Dissertations / Theses on the topic 'Fluid bed granulation and drying'

In this thesis, a thorough study of the batch top-spray fluidized bed granulation was carried out including experimental study, population balance model (PBM), computational fluid dynamic (CFD) study and control strategy development. For the experimental study, the influence variables of pulsed frequency, binder spray rate and atomization pressure of a batch top-spray fluidized bed granulation process were studied using the Box-Behnken experimental design method. Different mathematical models were developed to predict the mean size of granules, yield, relative width of granule distribution, Hausner ratio and final granule moisture content. Validation experiments have shown the reliability and effectiveness of using the Box-Behnken experimental design method to study a fluidized bed granulation process. The one-dimensional population balance models (ODPBMs) have been developed to model a pulsed top-spray fluidized bed granulation, linking the operating factors of the pulsed frequency, the binder spray rate, and atomization air pressure with the granule properties to predict granule growth behavior at different operating conditions. A multi-stage open optimal control strategy based on the developed ODPBMs was proposed to reduce the model and process mismatch through adjusting the trajectory of the evolution of the granule size distribution at predefined sample intervals. The effectiveness of the proposed modeling and multi-stage open optimal control strategy has been validated by experimental and simulation tests. In addition, an Eulerian-Eulerian two-fluid model (EETFM) was developed to describe the gas-particle two-phase flow in the fluidized bed granulator. By computational fluid dynamic analysis, it has been proven that the fluidized bed granulation system is not homogeneous, based on which a two-compartmental population balance model (TCPBM) was developed to describe the particle growth in the fluidized bed granulation. Validation experiments have shown the effectiveness and superior accuracy of the TCPBM comparing with the ODPBM in predicting the final particle size distribution.

The influence of operation parameters on the drying of spherical porous particles containing a mixture of solvents evaporating into nitrogen in a continuously worked vibrated fluid-bed dryer was studied. A simulation based on the analytical solution to heat and mass transfer equations was applied and modifications were suggested.   Four different ternary liquid mixtures were selected: Acetone-Chloroform-Methanol (ACM), Ethanol- 2-propanol-Water (EIpW), Water-Ethanol-Ethyl Acetate (WEEa) and Ethanol-Methylethylketone- Toluene (EMekT). For the solid, physical properties of Pyrex was used.   Comparison of composition- and temperature- profiles indicated that there is no resistance against heat transfer within the solid and that the heat transfer is much faster than mass transfer.   Selectivity diagrams were drawn. The results indicated that selectivity is an important parameter in predicting the drying behavior.   The retention ratio was studied as performance parameter. Its variation was studied in response to changes in operation parameters, including gas velocity and temperature, as well as solid temperature and particle size.   A  modification  to  the  model  was  examined  by  assuming  a  liquid-content-dependent  diffusion resistance factor. It was observed that implementing such an assumption yields decreased values for retention ratios.   The  effect  of  vibration  on  heat  and  mass  transfer  coefficients  was  included  using  a  correlation suggested by Sbrodov and the resulting effect on retention ratio was examined.
Inverkan   av   driftparameter  på  torkning  av   sfäriska  porösa  partiklar  som   innehåller lösningsmedelblandningar som avdunstar i kväve i en kontinuerligt viberande fluidbädd-tork studerades.  En  simuleringsmodell  baserad  på  den  analytiska  lösningen  till  värme-  och materieöverföringsekvationerna användes och ändringar föreslogs.   Fyra  olika  tärnar  vätskeblandningar  valdes:  aceton-kloroform-metanol(ACM),  etanol-2- propanolvatten,(EIpW),     vatten-etanol-etylacetat     (WEEa)     och     etanol-metyletylketon- toluen(EMekT). För den fasta fasen användes fysikaliska egenskaper liknande Pyrex.   Sammansättnings-  och  temperatur-profiler  visade  att  det  inte  finns  något  motstånd  mot värmeöverföring  i  den  fasta  fasen  och  att  värmeöverföringen  sker  mycket  snabbare  än materieöverförningen.   Selektivitetsdiagram ritades. Resultaten indikerar att selektivititen är en viktig parmeter för att förutsäga beteendet vid torkning.   Retentionsförhållandet  användes  som  ett  prestandamått.  Dess  variation  med  avseende  på förändringar av  driftsparmetrar,  bland  annat  gasen  hastighet  och  temperatur  samt  den  fasta  fasens temperatur och partikelstorlek, studerades.   En modifiering av modellen undersöktes genom att införa en vätskehalts-beroende faktor för diffusionsmotståndet. Detta minskade värdena på retentionsförhållandena.   Vibrationens inverkan på värme- och materieöverföring infördes genom att använda Sbrodov samband, och den resulterande effekten på retentionsförhållandet observerades.

Aim: The aim of this project was to optimize the clean-in-place program for a fluid bed dryer used after drying wet ferrous granules, with focus on shortening the total time used for the program. This clean-in-place program has two critical objectives; removing a hard to clean iron residue on the inside surface of the fluid bed dryer by using an acidic detergent and thereafter removing the acidic detergent by rinsing steps. Methods: The optimization was performed by down scaling the current clean-in-place program to laboratory scale, then varying the parameters volume and time by applying the statistical model Central Composite Circumscribe and use experimental design optimization to determine the influence of the parameters on the effect of cleanliness. Cleanliness in laboratory scale was assessed by visual inspection and UV/Vis spectroscopy. The cleanliness in production was determined by visual inspection, an iron test kit and a pH-meter. The results from the laboratory scale optimization lead to a new clean-in-place program that was evaluated twice in production after drying of ferrous batches. Results and conclusions: The hard to clean iron residue could be recreated in laboratory scale. The optimization in laboratory scale showed that the parameter water was the most significant parameter for removal of the iron residue. The new clean-in-place program evaluated in production was 40% (approx. 110 min) shorter than the current clean-in-place program. The results of cleanliness varied after the new clean-in-place program had been used in production, not all hard to clean areas tested had approved results. Further optimization is needed to be able to clean after varying amount of granules in left in the fluid bed dryer after production ended. An interesting side results was that two steps dedicated to rinse out the detergent could be removed. This fact can lead to that even more rinsing steps can be excluded in the future clean-in-place programs.

