Au cours de cette étude du procédé de granulation humide, nous avons mis l’accent sur l’intérêt que présente la distribution du liquide de mouillage dans la définition des propriétés finales de grains. Dans ce cadre, une méthode utilisant un traceur a été développée pour le suivi cinétique de la répartition du liquide de mouillage au cours de la granulation. Une formulation à base d’excipent pharmaceutique a été granulée dans un mélangeur-granulateur à haut cisaillement Mi-Pro. On a pu ainsi montrer que le début du procédé est caractérisé par l’hétérogénéité de la distribution du liquide de mouillage qui se redistribue ensuite selon une loi cinétique d’ordre un. Les propriétés des grains (taille, porosité et observation microscopique) ne deviennent uniformes qu’après une répartition homogène du liquide de mouillage entre les différentes classes de grains. L’étude de l’influence de certaines variables opératoires (vitesse d’agitation, débit et critère de mouillabilité) sur le phénomène de redistribution a été également menée. Par ailleurs, les bilans de population ont été utilisés comme outil de modélisation. Des écritures du noyau d’agglomération ont été proposées en se basant sur la taille des particules et leur teneur en liquide de mouillage. Bien que reproduisant les résultats expérimentaux, les bilans de population présentent certaines limites liées à la difficulté d’intégrer toutes les données de l’étude / In this study of wet granulation process, we are especially interested in binder liquid distribution as a mean to deduce final granule properties. Then, a tracer method is developed to study binder liquid distribution kinetics during granulation process. Granulation experiments are carried out in high shear mixer Mi-Pro using pharmaceutical excipients. The beginning of the process is characterized by heterogeneous binder liquid distribution. Then, liquid redistribution phenomenon is observed according to a first order model. Granule properties (size, porosity, microscopic observation) are found to be similar when binder liquid is homogeneously distributed among different granule classes. Finally operating conditions influence (speed rate, flow rate and wetting criterion) are discussed. In addition, population balances are used as a tool to model experimental results. Agglomeration kernels are presented depending on particle size and binder liquid ratio. Although experimental results could be satisfactorily modelled, population balances show some limitations related to the difficulty of integrating all the study data

Os fármacos pertencentes às classes II e IV do sistema de classificação biofarmacêutica são aqueles sujeitos a problemas relacionados com a sua biodisponibilidade. Um dos procedimentos utilizados para melhorar a solubilidade de fármacos pouco solúveis é a granulação com materiais lipídicos ou cerosos. Para aumentar a solubilidade da carbamazepina, fármaco de classe II, ou seja, que apresenta baixa solubilidade e alta permeabilidade, inicialmente esta foi associada com os excipientes Gelucire® 50/13 ou Polietilenoglicol 6000, através de uma mistura física ou dispersão sólida. Estas associações foram submetidas a procedimentos analíticos como DSC, Infravermelho, Difração de Raios-X e teste de solubilidade em água. Nas misturas físicas a carbamazepina permaneceu estável, porém nas dispersões sólidas houve o aparecimento de polimorfismo. No entanto estes polimorfos também apresentam atividade terapêutica. As misturas físicas e as dispersões sólidas foram submetidas ao teste de solubilidade e as amostras que continham Gelucire® 50/13 aumentaram em torno de 15 vezes a solubilidade da carbamazepina em água, enquanto que as amostras que continham Polietilenoglicol 6000 aumentaram em torno de 14 vezes. Optou-se pela utilização do PEG 6000 devido à melhor compatibilidade deste com o equipamento utilizado. A granulação por Hot Melt em leito fluidizado foi realizada após alguns ensaios de fluidodinâmica utilizando a lactose spray dried como substrato. Durante os experimentos as condições do processo permaneceram estáveis e a curva característica foi típica de leito fluidizado. Os granulados foram obtidos utilizando o planejamento fatorial Box Behnken cujos fatores estudados foram: vazão de dispersão sólida, quantidade de dispersão sólida e pressão de atomização e em seguida caracterizados e avaliados. A maioria das propriedades físicas e farmacotécnicas dos granulados foi dependente da quantidade de dispersão sólida. A utilização do método de granulação por fusão em leito fluidizado melhorou o perfil de dissolução das cápsulas contendo