Dissertations / Theses on the topic 'Coating of pellets'

The reduction behaviour of the olivine iron ore pellet MPBOwas studied in laboratory scale at KTH as well as in the LKABexperimental blast furnace. Initially, a newreduction-under-load, or so-called reduction/softening/melting,test equipment was developed. Experiments using differentreducing conditions, corresponding to different radialpositions of the blast furnace, were conducted. The experimentsincluded different temperature profiles, reducing atmospheresand mechanical loads applied on the sample bed to simulate thevarying conditions in the blast furnace process. The progressof reduction was investigated, as well as the processes ofsintering and contraction during reduction. A model of thecarburisation (pick-up of carbon by the reduced iron) andmelt-down process during rapid contraction was presented.

Laboratory testing of MPBO pellets was compared with resultsfrom the LKAB experimental blast furnace. The reduction of ironore pellets in the experimental blast furnace was surveyed by adissection of the furnace after quenching. The high temperaturephenomena occurring when reducing the MPBO pellet, with limitedsoftening and a short temperature range of the melting process,resulting in a thin cohesive zone, were found to be the same inlaboratorytests and in the experimental blast furnace. Thereduction down through the burden of the experimental blastfurnace was similar, but not identical to the results of theRUL experiments. The differences were found to be due todifferent reducing conditions. Therefore, it was concluded thata simulation of the reduction occurring in the blast furnacecan be performed in laboratory scale, provided the experimentalconditions are correctly chosen.

Finally, a modification to further improve the properties ofthe MPBO pellets was examined. With the aim to improve theblast furnace process, coating of blast furnace pellets wasinvestigated in laboratory scale, as well as in the LKABexperimental blast furnace. Olivine, dolomite and quartzitewere used as coating agents. In laboratory scale the stickingprevention action of the different coating materials wasverified, in established test methods as well as in new testmethods, modified for blast furnace conditions. Testing of thecoated pellets in the experimental blast furnace revealedseveral advantages; significantly reduced blast furnace fluedust generation, improved gas utilisation and a smoother blastfurnace operation with a potential for a lowered fuel rate.

Keywords:Olivine, pellets, pellet testing,reduction/softening/melting, MPBO, blast furnace, reduction,quenching, dissection, coating, sticking, coated pellets.

The research project focused on the study of different technologies for film coating of pellets using ethylcellulose as barrier-membrane coating polymer. In particular, two different approaches were investigated: the conventional aqueous film coating and the dry powder coating methods. The research carried out during the first part of the PhD provided a comprehensive study of the conventional aqueous film coating process of guaifenesin-loaded pellets in order to understand the variables affecting the drug migration through the barrier-membrane film coating and thus the stability over time of the final dosage form. The analysed process comprised the drug layering followed by the film coating technique in a Wurster fluid bed. The effect of curing conditions, drug loading and coating level and of the drug-layering solution on the technological properties of pellets was fully evaluated. In the second part of the research, an innovative dry powder coating technology was developed to apply the functional ethylcellulose based coating upon pellets avoiding the use of solvents (neither organic solvents nor water). In particular, the study was designed along three steps: i) Preparation of free films to evaluate the film formation process and to achieve the minimum film forming temperature of the coating formula; ii) Powder coating process of unloaded pellets; iii) Powder coating of drug-loaded pellets. This research analyzed different combinations of polymer, plasticizer, co-plasticizer and other adjuvant by evaluating free films and their assessment through curing and storage. Then suitable coating formulations were utilized for the development of the manufacturing process upon placebo pellets. Subsequently, the dry powder coating process was successfully optimized to coat caffeine-loaded pellets.

