Resumo: Ciclodextrinas (CD) têm sido relatadas em inúmeros estudos por interagir com muitos fármacos para a formação de complexos de inclusão com o objetivo de aumentar a solubilidade, estabilidade e biodisponibilidade. No processo usual para obtenção de comprimidos contendo Beta-CD, as dispersões líquidas de fármaco/Beta-CD são submetidas a processos de secagem por liofilização, evaporação ou spray-drying e o material seco é incorporado a vários excipientes. O objetivo principal deste trabalho foi avaliar processos de obtenção de comprimidos de Beta-CD/paracetamol. O paracetamol foi utilizado como fármaco modelo por ser pouco solúvel em água. No primeiro processo, a dispersão líquida de Beta-CD/paracetamol foi incorporada ao amido de milho, celulose microcristalina ou lactose monoidratada e o material foi granulado e submetido à secagem em leito estático (estufa). No segundo processo, a dispersão líquida de Beta-CD/paracetamol foi incorporada ao amido de milho e o material submetido à secagem em leito fluidizado (leito de jorro). Os materiais obtidos em ambos os processos foram comprimidos. Comparando os três excipientes utilizados no primeiro processo, tanto o amido quanto celulose são os excipientes que possibilitariam a incorporação de quantidade maior de fármaco. Como resultados, os granulados obtidos a partir dos excipientes amido e celulose apresentaram boas características de escoamento e compressibilidade. O segundo processo, originou um material que apresentou boas características de compressibilidade e comprimidos que apresentaram as melhores características físicas durante o processo de compactação. Concluiu-se que ambos processos representam uma estratégia tecnologicamente viável para obtenção de comprimidos contendo Beta-CD. / Abstract: Cyclodextrins (CDs) have been reported in a number of studies in the pharmaceutical field since it interact with many drugs to form water soluble inclusion complexes, thus improving not only the solubility but also the stability and biovailability of various drugs. In order to obtain Beta-CD tablets, liquid dispersions of drug/ Beta-CD are usually submitted to different drying process, like spray drying, freeze-drying or slow evaporation and further added to several excipients. In this work we evaluated different process for the preparation of Beta-CD/ acetaminophen tablets. Due to its low solubility, we have used acetaminophen as a drug model. In the first process, an aqueous Beta-CD/ acetaminophen dispersion were added to corn starch, microcrystalline cellulose or monohydrated lactose and the material was dried in a static bed. In the second process, an aqueous Beta-CD/acetaminophen dispersion were added to corn starch and further dried in a fluidized bed (spouted bed). As a result, in the first process the use of starch or cellulose led to mixtures with higher amount of drug with good flowability and compressibility, whereas the second process led to a mixture of good compressibility and to tablets that presented the best physical proprieties. In conclusion, both process represent viable technological approaches to obtain Beta-CD tablets. / Orientador: Maria Palmira Daflon Gremião / Coorientador: Ana Dóris de Castro / Banca: Leila Aparecida Chiavacci / Banca: Osvaldo de Freitas / Mestre

Made available in DSpace on 2014-06-11T19:25:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-28Bitstream added on 2014-06-13T19:12:10Z : No. of bitstreams: 1 silvajunior_np_me_arafcf.pdf: 678354 bytes, checksum: 4f229eb833483c2108d5ca9ff0af89b6 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / Ciclodextrinas (CD) têm sido relatadas em inúmeros estudos por interagir com muitos fármacos para a formação de complexos de inclusão com o objetivo de aumentar a solubilidade, estabilidade e biodisponibilidade. No processo usual para obtenção de comprimidos contendo Beta-CD, as dispersões líquidas de fármaco/Beta-CD são submetidas a processos de secagem por liofilização, evaporação ou spray-drying e o material seco é incorporado a vários excipientes. O objetivo principal deste trabalho foi avaliar processos de obtenção de comprimidos de Beta-CD/paracetamol. O paracetamol foi utilizado como fármaco modelo por ser pouco solúvel em água. No primeiro processo, a dispersão líquida de Beta-CD/paracetamol foi incorporada ao amido de milho, celulose microcristalina ou lactose monoidratada e o material foi granulado e submetido à secagem em leito estático (estufa). No segundo processo, a dispersão líquida de Beta-CD/paracetamol foi incorporada ao amido de milho e o material submetido à secagem em leito fluidizado (leito de jorro). Os materiais obtidos em ambos os processos foram comprimidos. Comparando os três excipientes utilizados no primeiro processo, tanto o amido quanto celulose são os excipientes que possibilitariam a incorporação de quantidade maior de fármaco. Como resultados, os granulados obtidos a partir dos excipientes amido e celulose apresentaram boas características de escoamento e compressibilidade. O segundo processo, originou um material que apresentou boas características de compressibilidade e comprimidos que apresentaram as melhores características físicas durante o processo de compactação. Concluiu-se que ambos processos representam uma estratégia tecnologicamente viável para obtenção de comprimidos contendo Beta-CD. / Cyclodextrins (CDs) have been reported in a number of studies in the pharmaceutical field since it interact with many drugs to form water soluble inclusion complexes, thus improving not only the solubility but also the stability and biovailability of various drugs. In order to obtain Beta-CD tablets, liquid dispersions of drug/ Beta-CD are usually submitted to different drying process, like spray drying, freeze-drying or slow evaporation and further added to several excipients. In this work we evaluated different process for the preparation of Beta-CD/ acetaminophen tablets. Due to its low solubility, we have used acetaminophen as a drug model. In the first process, an aqueous Beta-CD/ acetaminophen dispersion were added to corn starch, microcrystalline cellulose or monohydrated lactose and the material was dried in a static bed. In the second process, an aqueous Beta-CD/acetaminophen dispersion were added to corn starch and further dried in a fluidized bed (spouted bed). As a result, in the first process the use of starch or cellulose led to mixtures with higher amount of drug with good flowability and compressibility, whereas the second process led to a mixture of good compressibility and to tablets that presented the best physical proprieties. In conclusion, both process represent viable technological approaches to obtain Beta-CD tablets.

