Sistemas monolíticos particulados contendo os constituintes ativos veiculados na forma de grânulos revestidos - pellets - têm recebido crescente atenção nos últimos anos, em função da otimização na biodisponibilidade e segurança na liberação do fármaco. A utilização destas unidades, como componentes de comprimidos traz, como principal vantagem, a divisibilidade da forma sem a perda do perfil biofarmacêutico desejado para o fármaco. Para sua produção, é indispensável a manutenção da integridade do revestimento daquelas unidades. Uma estratégia para o alcance deste objetivo envolve a utilização de grânulos inertes deformantes, comprimidos em conjunto com os grânulos revestidos, que atuam como um sistema de amortecimento das forças de compressão. Neste trabalho investigou-se a produção de grânulos deformantes através de dois métodos de granulação por via úmida, avaliando a influência de adjuvantes sobre as características dos produtos obtidos. Empregando a técnica de extrusão/esferonização obtiveram-se grânulos com propriedades de fluxo, empacotamento e resistência mecânica aceitáveis. O efeito dos adjuvantes sobre as etapas tecnológicas foi estudado por meio de um planejamento fatorial. Testaram-se duas variedades de celulose microcristalina, os desintegrantes croscarmelose sódica e crospovidona e soluções aglutinantes aquosas e hidroetanólicas de povidona. Para o desenvolvimento dos comprimidos utilizaram-se, como modelo, grânulos revestidos gastro-resistentes contendo omeprazol. A influência da composição dos grânulos deformantes sobre a liodisponibilidade do fármaco dos comprimidos foi avaliada através de análise fatorial 23. Os grânulos deformantes protegeram o revestimento polimérico dos pellets com diferentes intensidades. / Monolythic particulate systems containing the active constituents as coated pellets became great interest due to the improvement of safety and bioavailability. The use of such units as components of tablets shows as main advantages the divisibility of the pharmaceutical dosage form without loosing the desired biopharmaceutical profile of the drug. Consequently for the tablet production, the integrity of the polymeric film must be attained. A strategic option involves the utilization of inert soft pellets, which could be compressed together with the film coated pellets, absorbing the compaction forces. In this work the production of soft pellets was investigated using two wet granulation methods and evaluating the influence of formulation adjuvants on the pellets properties. The extrusion/spheronization technique yielded pellets with acceptable flow, packing and mechanical characteristics. The influence of the adjuvants on the technological steps was carried out through a statistical designed experiment. Microcrystalline cellulose from two producers, the disintegrants sodium croscarmellose and crospovidone, and aqueous and hydroethanolic dispersions of povidone, as binder, were tested. For the tablets development omeprazol gastroresistant film coated pellets were used as model. Aiming at the study of the influence of the soft pellets composition on drug lyoavailability was performed a 23 factorial experiment. The soft pellets protected at different intensities the polymeric coating of the gastroresistant pellets.

