Granulation is an important process for industries ranging from plastics to food and pharmaceutics. In the last decades, the twin-screw extruder has been more and more studied as a continuous method for granulation. But there are many questions remaining to be answered such as the functions of kneading block and the granulation behavior in this zone, the influence of the wetting method, and also the influence of the active pharmaceutical ingredient (API) properties on the granulation process. Therefore, in this project, a series of experiments were performed based on a new technique to the granulation field named ‘screw pullout’ for understanding the granulation process within the twin-screw extruder. In order to understand the specific function of an important screw element known as a kneading block, the physical particle motion reflecting progress of granulation was monitored along the screw. Different feed rate and formulations were studied; the residence time and pressure in kneading block were measured; and the granules along the screw were characterized for their porosity and size distribution. It was found that granule consolidation and breakup within the kneading block allowed the production of granules with consistent properties and excellent mechanical strength. However, the changes produced by a kneading block are dependent upon the formulation. For example, the kneading block demonstrates no observable function with formulations containing a significant content of microcrystalline cellulose. The most notable benefit of the kneading block to all tested materials appeared to be distribution of the interstitial binding liquid rather than to compact the powders. A new wetting method using a foam binder has been studied intensively in this work to assess its influence on the granulation process. A series of studies have been performed to compare the granule development along the screws as powder formulation and screw design were varied to test for the differences induced by the two wetting methods (foam delivery or liquid injection). The evolution of the granules along the screw was characterized by analyzing the particles size distribution, porosity, and fracture strength. It was found that the wetting method had minor impact on the particle size distribution due to the strong mechanical dispersion inherent to the extruder. The major finding for the pharmaceutical industry was that the foam method reduces the required amount of liquid to granulate, thereby dropping drying time after the process. The foamed binder was also found to be preferred when the formulation contains powder components with poor spreading properties. Finally, the influence of an API’s physical properties on granulation was studied by comparing formulations with varying API hydrophobicity. It was found that the API and binder distribution was not affected by the hydrophilicity of API, while the particle size distribution, porosity and fracture strength were strongly dependent on the properties of the API. / Thesis / Master of Applied Science (MASc)

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

Darbo tikslas – parengti augalinės žaliavos granuliavimo ir kapsuliavimo technologiją, atlikti biofarmacinius tyrimus ir panaudojus gautus rezultatus pagaminti eksperimentinę kapsuliuoto produkto seriją. Darbo uždaviniai: Įvertinti karčiojo kiečio augalinių miltelių technologines savybes; Parinkti ir pritaikyti tinkamą granuliavimo technologiją; Atlikti granulių kokybės vertinimą; Pritaikyti augalinės žaliavos kapsuliavimo technologiją; Atlikti kapsulių kokybės vertinimą ir biofarmacinius tyrimus, palyginti ir įvertinti laboratorijoje ir pusiau pramoniniu būdu pagamintų kapsulių kokybės rodiklius. Tyrimo objektas – karčiojo kiečio milteliai ir jų pagrindu pagaminti produktai. Metodai: atliktas karčiojo kiečio miltelių vertinimas, nustatant miltelių birumą, kūgio kampą ir suberiamąjį tankį. Drėgnos granuliacijos būdu pagamintoms granulėms nustatytas procentinis drėgmės kiekis, atliktas suberiamojo tankio nustatymas, išmatuotas granulių dydis. Įvertinta vidutinė kapsulių masė, nustatytas kapsulių suirimo laikas ir bendras fenolinių junginių kiekis išsiskiriantis iš vienos kapsulės. Rezultatai: karčiojo kiečio milteliai yra nebirūs, įsielektrinę, vidutinis dalelių dydis – 22,15 µm, jos nelygiais kraštais. Atlikus drėgną granuliaciją miltelių dalelės tapo lygesniais kraštais, vidutinis dydis – 16,67 µm. Daugeliu atveju suberiamasis tankis viršijo 0,3 g/cm3, išskyrus 2 proc. želatinos tirpalą ir 64 proc. cukraus sirupo tirpalą. Didžiausią kapsulės svorį pasiekėme su 5 proc... [toliau žr. visą tekstą] / Objective of work: to prepare plant material granulation and encapsulation technology to perform biopharmaceutical research and use the results to produce a series of experimental encapsulated product. Tasks: Evaluate wormwood plant powder technological features; Select and apply appropriate granulation technology; Perform pellet quality; Adapt plant material encapsulation technology; Perform quality assessment capsules and biopharmaceutical research, compare , and evaluate laboratory and semi- industrial scale capsules made of quality indicators. The object of investigation – wormwood powder and products based on this material. Method: wormwood powder biopharmaceutical evaluation set pourability, cone angle and tapped density. Wet granulation extruded pellets fixed percentage of moisture carried tapped density of measured grain size. The estimated average weight of capsules set time capsule disintegration and total phenolic compounds, different from one capsule. Results: wormwood powder is non – bulk, charged an average particle size – 22.15 μm, it’s rough edges. After a wet granulation powder particles become more even edges, the average size – 16.67 μm. In most cases, tapped density over 0.3 g/cm3, with the exception of 2 percent gelatin solution and 64 percent sugar syrup solution. The greatest weight of the capsule reached the 5 percent gelatine, 5 percent. methylcellulose and 64 percent granulate sugar syrup. The hardest part was filled in capsules granulate made with... [to full text]

