddle) corresponding to 8 hours of experiment. The evaluation indicates that tablets produced were in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed., except for formulations 2 and 3 that the values for friability were low. And about dissolution rate of these tablets only formulation 13 applied to preconized value for dissolution method for theophylline extendedrelease capsules. Design Expert® was fed with the results obtained from experiments that showed surface result after that it were possible to analyze the influence of the composition of components on the friability and dissolution rate of theophylline parameters. Considering the specifications, 3 formulations were obtained and were analyzed. The results obtained were close to results predicted for regression analysis and in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed. The proposed experimental Design Expert® program strategy should allow a rapid evaluation and identification of the parameters important in determining the drug release rate from matrix tablets, providing a powerful support for their rational selection during preformulation studies and thus shortening the time necessary for the development of effective dosage forms with the desired drug release behavior.

A coerência do processo de fabricação, via granulação úmida, de comprimidos de dipirona sódica (500 mg) foi avaliada empregando ferramentas de qualidade e de estatística. No estudo foi desenvolvida base racional-científica objetivando determinar as etapas críticas do processo por meio da técnica de análise de modo e efeito da falha (FMEA). A análise de risco revelou as potenciais falhas do processo: variação da distribuição granulométrica da mistura final com elevado percentual de pó fino e problemas relativos a fluidez; ensaios de peso, espessura, dureza, friabilidade, tempo de desintegração e dissolução fora de especificação; não-uniformidade do conteúdo de dipirona sódica (OS) na mistura final e durante a compressão e ocorrência de laminação, capeamento, porosidade e aderência dos comprimidos às estações da máquina compressora. Os métodos analíticos relativos à determinação de (OS), empregando metodologia espectrofotométrica e de cromatografia líquida de alta eficiência (CLAE), foram previamente validados. As seguintes características de desempenho, em ambas metodologias analíticas, foram determinadas: especificidade, linearidade com coeficiente de correlação (r) > 0,99, repetibilidade aceitável com desvio padrão relativo (OPR) < 2% e precisão intermediária entre analistas e em dias diferentes. Além disso, a robustez e exatidão com percentual de recuperação entre 99,28% e 100,84% foram comprovadas para o método de CLAE. No que se refere às etapas críticas da validação do processo produtivo, foi elaborado plano de amostragem baseado nos critérios estabelecidos em compêndio oficial (FARMACOPÉIA BRASILEIRA, 1988), Guia da FOA (UNITEO STATES, 2003), duração de cada etapa de fabricação e tipo de equipamento utilizado. Além disso, foi empregada a lista Millitary Standard 105E (TAYLOR, ENTERPRISES, 1989). Os resultados relativos à estabilidade estatística do processo revelaram ausência de causas especiais. Os índices de capacidade Cp e Cpk foram calculados após avaliação da distribuição dos dados empregando teste de Anderson-Darling. Todos os dados apresentaram distribuição normal (p > 0,05), exceto àqueles relativos à uniformidade de conteúdo de OS na etapa de compressão. Esses dados foram tratados utilizando método proposto por Box-Cox (Iambda igual a 5) visando sua normalização. Os índices de capacidade Cp e Cpk. revelaram resultados > 1 e, portanto, permitiram determinar a consistência do processo e baixa probabilidade de falha. / The consistency of the metamizol tablets (500 mg) manufacturing process, via wetting granulation, was evaluated by quality and statistical tools. In this study, rational-scientific base was developed aiming determination of the critical steps of this process, using the Failure Mode and Effects Analysis (FMEA) technique. The risk analysis shows the potential failures of the process: variability of particle size distribution, high percentage of fine powder and flowability problems related to the final mixture; weight, thickness, hardness, friability, disintegration time and dissolution percentage of the tablets out-of-specifications; non-uniformity of the metamizol content in the final mixture and during the tabletting steps; laminating, capping, porosity and sticking of the tablets. The analytical methods performed by spectrophotometric and high performance liquid chromatography (HPLC), in order to assay metamizol, were previously validated. The following parameters were evaluated in both analytical methodologies: specificity, linearity with correlation coefficients more than 0.99, acceptable repeatability with relative standard deviation (RSD) less than 2% and intermediate precision between two different analysts and days. Besides that, the system suitability and accuracy were also proved by HPLC method. The recoveries obtained were between 99.28% and 100.84%. The sampling plan was elaborated according to official compendium (FARMACOPEIA BRASILEIRA, 1988), FOA Guidance (UNITED STATES, 2003), Military Standard 105E (TAYLOR ENTERPRISES, 1989), the duration of each step and the type of equipment used. This plan was just applied for critical steps identified by FMEA tool. The results related to the statistical stability of the process show no special cause. The capability indexes, Cp and Cpk, were calculated after the evaluation of the data distribution using Anderson-Darling test. Ali data showed normal distribution (p > 0.05), except for uniformity of metamizol content of the tablets. This data was treated by a method proposed by Box-Cox (Iambda equal -5.0) aimed at obtaining the normality of the data. The capability indexes, Cp and Cpk, obtained were all > 1. Therefore, this process can be considered consistent and with low probability of failures.