Made available in DSpace on 2016-06-21T13:45:02Z (GMT). No. of bitstreams: 2 9.pdf: 5002800 bytes, checksum: 1aab555cfe6db1a0cf1577ab298c8017 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2014 / Made available in DSpace on 2016-07-05T22:38:04Z (GMT). No. of bitstreams: 3 9.pdf.txt: 252589 bytes, checksum: b070d500ec1baafb988fc3fbf27085c1 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 9.pdf: 5002800 bytes, checksum: 1aab555cfe6db1a0cf1577ab298c8017 (MD5) Previous issue date: 2014 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / O escalonamento no processo de fabricação de comprimidos é um processo complexo e ainda bastante empírico, feito por método de tentativas e erros, cujos desafios são ainda maiores quando trata-se de formulação obtida por granulação úmida. Este trabalho realizou a transposição de escala de uma formulação de comprimidos revestidos contendo diclofenaco de sódio, fármaco de ação antiinflamatória,não esteroide e inibidor não seletivo das COX 1 e 2, avaliando os fatores relevantes para a obtenção tanto de uma formulação robusta, no que diz respeito ao processo de escalonamento em si, quanto de um medicamento que atendesse às exigências legais necessárias ao registro junto ao órgão regulador.Como resultado, o medicamento originário da formulação proposta apresentou-se aprovado em todos os ensaios exigidos, inclusive mostrando-se bioequivalente ao de referência. Este resultado ratificou a importância dos trabalhos preliminares,como a caracterização do ativo e os estudos referentes aos parâmetros a serem observados na transposição de escala. Na caracterização, as análises mostraram que a forma polimórfica do diclofenaco de sódio utilizado na formulação era a anidra,forma mais solúvel do fármaco; nas etapas de transposição de escala, identificou-se problemas com a alteração dos tempos de mistura do lote experimental para o lote piloto, pois não obteve-se uma boa compressibilidade para o lote piloto. Foi verificada, nas análises do granulado, uma diferença de granulometria que poderia justificar a diferença de desempenho entre os dois lotes. Um novo piloto foi manipulado, com a manutenção dos tempos de mistura do lote experimental, sendo que, dessa forma, os resultados satisfatórios do referido lote experimental foram reproduzidos para o segundo piloto, tanto em processabilidade quanto na avaliação granulométrica e demais ensaios. / Scaling up in the tabletting process is still a rather complex and empirical process carried out by trial and error methods, whose challenges are even greater when the formulation is obtained through wet granulation. Through this work, the development of large-scale production of a formulation of coated tablets containing diclofenac sodium, an anti-inflammatory drug, non-steroidal and non-selective inhibitor of COX 1 and 2, was conducted, evaluating the relevant factors for obtaining both a robust formulation with regard to the scale-up process itself and a drug which meets the legal requirements necessary for registration with the regulatory body. As a result, the product originating from the proposed formulation passed all of the required tests, and it was also proven to be bioequivalent to the reference drug. This result confirmed the importance of preliminary work, such as the characterization of active and studies concerning the parameters to be observed in the development of largescale production. In the characterization, the analysis showed that the polymorphic form of diclofenac sodium used in formulating was the anhydrous one, the more soluble form of the drug. In the steps of the development of large-scale production, there were problems with the alteration of the mixing times from the experimental batch to the pilot batch, as there was no good compressibility for the pilot batch. In the analyzes of the granulate, a difference of particle size was identified. It could explain the difference in performance between the two batches. Therefore, a new pilot batch was manipulated, with the maintenance of the mixing times of the experimental batch, and thus satisfactory results of the experimental batch were reproduced for the second pilot batch, regarding processability, particle assessment and other tests.