Le travail de thèse porte sur l’étude et la mise au point de nouvelles technologies et de procédés miniaturisés en lit fluidisé. Ce procédé représente une véritable rupture technologique devant les procédés à lits fluidisé traditionnels et offre de nombreux avantages : surface d’échange élevée, bon mélange gaz-solide dans le réacteur, utilisation de faible quantité de produit, coût faible... La présente étude regroupe trois études : conception des micro-lits fluidisés, diagnostic et analyse de l’hydrodynamique des couches fluidisées et modélisation numérique.Dans ce travail quatre MFBs (Micro Fluidized Bed) de 20-4 mm ont été étudiés et comparés à deux réacteurs relativement grands de 100-50 mm. Le rapport du diamètre du réacteur à la hauteur statique des particules (Hs/Dt) a été fixé entre 1-4. La vibration mécanique a été appliquée dans le réacteur de 4 mm. Une nouvelle méthode de diagnostic des régimes de fluidisation a été développée. Elle est basée sur les analyses des fluctuations de pression et le traitement du signal. La modélisation numérique suivant la méthode Eulérien-Eulérien (2D) a été développée. Les résultats obtenus permettent d’identifier six régimes d'écoulement: lit fixe, bouillonnant, bouillonnant/pistonnage, pistonnage, pistonnage/turbulent et bouillonnant/turbulent. On note une fluidisation partielle autour de Hs/Dt=1-2, tandis que le régime de pistonnage s’installe rapidement après le minimum de fluidisation à Hs/Dt=3-4. Dans le réacteur de 4 mm, la fluidisation des particules du groupe B de Geldart montre une meilleure qualité. Les résultats numériques (modélisation) montrent une très bonne concordance avec les données expérimentales / Micro-fluidized bed (MFB) exhibits great advantages such as a large specific contact surface, a fast dissipation of heat (ideal for exothermic reactions) and better mass and heat transfers, but suffers from difficulties in precise control and shows strong frictional wall effect. Present study was conducted experimentally and numerically to understand fundamental hydrodynamics in MFBs. Experimental work was carried out in four MFBs of 20-4 mm compared to two relatively large beds of 100-50 mm using three types of particles (B347: 347 μm, 2475 kg/m3; B105: 105 μm, 8102 kg/m3; A63: 63.8μm, 2437 kg/m3). The ratio of static bed height (Hs) to bed diameter (Dt) was set between 1-4. Mechanical vibration was applied to the 4 mm bed. A new method for flow regimes diagnosis was developed based on pressure fluctuation analyses, which mainly include calculating the standard deviation, autocorrelation function, probability density function, power spectral density function and time-frequency analysis. Numerical simulations were performed under Eulerian-Eulerian framework in 2D. Six flow regimes were identified: fixed bed, bubbling, bubbling/slugging, slugging, slugging/turbulent and bubbling/turbulent. Partial fluidization is encountered at Hs/Dt=1-2 while slugging prevails quickly after minimum fluidization at Hs/Dt=3-4. In the 4 mm bed, fluidization of B347 particles show better fluidization quality, while an increase in Umf is observed for B105 and A63 particles. Mechanical vibration reduces partial fluidization, thus resulting in larger ΔP and smaller Umf. A larger Umb and a delayed Uc were obtained as well. Results by simulations agree reasonably well with experimental data