os granulados, sendo que com o maior nível da quantidade de dispersão sólida houve um aumento significante na quantidade de carbamazepina liberada. Os resultados mostram que esta técnica é relevante para preparar dispersões sólidas com fármacos que apresentam baixa biodisponibilidade devido a sua baixa solubilidade. / Drugs belonging to classes II and IV in the biopharmaceutical classification system are those having bioavailability problems. Granulation with waxy lipids is one of the procedures used to improve the solubility of poorly soluble drugs. To increase the solubility of carbamazepine a drug of class II that has low solubility but high permeability, its association with the excipients Gelucire® 50/13 or Polyethylene 6000, was done by physical mixtures or solid dispersions. The associations were subjected to analytical procedures such as Differential Scanning Calorimetry (DSC), infrared light, X-ray diffraction and tests of solubility in water. In physical mixtures carbamazepine remained stable, but showed different polymorphic forms in solid dispersions. However, the polymorphic forms were also therapeutically active.Solubility tests of physical mixtures and solid dispersions indicated that samples containing Gelucire ® 50 / 13 increased the solubility of carbamazepine in water about 15 times, while the ones containing Polyethylene glycol 6000 had an increase of about 14 times. PEG 6000 was the chosen carrier due to its better compatibility with the equipment used.Fluid dynamic tests using spray dried lactose as a substrate were preliminary to the granulation experiments in the fluidised bed. The process conditions remained stable during the experiments and the characteristic curve tracing was typical of fluidised beds. Granules were obtained in experiments that followed a Box Behnken factorial design, where the factors studied were: flow rate of the solid dispersion, amount of solid dispersion and atomization pressure .Most physical and technical granule properties were dependent on the quantity of solid dispersion. The method of granulation by hot melt in a fluidised bed improved the solubility profile of carbamazepine in granule containing capsules.Granules containing the highest amount of solid dispersion showed a significant increase in the amount of carbamazepine released. The results proved that this technique is relevant to the preparation of solid dispersions with low bioavailable drugs due to their poor solubility.

"December 2009" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on January 5, 2010). Thesis advisor: David A. Wilson. Includes bibliographical references.

Os fármacos pertencentes às classes II e IV do sistema de classificação biofarmacêutica são aqueles sujeitos a problemas relacionados com a sua biodisponibilidade. Um dos procedimentos utilizados para melhorar a solubilidade de fármacos pouco solúveis é a granulação com materiais lipídicos ou cerosos. Para aumentar a solubilidade da carbamazepina, fármaco de classe II, ou seja, que apresenta baixa solubilidade e alta permeabilidade, inicialmente esta foi associada com os excipientes Gelucire® 50/13 ou Polietilenoglicol 6000, através de uma mistura física ou dispersão sólida. Estas associações foram submetidas a procedimentos analíticos como DSC, Infravermelho, Difração de Raios-X e teste de solubilidade em água. Nas misturas físicas a carbamazepina permaneceu estável, porém nas dispersões sólidas houve o aparecimento de polimorfismo. No entanto estes polimorfos também apresentam atividade terapêutica. As misturas físicas e as dispersões sólidas foram submetidas ao teste de solubilidade e as amostras que continham Gelucire® 50/13 aumentaram em torno de 15 vezes a solubilidade da carbamazepina em água, enquanto que as amostras que continham Polietilenoglicol 6000 aumentaram em torno de 14 vezes. Optou-se pela utilização do PEG 6000 devido à melhor compatibilidade deste com o equipamento utilizado. A granulação por Hot Melt em leito fluidizado foi realizada após alguns ensaios de fluidodinâmica utilizando a lactose spray dried como substrato. Durante os experimentos as condições do processo permaneceram estáveis e a curva característica foi típica de leito fluidizado. Os granulados foram obtidos utilizando o planejamento fatorial Box Behnken cujos fatores estudados foram: vazão de dispersão sólida, quantidade de dispersão sólida e pressão de atomização e em seguida caracterizados e avaliados. A maioria das propriedades físicas e farmacotécnicas dos granulados foi dependente da quantidade de dispersão sólida. A utilização do método de granulação por fusão em