O presente trabalho refere-se ao desenvolvimento de grânulos a partir de produto seco de A. satureioides obtido por spray drying, em escala semi-industrial, visando a superar as principais limitações tecnológicas apresentadas tais como a higroscopia excessiva do produto, baixa densidade, pequeno tamanho de partícula e instabilidade dos constituintes flavonoídicos frente à luz. Dois métodos foram empregados para a granulação: granulação em leito fluidizado e granulação via seca por desagregação. Estes métodos apresentaram, respectivamente, 15 e 60 % de rendimento do processo, levando a escolha da granulação seca para a produção dos grânulos do produto seco. A granulação seca resultou em grânulos assimétricos, de faixa granulométrica situada entre 0,3 mm e 1,9 mm e de superfície irregular e rugosa. O revestimento destes grânulos foi realizado em leito fluidizado, utilizando três tipos de polímeros, Eudragit® L 30D, Opadry® II e Opadry® AMB.O rendimento médio com o Opadry® II foi de 72 %. O revestimento com Opadry® AMB foi realizado utilizando-se um baixo e alto fluxo do líquido de revestimento, obtendo-se rendimentos de 75 e 85 %, respectivamente. A higroscopia dos grânulos foi avaliada em ambientes com umidade relativa controlada de 65 ou 99 %, comparando-se o comportamento dos grânulos revestidos com o dos grânulos sem a presença de revestimento. Ambos os filmes com Opadry® não protegeram os grânulos frente à umidade. As fotomicrografias por MEV, destes grânulos, revelaram que, ambos os tipos de revestimento, apresentaram superfícies rugosas e com presença de poros explicando, parcialmente, a falta de proteção contra a umidade. O estudo da fotoproteção indica, em um primeiro momento, que o filme de revestimento promove a proteção dos flavonóides frente a ação da luz. A avaliação preliminar da liberação dos flavonóides, a partir dos grânulos, foi realizada em células de fluxo Desaga® com os grânulos sem revestimento e revestidos com Opadry® AMB. A água não demonstrou ser o meio mais favorável para este ensaio. Em meio com pH 1,2 contendo 1 % de laurilsulfato de sódio, os flavonóides quercetina, luteolina e 3-Ometilquercetina foram liberados, respectivamente, após 90 minutos, em 70, 83 e 70 % a partir dos grânulos não revestidos, e 52, 54 e 45 % a partir dos grânulos revestidos com Opadry® AMB, denotando a influência do filme de revestimento sobre o perfil de liberação dos flavonóides. Em seu conjunto, os resultados obtidos nesta primeira abordagem deste tema abrem diversas perspectivas para oaprofundamento do estudo e desenvolvimento de granulados de A. satureioides, a partir de produto seco por spray drying.
The present work was designed to develop granules from Achyrocline satureioides spray dried powders in order to overcome the main technological limitations presented by this herbal raw material: high hygroscopy, low density, small particle diameter and flavonoid sensibility against light. Two methods were employed for granulation, fluidized bed and dry granulation. These methods presented, respectively, 15 and 60 % of process yield, leading to the selection of dry granulation for preparing the granules. By this method, the granules showed 0,3 to 1,9 mm particle mean diameter, rough surface and irregular morphology. For coating the granules, three types of polymers were employed, Eudragit® L30D, Opadry® II and Opadry® AMB, in fluidized bed. The first one resulted in atomizer obstruction becoming non viable its employment. The mean yield coating obtained with Opadry® II was 72 %. The Opadry® AMB was sprayed in low and high rates yielding, respectively, 75 % and 85 %. The hygroscopicity of the granules was evaluated in controlled conditions of 65 % or 99 % RH, comparing the behavior of the coated granules which that presented by non-coated particles. Both Opadry® coatings did not protect the granules against the humidity. The SEM photomicrographis of these granules revealed that both types of coating presented rough and porous surface explaining partially, at least, the lack of protection against the humidity. The preliminary photostability assay indicated, in a first view, that the coating promotes the flavonoid protection. The flavonoid release from the granules was performed in Desaga® flow cell from the non-coated granules and from Opadry® AMB coated granules. Water demonstrated not to be an appropriate media for both tested granules. In pH 1.2 media containing 1 % of sodium lauryl sulfate, the flavonoids quercetin, luteolin and 3-O-methylquercetin were, respectively, released, after 90 minutes, in 70 %, 83 % and 70 % from non coated granules and in 52 %, 54 % and 45 % from Opadry® AMB coated granules, denoting the influence of the coating on the flavonoid release profile. Taken together, the results of this first approach openmay perspectives for more detailed studies on Achyrocline satureioides granules from the corresponding spray dried powders.