The present work focuses on mineral reactions and slag formation of LKAB olivine iron ore pellets (MPBO) subjected to reducing conditions in the LKAB experimental blast furnace (EBF). The emphasis is on olivine reactions with surrounding iron oxides. Many factors influence the olivine behaviour. The study was performed by use of micro methods; optical microscopy, micro probe analysis, micro Raman and Mössbuer spectroscopy and thremodynamic modeling. During manufacturing, in oxidising atmosphere at high temperature (1350°C), olivine alterations occur through slag formation and rim reactions with iron oxides and other additives. To be able to describe olivine behaviour in the rather complex blast furnace reduction process one has to consider factors such as reactions kinetics, reduction degree of iron oxides, vertical and horizontal position in the furnace and reactions with alkali. Samples were collected from the EBF both from in shaft probing during operation and from excavation following quenching of the EBF. The initial slag forming olivine consist of primary forsterite – (Mg1.9Fe0.1)SiO4 – with inclusions of hematite and an amorphous silica rich phase, a first corona with lamellae of magnesioferrite, olivine and orthopyroxene, a second corona of amorphous silica and magnesioferrite. During reduction in the upper shaft in the EBF (700-900°C) Fe3+ reduces to Fe2+. The amorphous silica in the second corona absorbs alkali, Al, Fe2+, Mg, and Ca and form glasses of varying compositions. The lamellae in the first corona will merge into a single phase olivine rim. With further reduction the glasses in the second corona will merge with the olivine rim forming an iron rich olivine rim and leaving the elements that do not fit into the olivine crystal lattice as small silicate glass inclusions. Diffusion of magnesium and iron between olivines and iron oxides increase with increasing temperature in the lower shaft of the EBF (750-1100°C). In the cohesive zone of the EBF (1100-1200°C) Fe2+ is not stable any longer and Fe2+ will be expelled from the olivine as metallic iron blebs, and the olivine will form a complex melt with a typical composition of alkali-Al2O3-MgO-SiO2. Alkali plays an important role in this final olivine consumption. The quench time for samples collected with probes and excavation are minutes respectively hours. A study of the quench rate’s effect on the phases showed no differences in the upper shaft. However, in the lower shaft wüstite separates into wüstite and magnetite when wüstite grows out of its stability field during slow cooling of excavated samples. There is also a higher alkali and aluminium deposition in the glass phases surrounding olivines in excavated pellets as a result of alkali and aluminium gas condensing on the burden in the EBF during cooling. Coating applied to olivine pellets was studied in the EBF with the aim to investigate its behaviour, particularly its ability to capture alkali. The coating materials were kaolinite, bauxite, olivine and limestone. No significant reactions were observed in the upper shaft. In the lower shaft a majority of the phases were amorphous and reflecting the original coating compositions. Deposition from the EBF gas phase occurs and kalsilite (KAlSiO4) is found in all samples; coating used for binding alkali is redundant from a quality perspective.

Orientadores: Osvaldir Pereira Taranto, Marcello Nitz
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Química
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Resumo: Os pellets apresentam muitas vantagens biofarmacêuticas e são ideais para aplicação de recobrimento. Quando o recobrimento é funcional, um dos principais objetivos é formação de uma barreira que modifique o perfil de liberação da droga (liberação controlada ou gastrorresistente). Neste trabalho pellets de diclofenaco de sódio foram produzidos por extrusão/esferonização e, em seguida, foram recobertos em leito fluidizado tipo Wurster. Esse tipo de leito é um dos sistemas mais adequados para o recobrimento de partículas. Dentre suas vantagens destaca-se a não formação de zonas mortas. Este trabalho teve como objetivo estudar o recobrimento dos pellets produzidos com duas suspensões poliméricas aquosas comerciais entéricas, Advantia® Performance e Acryl-Eze® MP. O estudo do processo de recobrimento foi realizado por meio de um planejamento experimental 2³. As variáveis estudadas foram: temperatura do ar de entrada, vazão da suspensão e polímero de recobrimento. As variáveis de resposta foram: eficiência do processo, resultados acima de 78,2%, e fração de aglomerados, resultados inferiores a 8%. O efeito do tipo de polímero de recobrimento foi o que mais influenciou as variáveis de resposta, sendo que o Advantia® Performance resultou numa maior eficiência e uma maior fração de aglomerados. Determinou-se também o ganho de massa mínimo para atingir a gastrorresistência - Acryl-Eze® MP: 9,7% e Advantia® Performance: 8,6%. Os pellets revestidos passaram por testes de teor, dissolução e estabilidade. No teste de estabilidade os pellets recobertos com Advantia® Performance mantiveram seu perfil gastrorresistente. Porém, os pellets recobertos com Acryl-Eze® MP apresentaram um aumento da gastrorresistência após a exposição às condições de estabilidade, o que pode indicar que a coalescência das partículas do polímero aconteceu durante a estocagem. As suspensões foram caracterizadas quanto à sua reologia e ângulo de contato. O tempo de instantaneização do pó polimérico também foi testado
Abstract: Pellets have many biopharmaceutical advantages and are suitable for coating. When the coating is performed for functional purpose, one of the major goal is to form a barrier that modifies the drug release profile (controlled or enteric release). In this work, diclofenac sodium pellets were produced by the extrusion / spheronisation process and then coated in a fluidized bed coater column with a Wurster insert. This type of bed is one of the best suited systems for the coating of particles. One of the main advantages is that it avoids dead zones. This work aimed to study the coating of pellets produced with two commercial aqueous enteric polymer suspensions, Advantia® Performance and Acryl-Eze® MP. The study of the coating process was accomplished through a 2³ experimental design. The variables studied were: inlet air temperature, suspension flow rate and coating polymer. The response variables were: process efficiency, results above 78.2%, and agglomeration fraction, values below 8%. The effect of polymer coating type was the variable that influenced the response variables the most. The polymer Advantia ® Performance resulted in a better efficiency and increased the agglomerate fraction. The minimum mass gain to achieve the enteric profile was also determined - Acryl-Eze® MP: 9.7% and Advantia® Performance: 8.6%. The coated pellets were tested for content, dissolution and stability. In the stability test, pellets coated with Advantia® Performance maintained the enteric profile. However, the pellets coated with Acryl-Eze® MP presented a better enteric profile after the exposure to conditions of stability, which may indicate that coalescence of the polymer particles occurred during storage. The suspensions were characterized by rheology and contact angle. The static wettability of the polymeric powder was also tested
Mestrado
Engenharia de Processos
Mestre em Engenharia Química