Sistemas monolíticos particulados contendo os constituintes ativos veiculados na forma de grânulos revestidos - pellets - têm recebido crescente atenção nos últimos anos, em função da otimização na biodisponibilidade e segurança na liberação do fármaco. A utilização destas unidades, como componentes de comprimidos traz, como principal vantagem, a divisibilidade da forma sem a perda do perfil biofarmacêutico desejado para o fármaco. Para sua produção, é indispensável a manutenção da integridade do revestimento daquelas unidades. Uma estratégia para o alcance deste objetivo envolve a utilização de grânulos inertes deformantes, comprimidos em conjunto com os grânulos revestidos, que atuam como um sistema de amortecimento das forças de compressão. Neste trabalho investigou-se a produção de grânulos deformantes através de dois métodos de granulação por via úmida, avaliando a influência de adjuvantes sobre as características dos produtos obtidos. Empregando a técnica de extrusão/esferonização obtiveram-se grânulos com propriedades de fluxo, empacotamento e resistência mecânica aceitáveis. O efeito dos adjuvantes sobre as etapas tecnológicas foi estudado por meio de um planejamento fatorial. Testaram-se duas variedades de celulose microcristalina, os desintegrantes croscarmelose sódica e crospovidona e soluções aglutinantes aquosas e hidroetanólicas de povidona. Para o desenvolvimento dos comprimidos utilizaram-se, como modelo, grânulos revestidos gastro-resistentes contendo omeprazol. A influência da composição dos grânulos deformantes sobre a liodisponibilidade do fármaco dos comprimidos foi avaliada através de análise fatorial 23. Os grânulos deformantes protegeram o revestimento polimérico dos pellets com diferentes intensidades. / Monolythic particulate systems containing the active constituents as coated pellets became great interest due to the improvement of safety and bioavailability. The use of such units as components of tablets shows as main advantages the divisibility of the pharmaceutical dosage form without loosing the desired biopharmaceutical profile of the drug. Consequently for the tablet production, the integrity of the polymeric film must be attained. A strategic option involves the utilization of inert soft pellets, which could be compressed together with the film coated pellets, absorbing the compaction forces. In this work the production of soft pellets was investigated using two wet granulation methods and evaluating the influence of formulation adjuvants on the pellets properties. The extrusion/spheronization technique yielded pellets with acceptable flow, packing and mechanical characteristics. The influence of the adjuvants on the technological steps was carried out through a statistical designed experiment. Microcrystalline cellulose from two producers, the disintegrants sodium croscarmellose and crospovidone, and aqueous and hydroethanolic dispersions of povidone, as binder, were tested. For the tablets development omeprazol gastroresistant film coated pellets were used as model. Aiming at the study of the influence of the soft pellets composition on drug lyoavailability was performed a 23 factorial experiment. The soft pellets protected at different intensities the polymeric coating of the gastroresistant pellets.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Numerosos modelos in vitro e in vivo foram desenvolvidos para estudar o reparo de lesões e identificar os mecanismos chave deste processo. Visando avaliar o processo de cicatrização utilizamos um modelo de lesão excisional total e um modelo de queimadura promovida por escaldamento. No estudo utilizando o modelo de lesão excisional total, abordamos o uso da aspirina (um inibidor não seletivo da COX) e seu efeito diferenciado sobre os sexos na cicatrização cutânea de camundongos. Observamos que os grupos fêmea controle e tratado apresentaram contração atrasada comparado aos grupos macho controle e tratado, respectivamente. Entre os grupos fêmea e macho controles, as fêmeas apresentaram menor atividade da mieloperoxidase e menor quantidade de células MIF-positivas do que os machos controle. Já entre os grupos fêmea e macho tratados, foi observado que nas fêmeas tratadas, a atividade da mieloperoxidase e a quantidade de macrófagos F4/80-positivos estavam maiores do que no grupo macho tratado. Ainda entre os grupos tratados, as fêmeas apresentaram menores níveis de hidroxiprolina e maior expressão proteica de vWF e VEGF comparado aos machos. No estudo das lesões causadas por queimadura, avaliamos as propriedades anti- inflamatórias e antioxidantes do ácido cafeico fenetil ester (CAPE) no reparo destas lesões e observamos que em 7, 14, 21 e 70 dias após a queimadura, o grupo queimado+CAPE apresentou menor área