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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Introduction: Cyclodextrins have been used in several industries segments, mainly in the pharmaceutical industry. This material has been employed in the complexation of poorly soluble drugs with the aim to increase bioavailability and effect. Carvedilol (CARV) is a poor soluble drug used in the treatment of hypertension and congestive heart failure. Its oral bioavailability is reduced to β5%, due to their low aqueous solubility and first pass effect. Because of this, it is an excellent choice to form inclusion complexes with cyclodextrins. However, the use of cyclodextrins have some limitations, once it is necessary to use a large amount in the formulation and it can cause dilution of the drug and it can result in a solid oral form with inappropriate dimensions. Therefore, different strategies have been used to enhance complexation efficiency and reduce the amount of cyclodextrin, like the combination of the effect of drug ionization and inclusion complexes. In addition, the choice of the technique used to produce inclusion complexes is very important, because it is necessary to develop economic and effective techniques, which have been easily scalable to produce inclusion complexes in the industry. Spray drying technique have been extensively studied in cyclodextrin complexation, but this method is very expensive and presents lower efficiency. On the other hand, fluid-bed granulation has been widely used in the production of solid dosage forms but the use of this technique to produce cyclodextrin inclusion complexes is not described in the literature. Objective: The purpose of this study is to produce and characterize inclusion complexes containing carvedilol and cyclodextrin, using spray drying and fluidized bed techniques, with the aim to enhance drug dissolution rate. Material and methods: Phase solubility studies were performed using various cyclodextrins, in pH 1,β and 6,8, at room temperature, during 48 hours. Binary complexes were produced by spray drying and fluidized bed techniques. FTIR spectroscopy, DSC analysis, morphology, particle size, flowability and dissolution studies were performed to characterize the inclusion complexes. Results and discussion: Hidroxypropyl--cyclodextrin Cavitron W7 HP7 had the better solubility results. Thus, binary complexes CARV: HPCD prepared by spray drying and fluidized bed techniques in pH β,β showed better results and dissolution rate was 7 and 6 folds, respectively. However, solid dispersion prepared by fluid-bed presented better flowability indicating that this technique is the most appropriate for a large-scale production of solid dosage forms. Additionally, complexes containing HPȖCD showed good dissolution rate and could be considered as one more option for CARV complexation with great performance of inclusion complex formation in solid state.
Introdução: As ciclodextrinas têm sido amplamente utilizadas principalmente na indústria farmacêutica. Esses adjuvantes são usados na complexação de fármacos que apresentam baixa solubilidade aquosa, resultando em produtos com maior biodisponibilidade e portanto, efeito terapêutico superior. O carvedilol (CARV) é um fármaco pouco solúvel utilizado no tratamento da hipertensão e insuficiência cardíaca congestiva. Esse fármaco tem biodisponibilidade oral de apenas β5%, devido à sua baixa solubilidade aquosa e ao efeito de primeira passagem metabólica, sendo um excelente candidato a complexação com as ciclodextrinas. No entanto, o uso de ciclodextrinas em formas farmacêuticas sólidas é limitado pela necessidade de adicionar elevadas quantidades desses adjuvantes na formulação, o que ocasiona à diluição do fármaco e o aumento indesejado no tamanho da forma farmacêutica. Assim, diversas estratégias têm sido empregadas para aumentar a eficiência de complexação e reduzir a quantidade de ciclodextrina utilizada, como a ionização de fármacos associada a formação de complexos de inclusão. Outra preocupação importante é a seleção do método de complexação, pois é necessário desenvolver técnicas eficientes, econômicas e de fácil escalonamento visando a futura produção industrial dos complexos. O método de spray drying tem sido muito investigado para a obtenção de complexos com ciclodextrinas, mas apresenta baixa eficiência energética e custo elevado. Por outro lado, o método de leito fluidizado tem sido extensivamente utilizado na indústria farmacêutica, mas seu emprego como método de complexação durante a granulação de pós ainda não foi descrito na literatura. Objetivo: A proposta deste trabalho foi obter e caracterizar complexos de inclusão contendo carvedilol e ciclodextrinas, pelas técnicas de spray drying e leito fluidizado, visando melhorar a dissolução do fármaco a partir de formas farmacêuticas sólidas. Materiais e Métodos: Estudo de solubilidade de fases com diferentes tipos de ciclodextrinas foram realizados em soluções de pH 1,β e 6,8, sob temperatura ambiente, durante 48 horas. Complexos sólidos binários foram preparados pelas técnicas de spray drying e leito fluidizado. Os complexos de inclusão foram caracterizados por espectroscopia na região do infravermelho (FTIR), calorimetria exploratória diferencial (DSC), morfologia, tamanho de partícula, fluxo e avaliados quanto a dissolução do fármaco. Resultados e discussão: A ciclodextrina que apresentou melhor capacidade de solubilização do carvedilol foi a hidroxipropil-ȕ- ciclodextrina (HPȕCD) com maior grau de substituição (Cavitron W7 HP7). Complexos binários CARV: HPȕCD, preparados por spray drying e leito fluidizado, em pH β,β, apresentaram os melhores resultados, sendo o aumento na taxa de dissolução de 7 e 6 vezes, respectivamente. No entanto, a dispersão sólida preparada em leito fluidizado apresentou propriedades de fluxo superiores demonstrando que esta técnica é a mais adequada para a produção de formas sólidas em grande escala. Adicionalmente, os complexos contendo HPȖCD também apresentaram resultados de dissolução satisfatórios, sendo esta ciclodextrina modificada uma alternativa para a formação de complexos de inclusão contendo CARV.

Orientadores: Osvaldir Pereira Taranto, Marcelo Nitz da Costa
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica
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Resumo: Acetato de sódio e um sal orgânico produzido pela reação do acido acético com hidróxido de sódio. Depois da cristalização e separação os cristais úmidos são secos. Já o cloreto de potássio e um sal inorgânico extraído de rochas e águas salinas muito utilizado na industria química como fertilizante. Esses sais são higroscópicos, coesivos quando úmidos, e geralmente são secos em secadores de leitos fluidizados. No presente trabalho foi utilizado um secador de leito pulso-fluidizado (PFB) que e uma modificação do secador de leito fluidizado convencional. Neste equipamento uma taxa constante de ar e suprido para o secador. Um distribuidor de gás instalado sob a câmara de secagem promove a pulsação pela corrente de gás alternada. A principal vantagem desta técnica e o uso de uma vazão de ar menor quando comparada com outras. O PFB utilizado neste trabalho possui uma área de secção transversal de 0,18 metros quadrados e constituído de quatro seções. Inicialmente foi realizado o estudo fluidodinâmico dos sais secos e úmidos. Posteriormente as curvas de secagem do acetato de sódio e cloreto de potássio foram determinadas para diferentes condições de secagem (temperatura do ar e freqüência de pulsação). A secagem e fluidodinâmica em leito fluidizado convencional foram feitas para que a comparação com o leito pulsado fosse possível. Resultados mostraram que as taxas de secagem foram maiores na fluidizarão pulsante devido ao melhor comportamento fluidodinâmico: o fluxo intermitente ajuda a romper partículas aglomeradas e conseqüentemente prover melhor contato entre gás - partícula.
Abstract: Sodium acetate is a salt produced by the reaction of acetic acid with sodium hydroxide. After crystallization and separation, the wet crystals are dried. Potassium chloride is an inorganic salt extracted from rocks and saline water. It is mainly used in the chemical industry as a fertilizer. These salts are hygroscopic particulate materials, which are dried in fluidized beds or rotary dryers. In this work a pulsed-fluid bed (PFB) dryer was used, which is a variation of the conventional fluidized bed dryer. In this equipment, a constant airflow rate is supplied to the dryer. A gas distributor installed upstream of the drying chamber provides the pulsed-flow by alternating the gas stream. The main advantage of this technique is the lower airflow rate supplied when compared with competitive techniques. The PFB used in this work has a cross section area of 0.18 m2 and it has four sections. Initially, the fluid-dynamic study of dry and wet salts was performed. Subsequently the drying curves of sodium acetate and potassium chloride were determined for different drying conditions (inlet air temperature and pulsation frequency). Drying and Fluid-dynamic was performed in conventional fluidized bed drying, so that results could be compared. Results showed that the drying rates were higher under pulsed fluidization due to the better fluid-dynamic behavior: the intermittent flow can help to break particle agglomerates and therefore provide better contact between particles and the gas.
Mestrado
Engenharia de Processos
Mestre em Engenharia Química