Made available in DSpace on 2016-08-10T10:29:43Z (GMT). No. of bitstreams: 1 Fritz Eduardo Kasbaum.pdf: 8675531 bytes, checksum: fd4de7b5752ef941286dcf268c9d38da (MD5) Previous issue date: 2010-01-25 / The present work show the pharmaceutical development of new release systems of drugs, specifically dapsona's (DDS) prolonged release tablets, a sulfon with bacteriostatic action used on the leprosy treatment and several other skin diseases and also in the treatment of the other pathologies as malaria and pneumonia caused by Pneumocystis carinii. This drug, depending on the pathology, can be managed in doses trat vary between 25 to 300m/day, and the administration frequency added to the high doses is responsible for the sprouting of serious collateral effect in the hematologic system, amongst them the methemoglobinemia and in some cases hemolysis. Systems of modified release aim to optimize the medicines therapy by reduction of the usually managed doses, attainment of plasmatic levels more uniforms of the drug for bigger period of time in administrations frequency and also reduction of the observed collateral effect. Eight formulations of DDS were prepared using as excipients the microcrystalline cellulose, the monohydrated lactose spray dryer and magnesium stearate. To compose a matricial system of asset release it was formulated tablets sometimes contending matrix with hydrophilic characteristic and sometimes lipofilic, respectively, hidroxipropilmetilcelulose (HPMC) and gliceril monostearate (MEG). The prepared formulations were submitted to dissolution tests in medium that simulated the stomachal and enteric conditions and the respective profiles or release were evaluated the Kinetic of DDS release to elucidate the mechanisms that controls it. The results of release throughout the time had been treated in accordance with model zero-order, first-order, Higuchi and exponential model. The gotten coefficients of correlation indicate that DDS release from the chosen formulation follows exponential model. / O presente trabalho tem como objetivo o desenvolvimento farmacotécnico de novos sistemas de veiculação de fármacos, especificamente comprimidos de liberação prolongada de dapsona (DDS), uma sulfona com ação bacteriostática utilizada no tratamento da hanseníase e diversas afecções da pele e também no tratamento de outras patologias como a malária a pneumonia causada por Pneumocystis carinii. Esse fármaco, dependendo da patologia, poder ser administrado em doses que variam de 25 a 300mg/dia, e a frequencia de administração somada às altas doses são responsáveis pelo surgimento de efeitos colaterais graves no sistema hematológico, dentre eles a metemoglobinemia e em alguns casos hemólise. Sistemas de liberação modificada visam a otimização da terapia medicamentosa por redução das doses usualmente administradas e obtenção de níveis plasmáticos mais uniformes do fármaco por maior período de tempo em relação às formas de liberação imediata. Isso geralmente promove a redução na frequência de administração e também redução dos efeitos colaterais observados. Foram preparados oito formulações de DDS utilizando-se como excipientes a celulose microcristalina, a lactose monohidratada spray dryer e estearato de magnésio. Para compor o sistema matricial de liberação do fármaco, formularam-se comprimidos ora contendo matriz com caractéristica hidrofílica, ora lipofílica, respectivamente, hidroxipropilmetilcelulose (HPMC) e monoesterato de glicerila (MEG). As formulações preparadas foram submetidas a ensaios de dissolução em meios que simulavam as condições estomacal e entérica e os respectivos perfis de liberação avaliados por meio de análise de vâriancia (ANOVA). Para a formulação de escolha também avaliou-se a cinética de liberação da DDS de forma a elucidar os mecanismos que a controlam. Os resultados de liberação ao longo do tempo foram tratados de acordo com modelo cinéticos zero-ordem, primeira ordem, Higuchi e modelo exponencial. Os coeficientes de correlação obtidos indicam que a liberação da DDS a partir da formulação escolhida é governada modelo exponencial.