leito fluidizado melhorou o perfil de dissolução das cápsulas contendo os granulados, sendo que com o maior nível da quantidade de dispersão sólida houve um aumento significante na quantidade de carbamazepina liberada. Os resultados mostram que esta técnica é relevante para preparar dispersões sólidas com fármacos que apresentam baixa biodisponibilidade devido a sua baixa solubilidade. / Drugs belonging to classes II and IV in the biopharmaceutical classification system are those having bioavailability problems. Granulation with waxy lipids is one of the procedures used to improve the solubility of poorly soluble drugs. To increase the solubility of carbamazepine a drug of class II that has low solubility but high permeability, its association with the excipients Gelucire® 50/13 or Polyethylene 6000, was done by physical mixtures or solid dispersions. The associations were subjected to analytical procedures such as Differential Scanning Calorimetry (DSC), infrared light, X-ray diffraction and tests of solubility in water. In physical mixtures carbamazepine remained stable, but showed different polymorphic forms in solid dispersions. However, the polymorphic forms were also therapeutically active.Solubility tests of physical mixtures and solid dispersions indicated that samples containing Gelucire ® 50 / 13 increased the solubility of carbamazepine in water about 15 times, while the ones containing Polyethylene glycol 6000 had an increase of about 14 times. PEG 6000 was the chosen carrier due to its better compatibility with the equipment used.Fluid dynamic tests using spray dried lactose as a substrate were preliminary to the granulation experiments in the fluidised bed. The process conditions remained stable during the experiments and the characteristic curve tracing was typical of fluidised beds. Granules were obtained in experiments that followed a Box Behnken factorial design, where the factors studied were: flow rate of the solid dispersion, amount of solid dispersion and atomization pressure .Most physical and technical granule properties were dependent on the quantity of solid dispersion. The method of granulation by hot melt in a fluidised bed improved the solubility profile of carbamazepine in granule containing capsules.Granules containing the highest amount of solid dispersion showed a significant increase in the amount of carbamazepine released. The results proved that this technique is relevant to the preparation of solid dispersions with low bioavailable drugs due to their poor solubility.

La recherche s’appuie pour une grande part sur le développement de nanomatériaux. Ceux-ci constituent, en effet, les matières premières des nanosciences et ouvrent à l’industrie des perspectives extrêmement larges. Le développement des céramiques nécessite une grande maîtrise des procédés d'élaboration qui permettent d'obtenir des microstructures appropriées à l’élaboration de matériaux denses pour différentes applications par exemple biomédicales. Les évolutions récentes concernent les matériaux hybrides et bio-inspirés ; les problèmes de mise en forme et de structuration multi-échelles de ces derniers incitent au développement de nouveaux procédés telle que l’approche nouvelle dite ascendante (bottom-up) consistant à fabriquer un matériau à échelle microscopique voir macroscopique à partir de ses particules nanométriques.Dans ce contexte, les travaux de cette thèse ont pour objectif de faciliter, par l’intermédiaire d’une modification de surface, la mise au point d’une technique de mise en forme originale pour l’élaboration de céramiques issues d’un matériau nanométrique de type oxyde: la granulation par coagulation. Nous nous sommes intéressés au cas d’une nanopoudre de boehmite (AlO(OH)). Cependant, cette poudre nanométrique de boehmite présente de multiples instabilités en suspension. En effet, cette poudre est soumise à de fortes gélifications en fonction du pH et à basse concentration. Il est nécessaire dans ce cas pour obtenir une suspension stable de modifier les propriétés de surface. En conséquence, une partie de ces travaux est consacrée à la fonctionnalisation de surface par des organosilanes. Cette modification de surface n’est cependant qu’une étape à l’obtention d’une particule hybride constituée d’un cœur de boehmite et d’une couche polymérique. En réalité, le greffage d’organosilane à la surface permet de créer un pont entre la partie centrale inorganique et la partie externe organique constituée de latex pouvant se lier à l’organosilane utilisé (le MPS).Le matériau hybride boehmite-MPS-latex ainsi obtenu peut être utilisé