1 Abstract Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical technology Consultant: PharmDr. Ondřej Holas, Ph.D. Student: Tomáš Máčalík Title of Thesis: Problematics of active compounds recrystalisation in pharmaceutical preparations The topic of the thesis is the recrystallization of active substances in pharmaceutical preparations. The aim of this work is to demonstrate this phenomenon on a real particular pharmaceutical product, in which it has occurred. It includes a detailed description of the manufacturing process including all mandatory conditions, possible critical points, investigations and measures taken. The thesis consists of two parts. The first describes in details the current state of knowledge. It is based on the findings of the available literature on the subject. The basic concepts of crystallization and polymorphism are explained in detail, which form the basis for the subsequent case study. The case study includes a detailed description of a specific medicinal product. Subsequently, it's production, good manufacturing practice and gradual investigation of the discovered technological incompatibility are explained step by step. The result of the work points out that the issue of recrystallization and polymorphism is very closely related to...

Atualmente existe um considerável interesse no processamento de materiais com estrutura ultrafina de grãos. Estes materiais podem ser obtidos por deformação plástica severa via extrusão por canal angular (ECAE). Durante ECAE, uma barra lubrificada é pressionada através de uma matriz rígida consistindo de dois canais de mesma seção transversal, os quais se interceptam a um ângulo ?. Cisalhamento simples é o mecanismo de deformação predominante e ocorre paralelamente ao plano de intersecção entre os dois canais. Este trabalho enfoca a estabilidade térmica e sua influência sobre as propriedades magnéticas de ferro puro severamente deformado por ECAE. Uma barra de ferro puro foi deformada em temperatura ambiente por múltiplos passes de ECAE (8 passes), usando uma matriz com ângulo de intersecção ??= 90º, resultando em uma deformação equivalente _N = 9,2. Esta barra foi girada de 90o depois de cada passe de extrusão. Amostras da barra deformada foram recozidas em várias temperaturas entre 100 e 800°C, variando-se o tempo de recozimento entre 1 e 120 min. Uma segunda barra de ferro puro foi deformada por um único passe de ECAE, com um ângulo ??= 120o, resultando em uma deformação equivalente _N = 0,67. Amostras retiradas desta barra foram recozidas em várias temperaturas entre 300 e 800°C por 15 min. Em uma condição correspondente à segunda barra, uma terceira foi deformada sendo o passe de ECAE interrompido. A caracterização microestrutural foi efetuada utilizando-se microscopias ótica e eletrônica de varredura, microdureza Vickers e textura via difração de raios X. Curvas de magnetização em função do campo magnético aplicado até cerca de 9 T foram obtidas para amostras representativas da barra deformada por múltiplos passes de ECAE. Foram determinados os intervalos de temperatura de recozimento em que ocorrem a recuperação e a recristalização para esta barra e para a barra deformada por um único passe de ECAE. Com relação à barra do ensaio interrompido, várias seções do plano normal à direção de extrusão da barra foram analisadas a fim de se investigar a evolução da textura durante extrusão em canal angular. Os resultados foram comparados com aqueles reportados para outros materiais deformados via ECAE com estrutura ccc e também com as texturas previstas pelo Modelo Visco-plástico Autoconsistente (do inglês VPSC model). / There is considerable current interest in fabricating ultrafine-grained materials. Such materials can be obtained by severe plastic deformation via equal-channel angular extrusion (ECAE). During ECAE, a lubricated billet is pressed through a rigid die consisting of two channels of the same cross section intersecting each other at an angle ?. Simple shear is the predominant deformation mechanism and occurs parallel to the intersecting plane of the channels. This work focuses on thermal stability and its influence on the magnetic properties of severely deformed pure iron via ECAE. A billet of pure iron was deformed at room temperature by multiple ECAE passes (8 passes), using a die angle ??= 90o, to a total equivalent strain of _N = 9.2. The billet was rotated by 90o after each extrusion pass. Samples of the deformed billet were annealed at several temperatures between 100 and 800oC, varying the annealing time from 1 to 120 min. A second billet of pure iron was deformed using 1-pass ECAE, with ??= 120o, with an equivalent strain of _N = 0.67. Samples of this billet were annealed at several temperatures between 300 and 800°C for 15 min. Corresponding to second condition, a third billet was deformed by interrupting the ECAE pass. Microstructural characterization was performed using optical and scanning electron microscopies, Vickers microhardness, and texture measurements via X-ray diffraction. Magnetization curves as a function of applied magnetic field up to 9 T were obtained for representative samples of the billet deformed by multiple ECAE passes. The annealing temperature ranges corresponding to recovery and recrystallization for this billet and 1-pass ECAE billet were determined. Regarding the interrupted 1-pass ECAE billet, several sections normal to the extrusion direction were analyzed in order to investigate the texture evolution during equal channel angular extrusion. The obtained results were compared to those ones found in other deformed bcc materials via ECAE and also by using the visco-plastic self-consistent (VPSC) model to predict the final texture.