lesada, além de menor atividade da mieloperoxidase e dos níveis de nitrito do que o grupo queimado. Também foi observado que no grupo queimado+CAPE a expressão proteica de CD68 e de PECAM-1 estava reduzida comparada ao grupo queimado. Analisando os parâmetros de dano oxidativo foi observado que os níveis de MDA e de proteínas carboniladas estavam menores no grupo queimado+CAPE do que no grupo queimado, tanto no plasma quanto na lesão. Em suma, nosso estudo avaliou o processo de cicatrização de dois modelos de lesão, em roedores de diferentes espécies e em abordagens distintas. No modelo de lesão excisional total em camundongos observamos que a administração da aspirina prejudicou o processo de cicatrização em camundongos Balb/c fêmeas, mas não afetou esse processo nos machos da mesma linhagem, o que pode ser explicado pela redução dos níveis de estrógenos nas fêmeas. A utilização do CAPE na cicatrização de queimaduras em ratas comprovou sua eficácia anti-inflamatória e antioxidante devido ao grupo queimado+CAPE ter apresentado maior taxa de cicatrização, redução da resposta inflamatória, além da redução do dano oxidativo em lipídeos e proteínas comparado ao grupo queimado. / Several in vitro and in vivo models have been developed to study wound healing and to identify key mechanisms of this process. The most of these studies use animals models to reproduce the human physiology and possible therapeutic treatments. In order to evaluate the wound healing process in different wound models, we use a full-thickness excisional wound model and a burn model promoted by scalding. In the full-thickness excisional wound study, we approach the aspirin use (COX non-selective inhibitor) and its distinct effect on the gender in cutaneous wound healing on mice. It was observed that both female control and treated groups presented smaller wound area than male control and treated groups, respectively. Between female and male control groups, the females presented smaller myeloperoxidase activity and MIF-positive cells than control males. Comparing female and male treated groups it was observed that in female treated group, the myeloperoxidase activity and the F4/80-positive macrophages amount were greater than male treated group. Also between the treated groups, the females presented smaller hydroxyproline levels and greater vWF and VEGF protein expression compared to the males. In study of the burns performed by scalding, it was evaluated the caffeic acid phenethyl ester (CAPE) anti-inflammatory and antioxidant properties on repair of these lesions. It was observed that at 7, 14, 21 and 70 days after burning, the burn+CAPE group presented smaller wound area, beyond smaller myeloperoxidase activity and nitrite levels than burn group. It was also observed that the burn+CAPE group presented smaller CD68 and PECAM-1 protein expression compared to burn group. Analyzing the oxidative damage parameters, it was observed that the MDA and carbonilated proteins levels were greater in the burn group compared to burn+CAPE group. In conclusion, our study evaluated the wound healing process in 2 wound models on distinct rodent species with distinct approaches. In mice full-thickness wound model, under gender and aspirin action influence, it was seen that the aspirin administration impaired the wound healing process on Balb/c female mice, but did not alter the wound repair on males of the same lineage, what can be explained by reduction of the estrogen levels in these females. The CAPE use on rat burning healing demonstrated its anti-inflammatory and antioxidant efficiency because the burn+CAPE group presented greater burning healing, smaller inflammatory response, beyond smaller oxidative damage at lipid and protein level compared to burn group

A l'instar de la sismologie terrestre, l'astérosismologie est l'étude des tremblements d'étoiles. Ces vibrations internes sont observées via les variations de luminosité (ou de vitesse) qui se manifestent à leurs surfaces. A partir de ces séries temporelles, on calcule les spectres de puissance qui contiennent une véritable mine d'informations. En particulier, pour les pulsateurs de types solaires, nous pouvons observer le signal de la granulation ainsi que les modes propres d'oscillations stellaires qui sont tous deux une conséquence directe de la convection dans l'enveloppe de l'étoile. L'astérosismologie permet de sonder l'intérieur des étoiles comme une échographie. Par ailleurs, avec les grands relevés de photométrie