Orientadores: Sandra Cristina dos Santos Rocha, Nadia Rosa Pereira
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica
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Resumo: Polihidroxibutirato (PHB) é um poliéster completamente biodegradável e biocompatível. O interesse no desenvolvimento, produção e comercialização do PHB vem crescendo por ser um produto biodegradável e de produção integrada à cadeia de açúcar e álcool. A secagem é uma importante etapa do processo de produção do PHB, pois para o adequado pósprocessamento desse material deve-se garantir um teor de umidade limite de 0,5%. Neste contexto, este trabalho teve como objetivo estudar uma tecnologia de secagem, em um produto inovador e de importância na preservação ambiental. Foi realizado um estudo da fluidodinâmica e dos mecanismos de secagem do PHB em um leito fluidizado pulsado rotativo (LFPR). A escolha do equipamento baseou-se no fato de que o PHB úmido é coesivo e não apresenta fluidização convencional de qualidade. O secador de LFPR utiliza a pulsação do ar para desfazer os aglomerados de PHB melhorando a circulação das partículas dentro do leito. O presente estudo também incluiu a caracterização física do material antes e após a secagem. Para os ensaios de caracterização em que os equipamentos não trabalham em presença de umidade, a liofilização do PHB foi a alternativa encontrada para se caracterizar o material antes da secagem. O PHB apresentou um excelente comportamento fluidodinâmico em LFPR. A frequência de pulsação de 10 Hz foi a que apresentou comportamento mais favorável, com queda de pressão moderada e patamares de estabilidade. Por meio dos ensaios fluidodinâmicos foi possível determinar a velocidade de mínima fluidização vigorosa pulsada (VMV), parâmetro que ajudou a estabelecer a velocidade empregada para os experimentos de secagem. Durante a secagem do PHB foi avaliada a influência que a temperatura, velocidade e frequência de pulsação do ar exercem na cinética de secagem. Verificou-se excelente contato entre as partículas de PHB e o ar aquecido, com elutriação somente nos primeiros 10 minutos de secagem. As curvas de secagem do PHB indicaram períodos de taxa de secagem constante e decrescente. A temperatura e a velocidade do ar influenciaram positivamente o processo. Além disso, foi detectada a existência de um outro solvente além da água nas amostras de PHB, por meio da comparação entre as curvas de secagem obtidas com medidas de umidade feitas em estufa e em Karl Fischer. A análise termogravimétrica (TGA) também ajudou a detectar a presença de outro solvente além da água nas amostras de PHB. Os ensaios de caracterização física mostraram que as condições operacionais de secagem testadas não provocaram a degradação das partículas de PHB. Sob as condições consideradas ótimas de secagem, temperatura de 90 ºC, frequência de 7 Hz e velocidade do ar 0,40 m/s, foi atingida umidade igual a 0,56%, demonstrando a viabilidade do secador LFPR.
Abstract: Poly-hydroxybutyrate (PHB) is polyester, completely biodegradable and biocompatible. The interest on its development, production and commercialization has arisen due to its biodegradability and production integrated to the sugar and alcohol chain. Drying is an important step of the PHB production because an adequate post-processing is achieved only at moisture contents less than 0.5%. The goal of this work was to study a drying technology for this innovative product of relevant importance for the environmental preservation. The fluid-dynamic and drying mechanisms analyses were made in a rotating-pulsed fluidized bed (RPFB). The equipment was chosen based on the fact that the wet PHB is cohesive and doesn't work properly in a conventional fluid bed. The RPFB dryer uses the air pulsation to undo the PHB agglomerate improving the circulation of the particles inside the bed. This study also included the physical characterization of the material before and after the drying. For the characterization tests that wouldn't work with moisture presence, the liophilization was the best alternative to characterize the material before the drying process. The PHBshowed an excellent dynamic behavior in RPFB. The pulsation frequency of 10 Hz presented the most favorable fluid dynamic conditions, resulting in moderate pressure drop and regime stability. Based on the fluid-dynamic study it was possible to determine the minimum vigorous fluidizing air flow (MVF), an important parameter to set the air velocity range for the drying experiments. An excellent contact between the PHB particles and the hot air was obtained during the drying runs, with particles elutriation only during the first 10 minutes. The influence of the temperature, velocity and frequency of air pulsation was evaluated on the drying kinetics. The PHB drying kinetics presented constant and decreasing-rate drying periods. The drying process was positively influenced by the air temperature and velocity. Furthermore, the presence of another solvent additionally to the water was detected in the PHB samples through the comparison between the drying curves obtained with moisture measurements made in an oven and in Karl Fischer equipment. The thermo gravimetric analysis also helped to detect the presence of another solvent in the PHB samples. The physical characterization tests showed that the drying operating conditions didn't cause degradation on PHB particles. The RPFB dryer showed to be a viable technique to dry PHB, as moisture content of 0.56% was reached at optimal operating conditions of air temperature of 90oC, air velocity of 0,40 m/s and frequency of pulsation of 7 Hz.
Mestrado
Engenharia de Processos
Mestre em Engenharia Química

L'étude des phénomènes fondamentaux de

transport et de thermodynamique apparaissant lors de l'évaporation

en milieu poreux permet l'investigation d'applications pratiques

variées. Dans ce travail, nous développons des modèles fondamentaux

d'évaporation en milieu poreux que nous appliquons ensuite au

séchage en lit fluidisé de deux matériaux granulaires poreux :le

PVC et la levure.

Les modèles mis au point sont réalisés suivant une approche

multiéchelle. Nous nous intéressons tout d'abord aux phénomènes se

déroulant à l'échelle d'un pore. Les modèles développés à cette

échelle sont ensuite exploités dans le cadre d'une étude à l'échelle

d'un grain poreux. Le couplage des modèles de grain avec un modèle à

l'échelle du réacteur permet alors l'étude des applications

industrielles.

A l'échelle du pore, nous étudions les phénomènes de transport dans

un capillaire initialement rempli de liquide qui s'évapore vers

l'atmosphère ambiante. L'objectif est de prédire le taux

d'évaporation dans cette configuration. Nous nous intéressons

successivement à la modélisation du transport de matière par

convection-diffusion en phase gazeuse et la modélisation de l'impact

de films liquides adsorbés à la paroi du capillaire sur le transport

de matière. Ces deux modèles sont confrontés à des expériences

d'évaporation en capillaires cylindriques visualisées à l'aide de

deux dispositifs optiques. Le premier offre un suivi d'ensemble au

cours du temps du capillaire, alors que le second, un interféromètre

de Mach-Zehnder, permet une visualisation locale de la région

entourant le ménisque.