Atualmente existe um considerável interesse no processamento de materiais com estrutura ultrafina de grãos. Estes materiais podem ser obtidos por deformação plástica severa via extrusão por canal angular (ECAE). Durante ECAE, uma barra lubrificada é pressionada através de uma matriz rígida consistindo de dois canais de mesma seção transversal, os quais se interceptam a um ângulo ?. Cisalhamento simples é o mecanismo de deformação predominante e ocorre paralelamente ao plano de intersecção entre os dois canais. Este trabalho enfoca a estabilidade térmica e sua influência sobre as propriedades magnéticas de ferro puro severamente deformado por ECAE. Uma barra de ferro puro foi deformada em temperatura ambiente por múltiplos passes de ECAE (8 passes), usando uma matriz com ângulo de intersecção ??= 90º, resultando em uma deformação equivalente _N = 9,2. Esta barra foi girada de 90o depois de cada passe de extrusão. Amostras da barra deformada foram recozidas em várias temperaturas entre 100 e 800°C, variando-se o tempo de recozimento entre 1 e 120 min. Uma segunda barra de ferro puro foi deformada por um único passe de ECAE, com um ângulo ??= 120o, resultando em uma deformação equivalente _N = 0,67. Amostras retiradas desta barra foram recozidas em várias temperaturas entre 300 e 800°C por 15 min. Em uma condição correspondente à segunda barra, uma terceira foi deformada sendo o passe de ECAE interrompido. A caracterização microestrutural foi efetuada utilizando-se microscopias ótica e eletrônica de varredura, microdureza Vickers e textura via difração de raios X. Curvas de magnetização em função do campo magnético aplicado até cerca de 9 T foram obtidas para amostras representativas da barra deformada por múltiplos passes de ECAE. Foram determinados os intervalos de temperatura de recozimento em que ocorrem a recuperação e a recristalização para esta barra e para a barra deformada por um único passe de ECAE. Com relação à barra do ensaio interrompido, várias seções do plano normal à direção de extrusão da barra foram analisadas a fim de se investigar a evolução da textura durante extrusão em canal angular. Os resultados foram comparados com aqueles reportados para outros materiais deformados via ECAE com estrutura ccc e também com as texturas previstas pelo Modelo Visco-plástico Autoconsistente (do inglês VPSC model). / There is considerable current interest in fabricating ultrafine-grained materials. Such materials can be obtained by severe plastic deformation via equal-channel angular extrusion (ECAE). During ECAE, a lubricated billet is pressed through a rigid die consisting of two channels of the same cross section intersecting each other at an angle ?. Simple shear is the predominant deformation mechanism and occurs parallel to the intersecting plane of the channels. This work focuses on thermal stability and its influence on the magnetic properties of severely deformed pure iron via ECAE. A billet of pure iron was deformed at room temperature by multiple ECAE passes (8 passes), using a die angle ??= 90o, to a total equivalent strain of _N = 9.2. The billet was rotated by 90o after each extrusion pass. Samples of the deformed billet were annealed at several temperatures between 100 and 800oC, varying the annealing time from 1 to 120 min. A second billet of pure iron was deformed using 1-pass ECAE, with ??= 120o, with an equivalent strain of _N = 0.67. Samples of this billet were annealed at several temperatures between 300 and 800°C for 15 min. Corresponding to second condition, a third billet was deformed by interrupting the ECAE pass. Microstructural characterization was performed using optical and scanning electron microscopies, Vickers microhardness, and texture measurements via X-ray diffraction. Magnetization curves as a function of applied magnetic field up to 9 T were obtained for representative samples of the billet deformed by multiple ECAE passes. The annealing temperature ranges corresponding to recovery and recrystallization for this billet and 1-pass ECAE billet were determined. Regarding the interrupted 1-pass ECAE billet, several sections normal to the extrusion direction were analyzed in order to investigate the texture evolution during equal channel angular extrusion. The obtained results were compared to those ones found in other deformed bcc materials via ECAE and also by using the visco-plastic self-consistent (VPSC) model to predict the final texture.