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.

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)

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

Yes / Several contributions in answering granulation challenges including the use of computer simulation and well thought out experimental analyses are being researched. Using a twin screw granulator (TSG) by design of experiments (DoE), comparisons on 1) equipment similarities i.e., continuous and 2) shear forces, are made to previous literature on continuous equipment and a Cyclomix. This study proposes that equipment specific DoE, better explains the contribution of parameters than investigating an identified parameter from the experimental findings from a specific equipment. Granule strength and structure are presented together with the contribution of process parameters, speed, temperature, and binder content. Seeded structures are present in all but the Extrudomix. Longer residence times within the Cyclomix facilitates seeded structures. Granule crushing strengths are higher in TSG than all other continuous equipment. Optimum condition for the formation of stronger granules with least variation is around 65.4 °C. / The authors would like to acknowledge the support from the CCIP grant (Collaboration, Capacity and IP Development) fund from the University of Bradford for ordering cunsumables and equipment.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.

Cette étude est dédiée à la compréhension du processus de granulation humide en mélangeurs à haut taux de cisaillement. Une étude systémique et méthodologique a été menée permettant l'investigation de l'influence des paramètres opératoires, de la technologie employée et des propriétés physico-chimiques des matières premières. Cette investigation est réalisé a travers des techniques de caractérisation morphologiques, rhéologiques et mécaniques. En reliant les courbes de couple enregistrés lors de la granulation humide à la cinétique de croissance des granules, aux caractérisations microscopiques et aux propriétés mécaniques des granules la prédiction du comportement lors de la granulation devient possible. La caractérisation des propriétés mécaniques des granules a été étudié à deux échelles: à l'échelle du milieu humide la consistance a été caractérisé par un rheometre à torque et à l'échelle de l'agglomérat sec la résistance mécanique a été caractérisé par des mesures de compression directe des grains individuelles. Cette approche permet d'avoir des informations complémentaires permettant de mieux décrire l'évolution des courbes de couple dépendantes de propriétés de la masse humide et la compétition entre les forces interfaciales et visqueuses conditionnant la qualité des grains secs résultés. Les paramètres investigués par cette approche sont l'effet du taux de remplissage du réacteur, l'effet de la vitesse d'agitation, de la présence et de la conception de l'émotteur, de la conception du réacteur employé, des propriétés physico-chimiques de la solution liante et des propriétés des mélanges binaires des poudres hydro-solubles / hydro-insolubles. / This study is dedicated to the understanding of the wet granulation process in high shear mixers. A systematic study has been carried out that allows the investigation of the influence of operating conditions, technology and physico-chemical properties of the starting materials. This investigation is achieved by morphological, rheological and mechanical characterization methods. By linking recorded torque curves during the granulation process to granule growth kinetics, microscope characterizations and to the end-granule properties granulation outcome prediction becomes possible. The characterization of the mechanical properties has been done at two scales: at the granule bed scale the bulk wet mass consistency has been determined on a mixer torque rheometer, at the granule scale single dry granule direct compression tests were carried out. This approach gives complementary information allowing better description of the torque curves directly related to the wet mass properties and the competition between static and viscous forces conditioning the dry end granule quality. The factors investigated in this study are: the effect of fill ratio, impeller speed, chopper presence and design, mixer design, binder physico-chemical properties and formulation properties for binary water-soluble / water insoluble powder mixtures.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.