Le modèle portant sur le transport de matière par

convection-diffusion mène à la définition d'un critère non

dimensionnel permettant d'évaluer si la convection dans la phase

gazeuse dans le capillaire doit être prise en compte pour évaluer le

taux d'évaporation. Le modèle de film permet de prédire l'impact de

celui-ci sur l'évaporation en présence d'un gaz inerte lorsque les

mouvements convectifs en phase gazeuse sont négligeables. La

confrontation de ce modèle avec les profils d'épaisseur des films

obtenus à l'aide de interféromètre de Mach-Zehnder ne permet pas de

valider le modèle, et ce, suite à une trop grande incertitude sur

l'évaluation des interactions entre la paroi et le liquide.

A l'échelle d'un grain, nous développons un modèle discret par

réseau de pores et deux modèles continus pour tenter de prédire le

taux d'évaporation et la distribution des phases dans le milieu

poreux. Le modèle par réseau de pores prend en compte les transports

de matière par diffusion en phase gazeuse, par convection dans les

pores remplis de liquide et par convection dans les films liquides.

Les effets visqueux en phase liquide sont également modelisés. Pour

la prise en compte de ces derniers, nous montrons l'importance de

l'usage d'un algorithme approprié. Nous évaluons ensuite au travers

de trois nombres sans dimensions l'impact du transport par film et

des effets visqueux sur l'évaporation et la distribution des phases.

Cette analyse dimensionnelle est ensuite appliquée à l'étude de

réseaux de pores pour lesquels la section des liaisons les

constituant est idéalisée par des polygones réguliers. Pour les

modèles continus après une vérification simplifiée de

l'applicabilité de cette démarche, nous développons deux modèles

simples. Dans les deux modèles, l'étape de séchage à vitesse

constante est supposée limitée par le transport de matière externe

au grain. Le premier modèle, dit à front pénétrant, suppose que

l'étape de séchage à vitesse décroissante correspond à l'existence

d'un front d'évaporation qui s'enfonce dans la matrice poreuse. Le

second modèle, dit à surface d'échange variable, attribue cette même

étape du séchage à une diminution progressive de la surface

d'évaporation en surface du grain.

A l'échelle du réacteur, nous présentons deux modèles visant à

simuler deux types d'essais différents :le séchage en lit fluidisé

et la thermogravimétrie analytique. Ces deux modèles sont couplés

aux différents modèles à l'échelle de grain pour étudier le séchage

de PVC et de levure tant en lit fluidisé que lors des essais de

thermogravimétrie analytique.

Dans le cas du PVC, le modèle par réseau de pores ne peut pas être

appliqué de par la nécessité d'une trop grande puissance de calcul.

Au niveau des modèles continus, nous montrons que l'application du

modèle à surface d'échange variable permet de reproduire les courbes

de séchage expérimentales des essais en lit fluidisé.

Dans le cas de la levure, nous appliquons le modèle par réseau de

pores et le modèle à front pénétrant. L'utilisation du modèle par

réseau de pores nécessite une connaissance plus détaillée de la

structure poreuse des grains. Le traitement d'une analyse par

microtomographie nous permet d'obtenir un réseau de pores

expérimental. Celui-ci est utilisé pour montrer que la méthode de

caractérisation de la porosité par intrusion de mercure ne semble

pas adaptée à un matériau deformable comme la levure. Le même réseau

est utilisé pour simuler le séchage de grains de levure à l'aide du

modèle par réseau de pores. Les simulations sont réalisées sur des

réseaux équivalents à des coupes dans le solide. Le modèle par

réseau de pores et le modèle à front pénétrant permettent tous deux

de modéliser correctement le séchage de levure en lit fluidisé

moyennant l'ajustement de leurs paramètres ajustables,

respectivement la conductibilité des films liquide et la tortuosité.

Pour l'essai de thermogravimétrie, ils ne parviennent à approcher

que la première étape de celui-ci. Les avantages, défauts et

complémentarités de ces deux modèles sont discutés.

Nous évaluons ensuite l'impact du rétrécissement de la levure et des

types d'eau sur le séchage de ce matériau. Le rétrécissement est,

pour ce faire, mesuré à l'aide d'un stéréomicroscope. Ces premières

mesures, exploratoires, mènent à la définition d'un modèle empirique

de retrait du solide au cours de son séchage. En le prenant en

compte dans les modèles déjà appliqués à la levure, nous montrons

que le retrait a un impact significatif sur l'étape de séchage à

vitesse décroissante. Cet impact

peut cependant être masqué intégralement par la réévaluation

des paramètres ajustables des différents modèles. Finalement,

l'étude des types d'eau au travers d'un modèle simple appliqué à

l'essai de thermogravimétrie analytique montre que les types d'eau

ne doivent pas être pris en compte pour modéliser le séchage de

levure.

A l'issue de ce travail, nous disposons donc de modèles fondamentaux

d'évaporation en milieu poreux. Ceux-ci peuvent être appliqués à des

cas d'intérêt industriel, comme nous le réalisons pour le PVC et la

levure. Ils peuvent servir à améliorer la

compréhension de ces procédés. Ils représentent donc des

outils de choix pour la conception, le dimensionnement et

l'optimisation du séchage.
Doctorat en Sciences de l'ingénieur
info:eu-repo/semantics/nonPublished