spatiale CoRoT et Kepler, un nouveau champ d'application pour la sismologie est apparu. En effet, il est possible de caractériser au premier ordre les spectres d'oscillations des pulsateurs de types solaires à partir de quelques indices que nous appellerons indices sismiques. Ces derniers permettent via des relations simples d'estimer les paramètres fondamentaux de ces étoiles. Cela fait de l'astérosismologie un outil très puissant pour l'étude des populations stellaires.Dans la perspective du développement de la base de données Stellar Seismic Indices (SSI - Ouverture de la base SSI prévue pour l'été 2016. Lien vers la base: http://ssi.lesia.obspm.fr/), l'objet de ma thèse a été de développer une méthode automatique capable d'extraire simultanément les indices sismiques et les paramètres caractérisant la granulation des pulsateurs de types solaires. Cette méthode, appelée MLEUP, a été pour l'instant optimisée pour les géantes rouges car CoRoT et Kepler ont observé plusieurs dizaines de milliers de géantes rouges contre quelques centaines de pulsateurs de type solaire de séquence principale. Le MLEUP présente un avantage majeur par rapport à la plupart des méthodes existantes : il utilise le patron universel d'oscillations (UP) des géantes rouges comme modèle d'ajustement du spectre d'oscillations, ce qui permet d'analyser le spectre non lissé, donc non dégradé, et d'ajuster simultanément la composante de granulation et celle des oscillations par l'estimation du maximum de vraisemblance (MLE). Le MLEUP a dans un premier temps été testé par des simulations Monte Carlo afin de quantifier ses performances. Ces dernières se sont révélées très bonnes, avec de faibles biais et dispersions. Dans un second temps, nous avons appliqué le MLEUP à plus de 36.500 étoiles observées par CoRoT et Kepler, parmi lesquelles nous obtenons les indices sismiques et les paramètres de la granulation pour plus de 13.500 étoiles. Ces résultats ont d'ores et déjà été utilisés dans plusieurs travaux et leur utilisation devrait s'intensifier rapidement. / Like terrestrial seismology, asteroseismology is the study of star quakes. These internal vibrations are detected by observing the luminosity (or velocity) variations at the stellar surfaces. From these time series, one computes power spectra which contain a wealth of information. In particular, for solar-like pulsators, we are able to observe the signal of granulation as well as the eigenmodes of stellar oscillations, both of which are a direct consequence of the convection in the star's envelope. Asteroseismology allows us to probe the interior of stars much like an ultrasound. Furthermore, with the large spatial photometric surveys CoRoT and Kepler, a new scope for seismology appeared. Indeed, it is possible to characterise to first order the oscillation spectra of solar-like pulsators with few indices or parameters, called seismic indices. Using simple relations, they allow us to estimate fundamental parameters of these stars. Asteroseismology is by consequence a very powerful tool for the study of stellar populations.In the perspective of the development of the Stellar Seismic Indices (SSI - The opening of the SSI database is planned for the summer of 2016, see http://ssi.lesia.obspm.fr/).) database, the purpose of my thesis was to develop an automatic method able to extract simultaneously the seismic indices and the parameters characterizing the granulation signature of solar-like pulsators. This method, called MLEUP, was optimized for red giants because for the few hundred main-sequence solar-like pulsators observed by CoRoT and Kepler, several tens of thousands of red giants have been observed by these same missions. MLEUP has a major advantage over most existing methods: it relies on the use red-giant stellar oscillation universal pattern (UP) to fit the oscillation spectra. This allows us to analyse the unsmoothed spectrum and fit simultaneously both granulation and oscillations with the maximum likelihood estimate (MLE).As a first step, MLEUP was tested on Monte Carlo simulations in order to quantify its performances. These simulations have revealed that MLEUP achieves very good performances, with low biases and dispersions. As a second step, we applied MLEUP to more than 36,500 stars observed by CoRoT and Kepler, thereby yielding seismic indices and granulation parameters for more than 13,500 stars. Those results have already been used in several works and are expected to be used in many more.