dans une nouvelle technique de mise en forme colloïdale inspirée de la granulation par hétérocoagulation. En milieu aqueux, la polarité opposée des charges de surfaces de deux entités différentes conduit à l’hétérocoagulation en suspension. La coagulation observée dans cette thèse, met en relation deux particules identiques possédant chacune, les deux charges opposées à leur surface. Le principe de la granulation consiste à induire, sous l’effet d’un mouvement de rotation des échantillons, la coalescence des agglomérats en forçant leurs surfaces à interagir par contacts réciproques. En sélectionnant la formulation, la coalescence conduit à l'élaboration d'objets sphériques homogènes en taille et en forme. / Research in this field is multidisciplinary and relies largely on the development of nanomaterials. These are, in fact, the raw materials of nanoscience and open to industry extremely broad prospects. In the field of material sciences, nanostructured materials, among them nanostructured ceramics have grown considerably in recent years. Development of ceramic requires a mastery of production processes that achieve appropriate microstructures in the development of dense materials for various applications such biomédicals. Recent developments include hybrid and bio-inspired materials; the problems of shaping and multi-scale structure of these encourage the development of new processes such as the new so-called bottom-up approach of manufacturing and make macroscopic material from its nanoparticles. In this context, the work of this PhD aim to facilitate, through surface modification, the development of an original layout technique for the development of ceramics from a material nano-oxide type: granulation coagulation. We were interested in the case of a boehmite nanopowder (AlO(OH)). However, this nanoscale boehmite powder has many instabilities in suspension. Indeed, the powder is subjected to strong gelation as function of pH and at low concentrations. It is necessary in this case to obtain a stable suspension by modifying the surface properties. Accordingly, a part of this work is devoted to surface functionalization by organosilanes. This surface modification, however, is only one stage to obtain a hybrid particle comprised of a heart of boehmite and a polymeric layer. In reality, the grafting organosilane (MPS) at the surface permit to create a bridge between the inorganic core and organic outer part consists of latex. The boehmite-MPS-latex hybrid material thus obtained can be used in a new colloidal shaping technique inspired by heterocoagulation granulation. In aqueous medium, the opposite polarity of the charges of the surfaces of two different entities leads to heterocoagulation in suspension. Clotting observed in this thesis, connects two identical particles with each, the two charges opposite to the surface. The principle of the granulation is to induce, under the effect the rotational movement, the coalescence of the agglomerates by forcing their surfaces to interact by mutual contact. By selecting the formulation, coalescence leads to the development of homogeneous spherical objects in size and shape.

La fabrication d’un médicament sous forme de comprimés à base d'une plante fraîche reste actuellement encore un véritable enjeu et ce, à cause de la variabilité qui peut exister dans les différents lots d'extraits de plantes ainsi qu’à la limite imposée par les techniques de fabrication de comprimés existantes actuellement. Différents problèmes rencontrés avec la formulation actuelle de ce type de comprimés ont été observés tels que : les propriétés physiques du comprimé (très faible dureté des comprimés et temps de désagrégation assez long), goût désagréable, grande variabilité (variabilité de l'extrait sec) et mauvaise stabilité de la substance médicamenteuse. Des observations antérieures ont indiqué que la stabilité de la substance médicamenteuse dans les comprimés d'Echinacea purpurea ainsi que le goût peuvent être améliorés en la mélangeant avec de la bêta-cyclodextrine (β-CD). Dans la thèse de doctorat, une formulation actuelle commercialisée de comprimés d’Echinacea purpurea a été réalisée par la technique de la granulation par voie humide, avec un mélangeur à cisaillement élevé. Dans la formulation, presque la totalité de l'excipient (lactose monohydraté) est mouillé par le concentré d'Echinacea purpurea. Afin de réduire la quantité d'excipients à granuler et à sécher et d’obtenir un produit avec moins cher des couts de matériaux premières, un procédé de granulation classique a été proposé où seulement une fraction de la