QC 20100927

De nos jours, le contexte de mondialisation des marchés impose aux industriels des contraintes économiques sans précédent. Afin de rester concurrentiels, ils n’ont d’autre choix que de modifier leur façon de concevoir et d’innover. Les techniques de production sont directement concernées avec par exemple une volonté de réduire les cycles de mise au point visant à définir les paramètres optimaux de mise en forme. On constate alors l’immersion d’un besoin fort en moyens de support, flexibles et prédictifs, permettant de limiter les campagnes d’essais et de faciliter leur exploitation. La simulation numérique se présente comme un outil pouvant répondre à ces critères. Ce travail s’est inscrit dans une démarche d’amélioration de la modélisation et de la simulation des opérations d’usinage, et à une échelle plus locale, de la modélisation de la coupe des métaux. Il aborde donc un problème complexe, fortement couplé, faisant intervenir mécanique, thermique, tribologie et métallurgie dans des conditions extrêmes. Une première partie expérimentale s’est donc orientée vers une compréhension plus fine des mécanismes de coupe mis en jeu en usinage d’un C45 normalisé et d’un 42CrMo4 trempé revenu. Elle a notamment permis de mettre en évidence, dans les zones de déformation intense, des affinements de grain conséquents, produits par l’activation d’un processus de recristallisation dynamique (DRX). L’inspection des zones de contact outil-matière a également montré les fortes hétérogénéités de contact existantes à l’interface outil-copeau et révélant la formation d’une résistance thermique de contact. Une étude rhéologique des deux nuances s’est appuyée sur des essais de compression dynamique. Menée à haute déformation, elle a permis de reproduire les évolutions microstructurales observées en coupe et d’appréhender leur influence sur la limite d’écoulement des matériaux. Deux modèles de comportement "à base métallurgique" ont été identifiés, présentant une retranscription plus fidèle que les modèles phénoménologiques standards. Des essais tribologiques dédiés ont permis d’extraire des modèles de contact capables de reproduire les phénomènes locaux existants à l’interface outil-matière. L’accent s’est principalement porté sur la thermique de contact au travers de lois de partage variables intégrant la notion de résistance thermique. L’intégralité de ces modèles a enfin été implémentée dans le code de calcul Abaqus© grâce à des développements spécifiques. Une stratégie de modélisation a été mise en place autour d’un modèle de coupe 2D afin de restituer les tendances majeures observées lors de la coupe d’aciers spéciaux. L’association de modèles 2D et 3D à copeau continu, de modèles à copeau segmenté ainsi que de simulations thermiques découplées présente un fort potentiel permettant, à terme, de modéliser une opération d’usinage dans sa globalité. / Nowadays, in a context of globalization, companies are submitted to unprecedented economic constraints. To remain competitive, they are forced to change their way of designing and innovating. Manufacturing is directly concerned with in mind to reduce the development steps necessary to define the optimal processing parameters. A need of flexible and predictive support tools is clearly rising in order to limit the experimental campaigns and make easier their exploitation. The numerical simulation appears as a relevant tool that match these criteria. This work is a contribution to an approach which aims at improving the modeling and simulation of machining operations, and on a more local scale, the modeling of metal cutting. It therefore addresses a complex and tightly coupled problem, involving mechanics, thermal sciences, metallurgy and tribology in extreme conditions. A first experimental part was thus directed towards a more sophisticated understanding of the cutting mechanisms occuring in machining of a normalized AISI 1045 and a quenched and tempered AISI 4140. It made possible to highlight, in the main intensive deformation zones, drastic grain refinements produced by the activation of dynamic recrystallization (DRX). Inspection of the tool-material contact areas also showed the strong heterogeneities of contact existing at the tool-chip interface, revealing the formation of a thermal contact resistance. A rheological study of these two grades was based on dynamic compression tests. Conducted at high strain, it reproduced the microstructural changes observed in cutting and enabled to understand their influence on the flow stress of both materials. Two "metallurgy based" models have been identified, leading to a better description of the material behaviour than standard phenomenological models. Special tribological tests have been conducted and analyzed to extract contact models able to reproduce local phenomena existing at the tool-material interface. The study has especially been focused on the thermal contact through heat partition models including the concept of thermal contact resistance. The proposed constitutive and contact models were finally implemented in a finite element code Abaqus© thanks to some specific developments. A modeling strategy has been developed around a 2D cutting model in order to simulate the major trends observed during the cutting of the mentioned steels. The combination of 2D and 3D continuous chip models, 2D segmented models and uncoupled thermal simulations appears as promising to model the different aspects of a machining operation.