Abstract Biomass, such as wood, binds CO2 as it grows, and is thus considered an environmentally friendly alternative fuel to replace coal. In Finland, biomass is typically co-combusted with peat, and also municipal waste is becoming more common as a fuel for power plants. Wood, peat and waste-based fuels are typically burned in fluidized bed combustion (FBC) boilers. Ash is the inorganic, incombustible residue resulting from combustion. The annual production of biomass and peat ash in Finland is 600 000 tonnes, and this amount is likely to increase in the future, since the use of coal for energy production will be discontinued during the 2020s. Unfortunately, FBC ash is still largely unutilized at the moment and is mainly dumped in landfills. The general aim of this thesis was to generate information which could potentially improve the utilization of FBC ash by alkali activation. The specific objective was to produce geopolymer aggregates by means of a simultaneous alkali activation-granulation process. It was shown that geopolymer aggregates with physical properties comparable to commercial lightweight expanded clay aggregates (LECAs) can be produced from FBC fly ash containing heavy metals. Although the ashes were largely unreactive and no new crystalline phases were formed by alkali activation, a new amorphous phase was observed in the XRD patterns, possibly representing micron-sized calcium aluminate silicate hydrate-type gels. The heavy metal immobilization efficiency of alkali activation varied with the type of fly ash. Good stabilization was generally obtained for cationic metals such as Ba, Pb and Zn, but in common with the results obtained with alkali activation of coal fly ash, anionic metals became leachable after alkali activation. The efficiency of immobilization depended on the physical and chemical properties of the fly ash and was not related to the total content of the element. All the geopolymer aggregates met the criteria for a lightweight aggregate (LWA) as defined by EN standard 13055-1. Their strength depended on the reactivity and particle size distribution of the fly ash. Mortars and concretes prepared with such geopolymer aggregates had higher mechanical strength, higher dynamic modulus of elasticity and higher density than concrete produced with commercial LECA, while exhibiting similar rheology and workability. / Tiivistelmä Biopolttoaineet, esimerkiksi puu, ovat ympäristöystävällinen vaihtoehto kivihiilelle, koska ne sitovat hiilidioksidia kasvaessaan. Suomessa biopolttoaineita poltetaan tyypillisesti turpeen kanssa, ja nykyään myös jätteen hyödyntäminen polttoaineena on yleistynyt. Puu, turve ja jätepolttoaineet poltetaan tyypillisesti leijupetipoltto-tekniikalla. Tuhka on polton epäorgaaninen, palamaton jäännös. Puun ja turpeen tuhkaa tuotetaan Suomessa 600 000 tonnia vuodessa ja määrän odotetaan kasvavan, sillä kivihiilen poltto lopetetaan 2020-luvulla. Leijupetipolton tuhkaa ei tällä hetkellä juurikaan hyödynnetä ja tuhka päätyykin pääasiassa kaatopaikoille. Tämän tutkielman päämääränä oli tuottaa tietoa, joka parantaisi leijupetipolton tuhkien hyödyntämistä alkali-aktivaatiolla. Erityisesti tavoitteena oli valmistaa geopolymeeriaggregaatteja yhtäaikaisella alkali-aktivaatiolla ja rakeistuksella. Tutkielmassa osoitettiin, että raskasmetalleja sisältävistä tuhkista valmistettujen geopolymeeriaggregaattien fysikaaliset ominaisuudet ovat vertailukelpoiset kaupallisten kevytsora-aggregaattien (LECA) kanssa. Vaikka tuhkien reaktiivisuus oli matala, ja uusia kidefaaseja ei muodostunut alkaliaktivaatiolla, uusi amorfinen faasi havaittiin XRD-mittauksissa. Uusi amorfinen faasi oli mahdollisesti mikrometrikokoluokan kalsium-aluminaatti-silikaatti-hydraatti-tyyppinen rakenne. Raskasmetallien stabiloinnin tehokkuus vaihteli tuhkien välillä. Kationiset metallit, kuten barium, lyijy ja sinkki, stabiloituivat pääasiassa hyvin, mutta anionisten metallin liukoisuus kasvoi alkali-aktivoinnin myötä. Stabiloinnin tehokkuus riippui tuhkien fysikaalisista ja kemiallisista ominaisuuksista, mutta raskasmetallin kokonaispitoisuudella ei ollu vaikutusta. Kaikki geopolymeeriaggregaatit olivat kevytsora-aggregaatteja standardin EN 13055-1 mukaisesti. Aggregaattien lujuus riippui tuhkan reaktiivisuudesta ja partikkelikokojakaumasta. Geopolymeeriaggregaateilla valmistettujen laastien ja betonien mekaaninen lujuus, Youngin moduuli ja tiheys olivat korkeampia kuin kaupallisella kevytsora-aggregaateilla valmistetut, vaikka niiden reologia ja työstettävyys olivat samanlaisia.