quantité totale de charge (cellulose microcristalline (MCC)) est utilisée pour la granulation et le séchage; le reste de la charge (sorbitol) est ajouté après la granulation. Ce granulat peut servir de matériau de base des différents comprimés. Dans les différentes expérimentations réalisées, la teinture d’Echinacea purpurea a été utilisée comme modèle pour l'optimisation de la fabrication des comprimés à base de plantes. L'objectif de la thèse était par conséquent de développer une nouvelle formulation de comprimés d’Echinacea purpurea en utilisant un procédé de granulation classique. Avec une meilleure maîtrise de la granulation humide (WGP) et son influence sur les propriétés physiques des comprimés, ceux-ci doivent être optimisés du point du vue de la stabilité de l'ingrédient actif qui se présente sous forme solide (alkylamides) et des propriétés physiques des comprimés, en particulier le taux de dissolution et les propriétés physiques des comprimés. / One current formulation of Echinacea tablets which is examined in the present thesis is to produce tablets in a wet granulation process (WGP) with a high shear mixer. During the manufacturing, almost the whole amount of the excipient (lactose monohydrate) is wetted by Echinacea purpurea concentrate. In order to reduce the amount of excipients being granulated and dried by a basis granulate method was proposed where only a fraction of the total amount of filler (Microcrystalline cellulose, MCC) is used for granulation and drying, the rest of the filler (sorbitol) is added after granulation. This granulate can serve as basis material for different tablets.Purpose: in the PhD thesis, tablets containing Echinacea purpurea tincture were used as a model for the optimization of herbal tablets. The aim of the dissertation was to develop a new Echinaforce formulation based on the “Basis Granulate” technology. With deeper understanding of the WGP and its influence on the physical tablet properties, the new Echinaforce tablets should be optimized in term of cost of goods, taste of tablets, stability of the active ingredient in solid forms (alkylamides) and the physical tablet properties of Echinaforce tablets, especially the dissolution rate and the compaction properties of the final tablet.

Certains procédés de production d’énergie nécessitent l’utilisation de poudres de biomasse, par exemple la gazéification en réacteur à flux entraîné (RFE). Cependant, les poudres de biomasse ont une mauvaise coulabilité. L’objectif de cette thèse est d’étudier leurs propriétés d’écoulement dans le contexte de la gazéification en RFE, à l’échelle du laboratoire et à l’échelle pilote. A l’échelle du laboratoire, des mesures en tambour rotatif, des tests de cisaillement et des mesures de densité ont été effectués. D’une part, une corrélation est mise en évidence entre la cohésion (issue des tests de cisaillement), la densité et l’angle d’avalanche (tiré des mesures en tambour). Ainsi, un paramètre difficile à obtenir comme la cohésion peut l’être à partir de mesures simples. D’autre part, l’influence de l’humidité sur la coulabilité des poudres de biomasse a été évaluée. L’humidité n’a pas d’effet significatif sous 15 % (en masse, base humide), car l’eau est adsorbée dans la structure de la biomasse ; les particules gonflent et ne sont pas liées par des ponts liquides. Un procédé de granulation humide est proposé. Un liant issu de déchets de biomasse est ajouté à la poudre pour former des granulés d’environ 1 mm. Leur forme sphérique diminue l’entrelacement des particules et leur faible polydispersité diminue le nombre de points de contact. Une amélioration de l’écoulement est observée à l’échelle labo. Une étude énergétique montre que la consommation énergétique du procédé peut descendre jusqu’à 12% du pouvoir calorifique inférieur, ce qui suggère une potentielle rentabilité économique du procédé. Enfin, la caractérisation à l’échelle supérieure est effectuée dans un pilote reproduisant l’injection en RFE. Les résultats montrent le rôle essentiel de la sphéricité et d’une faible polydispersité des particules. L’effet positif de la torréfaction et de la granulation sur la coulabilité est mis en évidence. / Some power generation processes require the biomass to be finely ground, such as biomass gasification in entrained flow reactors. However, fine biomass powders are cohesive and present flow issues. This thesis aims to study the biomass powder flowability in the context of the entrained flow gasification process. Biomass powders are characterized both at laboratory scale and pilot scale. Characterization at lab scale