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The oral administration of drugs for systemic effects is the most common way used in medical treatment. Among these, drugs as tablets are the most used. The granulation is a process that seeks to improve the transportation of powder in the compacting machine by the agglomeration of particles. The fluidized bed drying added to "spray dryer" technique is commonly used to form granules that reaches the required characteristics of a uniform grain, with strict control of final humidity of the granules and relatively short process when compared to other techniques for drugs production. Metformin is a drug displayed as hydrochloride and orally administered as coated tablets. It is indicated for the treatment of type 2 Diabetes mellitus. In order to improve productivity in an industrial fluidized bed used in the granulation and drying of Metformin, it is necessary to evaluate the effects of operation conditions used in the process, as particulate material and in the production process. For that purpose, it was performed the study of fluiddynamic granulation and drying of Metformin in fluidized bed in order to investigate the minimum fluidization velocity for the process of this drug. The influence of temperature and speed of drying air in processing time of the formula, and the average particle size were also evaluated. The experiments were elaborated based on the Evolutionary Operation Theory, proposed by Box (1957). It performed the shaping at drying stage. With these experiments was possible to reduce to zero the reworks of batches caused by the formation of preferential channels, which could occur deposition polymer solution on the particulate material. It was also possible to reduce the average processing time in 8 minutes, adding greater productivity and savings for the company where the work was developed. The results achieved, besides the gain in productivity, guide to where efforts should be directed to continue improving productivity, providing a practical methodology for applying the technique that can be applied in the production of other drugs that use the granulation process in fluidized bed.
A administração de fármacos para efeitos sistêmicos por via oral é a forma mais comum dentre os medicamentos. Dentre estes, os medicamentos na forma de comprimidos são os mais empregados. A granulação é um processo que visa melhorar o transporte do pó na máquina compressora por meio da aglomeração de partículas. A secagem em leito fluidizado acoplado à técnica de spray dryer é a técnica comumente empregada para a formação de grânulos que atendam as características necessárias de granulometria uniforme, com controle rigoroso da umidade final do granulado e tempo relativamente curto de processo quando comparado a outras técnicas para produção de medicamentos. A metformina é um fármaco, apresentado na forma de cloridrato, e administrado como comprimidos revestidos por via oral. É indicado no tratamento de diabetes, mais especificamente diabetes mellitus tipo 2. Com o objetivo de aprimorar a produtividade em um leito fluidizado industrial utilizado na granulação e secagem de metformina, faz-se necessário avaliar os efeitos das condições operacionais utilizadas no processo referentes a qualidade material particulado e o processo de produção propriamente dito. Para tanto, realizou-se o estudo fluidodinâmico da granulação e secagem de metformina em leito fluidizado investigando assim a velocidade mínima de fluidização para o processamento deste fármaco. A influência da temperatura e da velocidade do ar de secagem no tempo de processamento da fórmula e no tamanho médio da partícula também foram avaliados. Os experimentos foram elaborados a partir da teoria da Operação Evolutiva, proposta por Box (1957). A modelagem da etapa de secagem também foi realizada. Por meio dos experimentos realizados conseguiu-se reduzir a zero os reprocessos de bateladas por formação de canais preferenciais, onde poderia ocorrer deposição de solução polimérica sobre o material particulado. Foi possível também reduzir o tempo médio de processamento em 8 minutos, agregando maior produtividade e economia para a empresa na qual este trabalho foi desenvolvido. Os resultados obtidos mostram que houve ganhos em relação a produtividade, e norteiam para onde os esforços devem ser direcionados para continuidade do melhoramento de produtividade, fornecendo uma metodologia prática para aplicação da técnica que poderá ser aplicada na produção de outros fármacos que utilizam o processo de granulação por via úmida em leito fluidizado.

The aim of this thesis was to create a model of thermal conversion of solid fuel. This is achieved by means of standard modelling tools included in software ANSYS Fluent in combination with user-defined functions (UDF). In first part of thesis basic approaches to CFD modelling of solid fuel combustion are presented. Building of a mathematical model and corresponding algorithms follows. Individual parts of a created model and its parts are tested on simple physical cases and then on case of experimental reactor for analysing biomass combustion.

Resumo: Este projeto teve como objetivo estudar a influência de diferentes processos de desidratação (secagem em leito pulso-fluidizado, atomizador - "spray dryer" e em liofilizador) de polpa de maracujá na qualidade do produto final em pó. Todos estes processos visam à obtenção do produto em pó, apresentando vantagens e desvantagens em nível de manuseio e custos. Entretanto, são escassos na literatura estudos que comparem estes processos com foco na qualidade do produto final. O leite desnatado foi utilizado para avaliar sua eficiência na substituição de parte dos aditivos comumente utilizados na produção deste tipo de produto, como, por exemplo, a maltodextrina e a goma Arábica, os quais têm como função a diminuição das dificuldades tecnológicas encontradas na secagem de sucos de frutas e outros produtos com alta quantidade de açúcar devido à higroscopicidade, termoplasticidade e capacidade de caramelização. Inicialmente, realizaram-se as análises físico-químicas da polpa de maracujá e do leite desnatado, onde foram obtidos resultados muito próximos aos da literatura, sendo que as pequenas diferenças obtidas foram atribuídas à variedade do maracujá utilizado, época e local de cultivo e no caso do leite em pó desnatado, devido provavelmente às diferentes marcas comerciais analisadas na literatura. A secagem da polpa de maracujá sem aditivos, em diversas condições operacionais, levou a um rendimento praticamente nulo, fazendo com que o processo fosse considerado inviável nestas condições. Conseguiu-se obter o pó com a polpa de maracujá e os aditivos no secador por atomização ("spray dryer"). Utilizando a maltodextrina como aditivo, o maior rendimento (23.32%) obtido foi para a proporção de 1:4:4 (polpa de maracujá:maltodextrina:leite desnatado) ou seja, 50% dos sólidos de aditivo substituído por leite desnatado... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The aim of this research was to study the influence of different drying methods (pulsed fluid bed dryer, spray dryer and freeze dryer) of passion fruit pulp in the quality of final powder product. All these processes have the purpose to obtain a powder product, showing advantages and disadvantages in terms of handmade and costs. Nonetheless, the literature has a few studies related to comparison between these processes, focusing final product quality. Skim milk was utilized to evaluate its efficiency on partial substitution of additives commonly used in this kind of processes like maltodextrin and Arabic gum, which have the function of minimizing technologies difficulties in drying fruit juices and other products with high quantity of sugar due to hygroscopicity and termoplasticity in high temperatures and humidity. Initially, physicochemical analysis of passion fruit pulp and skim milk showed values close to those described by literature, with little differences due to passion fruit varieties used, time and place of culture. For skim milk the differences can be explain due to existence of a lot of commercial marks. Drying of passion fruit pulp without additives in many operations conditions had a small yield, becoming process impracticable in these conditions. It was obtained powdered passion fruit and additives in spray dryer. Using maltodextrin the greater yield (23.32%) was obtained for 1:4:4 ratio (passion fruit pulp:maltodextrin:skim milk) that is 50% of solids from additives substituted by skim milk. To Arabic gum the best results (21.96%) was obtained to 1:2:6 (passion fruit pulp:Arabic gum:skim milk) with 75% of solids from additives substituted by skim milk. The total substitution of additives (maltodextrin or Arabic gum) by skim milk also showed good results (15.5%). These better yield were obtained in 120°C and feed flow 0.4 l/h considering ratio of pulp... (Complete abstract click electronic access below)
Orientador: Javier Telis Romero
Coorientador: Carmen Sílvia Fávaro Trindade
Banca: João Borges LAurindo
Banca: Célia Maria Landi Franco
Mestre