According to ICH Q8 process analytic technology (PAT) should be established to monitor critical quality attributes (CQAs) during manufacturing processes. Ethinylestradiol (EE) is a highly active and low dosed steroid hormone that is prone to oxidative degradation. The stability of this compound is therefore a critical quality attribute that has to be considered during drug formulation development. Beside the stability of EE, granule particle size and moisture are CQAs influencing the tableting ability of the resulting granules and the stability of EE. Both CQAs should be monitored during the production process. The investigations described in this thesis evaluate the implementation of in-line-sensors for monitoring of particle size (spatial filtering technology, SFT) and granule moisture (microwave resonance technology, MRT) during the fluid bed granulation process and the influence of process-variations on the stability of EE. The aim of these investigations was to develop an effective and mild fluid bed granulation process for a new model formulation based on microcrystalline cellulose as replacement for lactose as main filler excipient. The EE degradation products 6-alpha-hydroxy-EE, 6-beta-hydroxy-EE, 9(11)-dehydro-EE and 6-oxo-EE were quantified as an index for the stability of EE. It could be demonstrated that the surface of the filler substance influences the stability of EE due to the impact of water molecules. Hence, spraying sequence was determined to be a useful tool to improve the stability of EE. Correlations could be established for 6-oxo-EE with granule moisture and thermic parameters. The implementation of the SFT-sensor in the granulation process was successful. Measurement with the MRT-sensor for monitoring of granule moisture has to be improved.:Chapter I 1 1 Introduction Chapter II 41 2 Materials and Methods Chapter III 54 3 In-line Monitoring of Particle Size in a Fluid Bed Granulator: investigations concerning positioning and configuration of the sensor Chapter IV 72 4 Influence of in line monitored fluid bed granulation process parameters on the stability of Ethinylestradiol Chapter V 90 5 Influence of filler excipients on stability of EE Chapter VI 105 6 Discussion and Conclusion Chapter VII 131 7 Summary Chapter VIII 138 8 Zusammenfassung Reference List 146 Appendix 158

Barium sulfate (BaSO₄)-containing polytetrafluoroethylene (PTFE) granular powder was prepared through a two-phase emulsion dispersion granulation method. Because of its large bulk density, small average particle size, narrow particle size distribution, and superior powder flowability, the granular powder is suitable for use in automatic molding machines. The effects of granulation on the tensile strength of the BaSO₄/PTFE composite were investigated, and the composite’s microstructures were characterized and analyzed using scanning electron microscopy. All these indicated that the granulation could make BaSO₄ disperse more homogeneously in PTFE and reduce many defects in molded articles. So the properties of the BaSO4/PTFE composites made by the granular powder were superior to the composite obtained from the nongranular powder. The tensile strength and elongation of the composite obtained from the granular powder could be achieved to a level of 19.4 MPa and 420%, respectively.

A study was conducted on sol-gel synthesis of an adsorbent (phosphotungstic acid embedded in silica gel, H-PTA/SiO­2) of radioactive cesium. A novelty of this work is covalent bonding of PTA to the surface of solid support that prevents leaching from the surface of the material. The sample was granulated with a binder, aluminium oxide (γ-Al2O3). Solid-state NMR and FT-IR spectroscopy were used to confirm the presence of Keggin units of PTA in the bound materials. Thermal analysis of H-PTA/SiO­2 - γ-Al2O3 (50 %) showed that the water content in the bound material was appreciably lower than in the pure adsorbent. Quantitative determination of surface acidity of porous materials is an important analytical problem in characterization of the adsorbents. This problem was solved by reversed titration after saturation of the materials by anhydrous solution of pyridine. Batch and column adsorption tests showed that the adsorbent demonstrated high adsorption capacities towards cesium.

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.