consisted of rotating drum measurements, shear tests and density measurements. First, a correlation is found between the cohesion (derived from shear tests), the powder density and the avalanche angle (derived from the rotating drum measurements). Thus, parameters difficult to get such as the cohesion can be obtained with easy to perform measurements. Then, the influence of moisture content on wood powder flowability has been assessed. No significant effect of the water content is found below 15 wt% (wet basis). Below 15%, as water is adsorbed in the biomass structure, the particles swell without being linked by liquid bridges. A wet granulation method is proposed. Biomass waste binders are added to the powder to form granules around 1 mm. The spherical shape lowers the interlocking phenomenon. The low size dispersity of the grains decreases the number of contact points between particles. An improvement of the flowability at lab scale is observed. An energetic study of the granulation process is proposed, showing the energy consumption can be as low as 12% of the biomass Lowest Heating Value. Thus, the process is potentially economically profitable. Finally, characterization at pilot scale is performed with a device mimicking the injection in an entrained flow reactor. The results show the essential roles in the injection step of both the spherical shape and the narrow size distribution of the particles. The positive effect of torrefaction and granulation on the flowability is highlighted.

Continuous wet granulation using a twin-screw extruder has attracted considerable attentions in pharmaceutical industry as it ensures consistent tablet quality at a high production rate. However, challenge still exists in controlling desired granule properties especially when different sized twin-screw granulators are used. This study therefore explored the potential of scalability of two sized twin-screw extruders and the how raw materials affect granules properties in two twin-screw extruders. The first study focuses on aspects of scaling using two twin-screw extruders, 18mm and 27mm. Dimensionless groups including Fr Number, Powder Feed Number and Degree of Fill (<30%) were studied to observe their influences on granule attributes. It was found that these dimensionless groups demonstrated inconsistent effects on granule properties and the effect of Powder Feed Number was highly dependent on Degree of Fill. Different extruder still exerts significant impact on granule properties. A scaling rule was established for median granule size (d50) only, but only moderate degree of fit was found. Although a considerable number of studies have been published on controlled-release and extended-release excipients, little attentions have been given to the influence of microcrystalline cellulose (MCC) grades in twin-screw wet granulation. The second study therefore investigated the processability of five grades MCC from the Avicel® PH family using two twin-screw extruders again, 18mm and 27mm. Granule attributes including particle size, density, moisture, and strength were tested and it was found that MCC inherent density has the most significant impact on granule properties while particle size of MCC has minor positive effect on granule size. This study also concluded that better granule flowability and uniformity can be achieved by using low moisture, larger particle size and high density MCC as excipients. / Thesis / Master of Applied Science (MASc)

published_or_final_version / Civil Engineering / Doctoral / Doctor of Philosophy

O presente estudo teve como objetivo principal identificar as condições necessárias para a formação de lodo granular aeróbio em um reator de bateladas sequenciais, desenvolvendo uma estratégia de partida para obter a granulação e também avaliando as propriedades morfológicas do lodo formado. Ao longo da pesquisa, também foram avaliados os resultados que podem ser alcançados mediante a aplicação deste tipo de tratamento para esgoto universitário, em termos de remoção de matéria orgânica, nitrogênio e fósforo. Dividiu-se a pesquisa em duas fases, onde na primeira, desenvolvida no Laboratório de Saneamento da Escola Politécnica, utilizou-se um reator em escala de bancada e na segunda, desenvolvida no Centro Tecnológico de Hidráulica, um reator em escala piloto, ambos operando em bateladas sequenciais e com uma mesma razão altura diâmetro (H/D) de aproximadamente 10. Ambas as fases foram divididas em cinco etapas, cujo critério de divisão foi a redução progressiva do tempo de sedimentação do ciclo da batelada, inicialmente em 30 minutos, na