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Este projeto teve como objetivo estudar a influência de diferentes processos de desidratação (secagem em leito pulso-fluidizado, atomizador – “spray dryer” e em liofilizador) de polpa de maracujá na qualidade do produto final em pó. Todos estes processos visam à obtenção do produto em pó, apresentando vantagens e desvantagens em nível de manuseio e custos. Entretanto, são escassos na literatura estudos que comparem estes processos com foco na qualidade do produto final. O leite desnatado foi utilizado para avaliar sua eficiência na substituição de parte dos aditivos comumente utilizados na produção deste tipo de produto, como, por exemplo, a maltodextrina e a goma Arábica, os quais têm como função a diminuição das dificuldades tecnológicas encontradas na secagem de sucos de frutas e outros produtos com alta quantidade de açúcar devido à higroscopicidade, termoplasticidade e capacidade de caramelização. Inicialmente, realizaram-se as análises físico-químicas da polpa de maracujá e do leite desnatado, onde foram obtidos resultados muito próximos aos da literatura, sendo que as pequenas diferenças obtidas foram atribuídas à variedade do maracujá utilizado, época e local de cultivo e no caso do leite em pó desnatado, devido provavelmente às diferentes marcas comerciais analisadas na literatura. A secagem da polpa de maracujá sem aditivos, em diversas condições operacionais, levou a um rendimento praticamente nulo, fazendo com que o processo fosse considerado inviável nestas condições. Conseguiu-se obter o pó com a polpa de maracujá e os aditivos no secador por atomização (“spray dryer”). Utilizando a maltodextrina como aditivo, o maior rendimento (23.32%) obtido foi para a proporção de 1:4:4 (polpa de maracujá:maltodextrina:leite desnatado) ou seja, 50% dos sólidos de aditivo substituído por leite desnatado...
The aim of this research was to study the influence of different drying methods (pulsed fluid bed dryer, spray dryer and freeze dryer) of passion fruit pulp in the quality of final powder product. All these processes have the purpose to obtain a powder product, showing advantages and disadvantages in terms of handmade and costs. Nonetheless, the literature has a few studies related to comparison between these processes, focusing final product quality. Skim milk was utilized to evaluate its efficiency on partial substitution of additives commonly used in this kind of processes like maltodextrin and Arabic gum, which have the function of minimizing technologies difficulties in drying fruit juices and other products with high quantity of sugar due to hygroscopicity and termoplasticity in high temperatures and humidity. Initially, physicochemical analysis of passion fruit pulp and skim milk showed values close to those described by literature, with little differences due to passion fruit varieties used, time and place of culture. For skim milk the differences can be explain due to existence of a lot of commercial marks. Drying of passion fruit pulp without additives in many operations conditions had a small yield, becoming process impracticable in these conditions. It was obtained powdered passion fruit and additives in spray dryer. Using maltodextrin the greater yield (23.32%) was obtained for 1:4:4 ratio (passion fruit pulp:maltodextrin:skim milk) that is 50% of solids from additives substituted by skim milk. To Arabic gum the best results (21.96%) was obtained to 1:2:6 (passion fruit pulp:Arabic gum:skim milk) with 75% of solids from additives substituted by skim milk. The total substitution of additives (maltodextrin or Arabic gum) by skim milk also showed good results (15.5%). These better yield were obtained in 120°C and feed flow 0.4 l/h considering ratio of pulp... (Complete abstract click electronic access below)

L'amélioration de la dissolution des médicaments peu solubles présente de nombreux défis.Dans cette thèse, un procédé d'extrusion-sphéronisation a été étudié en profondeur pour améliorer la dissolubilité du médicament avec une formulation de nano-émulsion. Le but du travail de thèse est de décrire les propriétés et les procédés de fabrication de minigranules permettant d'augmenter la solubilité des principes actifs peu solubles dans l'eau et donc d‘améliorer leur biodisponibilité lors de l'administration par voie orale, pour deux modèles de molécules différentes qui sont l‘acide folique (vitamine peu soluble dans l'eau) et le kétoprofène (anti-inflammatoire non stéroïdien qui présente une solubilité limitée dans les fluides gastriques à cause de son pKa (classe II dans le système de classification biopharmaceutique – BCS, ayant une action anti-inflammatoire, antalgique et antipyrétique). Cette étude décrit la préparation par extrusion-sphéronisation, caractérisation et étude de dissolution in vitro d'acide folique et de pastilles de kétoprofène revêtues de Acryl-EZE®, Advantia® Performance dans un minicoatère à lit fluidisé. Les résultats des essais ont montré la faisabilité de la préparation de pastilles enrobées entériques contenant un AINS et que, en revêtant le système multiparticulaire avec Acryl-EZE® 93A92545 et Advantia® Performance190024HA49 à un gain pondéral de 17,5%, 12,0%, respectivement, du médicament à partir des pastilles peuvent être obtenus. Les résultats des essais de dissolution ont indiqué que dans un milieu acide, le revêtement de film a entraîné un retard dans la libération du médicament, alors qu'aucun retard n'a été observé dans un milieu tampon à pH 6,8
Improvement in dissolution of poorly soluble drugs has many challenges.In this thesis, an extrusion-spheronization process was thoroughly studied forimproving dissolubility of drug with nano-emulsion formulation.The aim of the thesis work is to describe the properties and manufacturing processes ofpellets to increase the solubility of poorly soluble active ingredients in water and thus improvetheir bioavailability when administered orally: folic acid (water-insoluble vitamin) andketoprofen (Non-steroidal anti-inflammatory, having anti-inflammatory, analgesic andantipyretic action, class II in the Biopharmaceutical Classification System).This study describes the preparation by extrusion-spheronization, characterisation andin vitro dissolution study of folic acid and ketoprofen pellets. Ketoprofen pellets coated withAcryl-EZE®, Advantia® Performance in a fluid-bed minicoater. The results of the tests showedthe feasibility of the preparation of enteric-coated pellets containing a NSAID and that bycoating the multiparticulate system with either 17.5% Acryl-EZE® 93A92545 or with 12%Advantia® Performance 190024HA49 weight gain, an enteric release of the drug from thepellets can be obtained. The results of dissolution testing indicated that in acidic media, entericfilm coating resulted in a delay in the release of the drug, while no delay was observed in pH6.8 buffer media