etapa 1, e 5 minutos na etapa 10. Primeiramente, foi operado o reator de bancada por 330 dias, onde alimentou-se o sistema com efluente sintético. Em seguida, o reator piloto foi operado também por aproximadamente 330 dias, o qual foi alimentado com esgoto universitário. A pesquisa pode ser caracterizada como um período de partida para ambas as fases, onde não se obteve uma operação estável dos reatores, não sendo possível atingir um regime estacionário, uma vez que não foi realizado descarte de lodo intencional, devido à alta perda de sólidos com o efluente tratado ao final de cada ciclo. Os resultados mostraram que é possível obter a granulação aeróbia, indicando que as condições essenciais são a hidrodinâmica do reator, ou seja, a forte aeração gerando uma alta força de cisalhamento sobre as partículas e a alimentação de efluente pelo fundo do reator, fazendo com que este escoe em contato com o lodo em um ambiente anaeróbio. A estratégia operacional que envolve redução progressiva do período disponibilizado para a sedimentação do lodo contribui para aumentar a porção de biomassa granular dentro do sistema e assim favorecendo o desenvolvimento e crescimento das partículas granulares maiores e mais pesadas. No final da Etapa I foi pela primeira vez observada à presença de partículas granulares. A morfologia dos grânulos foi avaliada em termos do diâmetro de Feret e circularidade das partículas presentes. Outras propriedades do lodo foram avaliadas, como os índices volumétricos de lodo, sólidos sedimentáveis, as propriedades de remoção de carga orgânica e nutrientes. Os valores de Índice Volumétrico de Lodos (IVL) observados ficaram na faixa tipicamente observada para lodo floculento de boa sedimentabilidade. Ocorreram boas remoções de carga orgânica (DBO solúvel de 87% e DQO solúvel de 82%), assim como a eficiência de remoção de amônia, cuja média na fase I foi de 68%. Também ocorreu desnitrificação, com valores de nitrito e nitrato no efluente tratado com médias de 2,62 e 3,26 mg/L respectivamente. A remoção de fósforo foi avaliada em termos de fósforo solúvel, onde a eficiência média obtida foi de 41%. Observaram-se grânulos cujos diâmetros médios ficaram em torno de 0,3 mm, sendo que a média dos valores máximos de cada Etapa da Fase I foi de 2,3 mm. Com aproximadamente 250 dias de operação surgiram organismos filamentosos aderidos às superfícies dos grânulos formados. O crescimento de tais organismos foi progressivo, primeiramente refletindo na queda do coeficiente de circularidade dos grânulos, conferindo forma mais irregular aos mesmos e depois levando à finalização da operação do reator de bancada aos 330 dias, quando a proliferação acentuada de filamentosos resultou na quebra dos grânulos e desaparecimento destes. Na fase II, operou-se o reator em escala piloto por aproximadamente 330 dias. Nesta fase da pesquisa aplicou-se um fator de carga volumétrica e uma relação alimento-microrganismos menor do que na Fase I, contudo também foi possível observar o início do processo de granulação ainda sob tempos de sedimentação elevados (25 minutos), sendo que a granulação evoluiu ao longo da operação do reator, onde realizou-se a redução progressiva do período de sedimentação do ciclo da batelada. Os diâmetros médios dos grânulos, durante todo esse período, foram de 0,8 mm, sendo que a média dos diâmetros máximos de cada Etapa da Fase II foi de 4,8 mm. Os valores de índice volumétrico de lodo foram baixos, mostrando evolução do processo de granulação, contudo ainda na faixa considerada para lodo floculento, evidenciando ainda a presença de uma parcela considerável da biomassa na forma de flocos. Os resultados obtidos para as velocidades de sedimentação por zona também levaram à mesma conclusão. As propriedades de tratamento do lodo foram monitoradas e os resultados mostraram uma remoção de carga de 91% para DBO solúvel e 88% para DQO solúvel. A remoção de amônia apresentou eficiência média para o período de 50% e a remoção de nitrogênio kjeldahl total foi de 52%. Observaram-se valores baixos de nitritos e nitratos ao longo de toda a segunda fase, indicando a ocorrência de desnitrificação. As remoções de fósforo total e solúvel apresentaram média para o período de 75% e 76%, respectivamente. Não ocorreu proliferação de organismos filamentosos durante a operação do reator piloto. / The present study\'s main objective was to identify the necessary conditions for the formation of aerobic granular sludge in a sequential batch reactor, developing a starting strategy to obtain granulation and also evaluating the morphological properties of the formed