The U.S. Food and Drug Administration has accepted the guidelines put forth by the International Conference on Harmonization (ICH-Q8) that allow for operational flexibility within a validated design space. These Quality by Design initiatives have allowed drug manufacturers to incorporate more rigorous scientific controls into their production streams.
Fully automated control systems can incorporate information about a process back into the system to adjust process variables to consistently hit product quality targets (feedback control), or monitor variability in raw materials or intermediate products to adjust downstream manufacturing operations (feedforward control). These controls enable increased process understanding, continuous process and product improvement, assurance of product quality, and the possibility of real-time release. Control systems require significant planning and an initial investment, but the improved product quality and manufacturing efficiency provide ample incentive for the expense.
The fluid bed granulation and drying unit operation was an excellent case study for control systems implementation because it is a complex unit operation with dynamic powder movement, high energy input, solid-liquid-gas interactions, and difficulty with scale-up development. Traditionally, fluid bed control systems have either used first principle calculations to control the internal process environment or purely empirical methods that incorporate online process measurements with process models. This dissertation was predicated on the development of a novel hybrid control system that combines the two traditional approaches.
The hybrid controls reduced the number of input factors for the creation of efficient experimental designs, reduced the variability between batches, enabled control of the drying process for a sensitive active pharmaceutical ingredient, rendered preconditioned air systems unnecessary, and facilitated the collection of data for the development of process models and the rigorous calculation of design spaces. Significant variably in the inlet airstream was able to be mitigated using feedforward controls, while process analytical technology provided immediate feedback about the process for strict control of process inputs. Tolerance surfaces provided the ideal tool for determining design spaces that assured the reduction of manufacturing risk among all future batches, and the information gained using small scale experimentation was leveraged to provide efficient scale-up, making these control systems feasible for consistent use.
Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences
Pharmaceutics
PhD
Dissertation

碩士
東海大學
高階經營管理碩士在職專班
106
Title of Thesis: A Study of Fluid Bed Dryer for Pharmaceutical Drugs Drying Name of Institute: Tunghai University Executive Master of Business Administration Program Graduation Time: 06 / 2018 Student Name: Mou-Kuan Lee Advisor Name: Pu-Tai Yang Abstract: This paper discusses the use of fluidized bed dryer for pharmaceutical manufacturing in imperfect drying conditions. This study found that the general drying process without humidity control could reduce manufacturing time, but the results are not qualified. The current drying process yields granules with inconsistent dryness. As a result, the productivity and quality are affected. In this study, drug substance can be fully controlled with regulated ambient temperature and humidity. When the ideal drying conditions are achieved, the production becomes more cost- effective. Conditions with significant improvements in granulation are as follows: 1. For wet organic solvent granulation, the target drying temperature should be set slightly higher than its surrounding temperature. 2. For water granulation, the target drying temperature should be set as approximately 60 °C. Keywords: Fluid Bed Dryer, Organic Solvents, Semi-Finished Products, Water Content.

碩士
國立中興大學
食品暨應用生物科技學系所
100
In the the process, consistent, and precise control of the fluid bed granulation technology is inevitable, and this was the only way to build the model and understand the mechanism. unfortunately, fluid bed granulation technology has still more like the art than science. Therefore, this study takes apart to two parts. First part uses FTIR, thermo-analysis and texture analysis to study the physicochemical properties and the gelling mechanism of binder. Second part uses different operational parameters to describe and establish the model, mechanism and physico-chemical properties. The operational parameters is in the following. (1) different powder type, water caltrop hull powder and corn starch, (2) different initial quantity in the chamber, 700, 1000 and 1300 g, (3) binder concentration 3, 4 and 5 % (pectin, w/w), (4) spray binder flow rate, 5, 10 and 15 rpm, (5) inlet air temperature 50, 60 and 70 ℃. The first research results showed that pectin and CMC have good thermostability (slope = 0.23, 0.23, 0.23 and slope = 0.95, 1.01, 1.05). It is the same thermostability with corn starch and better than tapioca starch. Moreover, pectin is better than CMC. We choose the pectin as a binder in the second part. The second research results showed that the mean nucleation size of granulation made by water caltrop hull is 35 ~ 37 μm. It is the same with granulation made by corn starch (35 ~ 37 μm). With increasing granulation time, the particle size distribution tend to showing the peak at 260 ~ 270 μm and 490 ~ 500 μm until the balance in the granulation system. The feeding amount of the initial powder changes the effective pore radius (Rpore). It results to chang the theoretical droplet penetration time (τd). It decreased the dimensionless spray flux (Ψa) with increasing the feeding amount of the initial powder. The concentration and feeding rate of binder change the viscosity, stickiness and the cosine of contact angle. We prove that the surface tension and cosine of contact angle are important, too. Different inlet air temperature change the drying time of binder. It results to make a weak nucleation structure causing the insufficienct for forming time of liquid bridge. In this study, the best condition is in the following. (1) water caltrop hull powder is beter than corn starch, (2) 700 g feeding amount of water caltrop hull powder, (3) 4 % binder concentration, (4) 15 rpm of binder spraying rate, (5) 60 ℃ inlet air temperature. It is hoped that the research results can be used as research references for the multiple applications in the fluid bed granulation industry.

The fluid bed granulation is a well-established method how to improve such properties of powders as flowability and increase content uniformity of the tablets. In this thesis, there was evaluated a granulation process on a lab scale fluid Glatt bed granulator and optimized for highest possible yield. Product yield in the size range of 80-90 % of granules and process reproducibility were stated as most effective. The product was analysed for its particle size distribution, the API distribution within the different particle size fractions and the flowability of the final granules. For process optimization, the most critical parameters such as spraying rate, particle size of raw materials and fluid bed pressure were identified and evaluated. As the highest-yielding dosage for the powder binder was found the spraying rate of 9 g/min. Changes in bed fluid pressure and nozzle pressure showed no significant improvement. Different grades of caffeine were compared for their impact on the granulation properties. Sieved caffeine enhanced yield of the product and reproducibility compared to bulk or disagglomerated caffeine.

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

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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.