sludge. It was also evaluated the aerobic sludge\'s treatment properties in terms of organic matter, nitrogen and phosphorus removal, the main contaminants present in the low strength wastewater fed to the reactor. The research was divided into two phases, where the first one a bench scale reactor was operated and a second one where a pilot scale reactor was used, both in sequential batch mode and with the same height diameter ratio (H/D) ratio of approximately 10. Phase I, (bench scale reactor) lasted for 330 days, and the system was fed with synthetic effluent. Then the pilot reactor was also operated for about 330 days (Phase II), which was fed with low strength wastewater. The research can be characterized as a start-up period for both phases, where a steady state for the reactor was not obtained, once no intentional sludge discharge was performed and an increased suspended solids concentration was observed in the effluent withdrawn at the end of each cycle during all the survey. The results showed that the essential conditions to obtain aerobic granulation are the hydrodynamics/flow patterns inside the reactor, that is, the strong aeration generating a high shear force over the particles surface and the plug flow effluent feed from the bottom of the reactor, in an anaerobic environment. The operational strategy that involves progressive reduction of the batch settling period creates a selective pressure that increases the portion of granular biomass within the system and thus favoring the development and growth of larger and heavier granular particles. At the end of phase I the presence of granular particles was observed for the first time. The morphology of the granules was evaluated in terms of the Feret\'s diameter and the circularity coefficient from the particles present in the sludge. Other properties of the sludge were evaluated, such as the sludge volumetric index, settleable solids and organic load and nutrient removal capacities. The observed values of SVI remained within a range typically correlated for flocculent sludge with good settling properties. Satisfactory organic load removal (87% soluble BOD and 82% soluble COD) was observed, as well as ammonia removal, which average value was around 68%. Denitrification also occurred, once nitrite and nitrate values in the treated effluent were low throughout the bench reactor operation. The removal of phosphorus was evaluated in terms of soluble phosphorus, where the average removal efficiency obtained was 41%. The granules average Feret\'s diameter for all this period was 0.3 mm and the average maximum value for all the stages of the first phase was 2.3 mm. With approximately 250 days of operation, filamentous organisms appeared adhered to the formed granules surfaces. The growth of these organisms was progressive, firstly reflecting in the drop of the circularity coefficient, resulting in a more irregular shape of the granules surface and then leading to the reactor\'s failure at 330 days of operation, when the filamentous overgrowth resulted in the granules breaking and disappearance. In phase II a pilot scale reactor was operated for approximately 330 days. In this phase, a lower volumetric loading factor and food to microorganism feed ratio were applied, compared to Phase I. However, it was also possible to observe the beginning of the granulation process still under high settling periods (25 minutes), with development of the granulation process throughout Phase II, using the same strategy based on the progressive reduction of the batch settling interval. The average Feret\'s diameter during this whole period was 0.8 mm, and the average maximum value for all the stages of the second phase was 4.8 mm. The values of sludge volumetric index decreased indicating evolution of the granulation process, yet still in the range considered for flocculent sludge, evidencing also the presence of a considerable amount of flocculant biomass. The results obtained for settling velocities also led to the same conclusion. The sludge treatment properties were monitored, and the results showed a 91% removal efficiency for soluble BOD and 88% removal efficiency for soluble COD. The average ammonia removal efficiency for the period was 50% and the average total kjeldahl nitrogen removal of 52%. Low nitrite and nitrate values were observed throughout the second phase in the treated effluent, indicating the occurrence of denitrification. The average total and soluble phosphorus removal for the period was 75% and 76%, respectively. No filamentous overgrowth was observed during the pilot reactor operation.