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of mild to moderate pain in chronic inflammatory conditions. Due to its superior potency ketoprofen can be used in the treatment of inflammatory bowel disease (IBD). The treatment of IBD becomes safer and more effective when the drug is incorporated into colon-specific drug delivery systems. Pellets are multiparticulate solid dosage forms extensively investigated as colon-specific drug delivery systems. Pellets can be introduced into capsules or compressed into tablets. The industrial production of tablets containing pellets has several advantages when compared to the production of capsules. However, the compression of the pellets should not affect the release of the drug and the tablets should quickly disintegrate following administration. Therefore, the aim of this study was to develop tablets containing ketoprofen coated pellets for colon-specific drug release. For this, pellets were produced by extrusion and spheronization technique containing 40% (w / w) ketoprofen. Ketoprofen pellets obtained were coated with two different pH - dependent polymers derived from methacrylic acid (Opadry ® k 94 or Eudragit ® FS 30D) with weight gains of 10 or 20% (w / w). The coated pellets were then compressed under different pellets’ amounts and different compression forces. An extra- granular mixture of lactose and microcrystalline cellulose was used as compression aid. The in vitro release of ketoprofen from the systems obtained was evaluated in Bio Dis ® apparatus. The morphological and physical properties of pellets and tablets were assessed. The Eudragit ® FS 30 D coated pellets with weight gains of 10 or 20% showed higher efficiency of colon-specific delivery (94 %), however, the drug was released slowly and incompletely in conditions mimicking the pH of the colonic region. After compression of the pellets, the efficiency of colon – specific drug delivery was lowered after compression (between 20% and 61%, depending on the formulation). The lowest decrease of colon specific efficiency was observed in formulations containing lower amount of pellets, which also produced disintegrating matrices with potential for use in the topical treatment of IBD.
O cetoprofeno é um antiinflamatório não esteroidal usado para o tratamento de dores leves a moderadas, em condições inflamatórias crônicas. Devido a sua elevada potência antiinflamatória, o cetoprofeno pode ser aproveitado no tratamento das doenças inflamatórias intestinais (DII). O tratamento das DII se torna mais seguro e eficaz quando o fármaco é incorporado em sistemas de liberação cólon-específica. Pellets são formas farmacêuticas multiparticuladas bastante investigadas como sistemas de liberação cólon-específica. Após sua produção, os pellets podem ser inseridos em cápsulas ou comprimidos. A produção industrial de comprimidos contendo pellets apresenta inúmeras vantagens quando comparada ao processo de enchimento de cápsulas. No entanto, a compressão dos pellets não deve afetar as características de liberação do fármaco e os comprimidos formados devem se desintegrar rapidamente. Dessa forma, o objetivo deste trabalho foi desenvolver comprimidos contendo pellets revestidos para liberação cólon-específica de cetoprofeno. Para tanto, foram produzidos pellets contendo 40% (p/p) de cetoprofeno e celulose microcristalina pela técnica de extrusão e esferonização. Os pellets de cetoprofeno obtidos foram revestidos com dois diferentes polímeros pH-dependentes, ambos derivados do ácido metacrílico (Opadry ® 94 k ou Eudragit ® FS 30) com ganhos de massa 10 ou 20% (p/p). Os pellets revestidos foram então comprimidos com diferentes cargas de pellets e submetidos a diferentes forças de compressão, utilizando como adjuvante extra-pellets uma mistura granulada de lactose e celulose microcristalina. A liberação in vitro do cetoprofeno a partir das formas farmacêuticas obtidas foi avaliada em dissolutor Bio Dis aparato III. As caracterizações morfológicas e físicas dos pellets e comprimidos foram conduzidas. Os pellets obtidos por revestimento com Eudragit ® FS 30 D, com ganhos de massa de 10 ou 20%, mostraram elevada eficiência de liberação cólon-específica in vitro (até 94%), no entanto, o fármaco foi liberado de forma lenta e incompleta em meio com pH similar ao encontrado na região colônica. Após a compressão dos pellets, os valores de eficiência de liberação cólon-específica sofreram reduções entre 20% e 61%. A menor diminuição da eficiência de liberação cólon-específica foi observada nas formulações contendo a menor carga de pellets, as quais deram origem à matrizes desintegráveis com potencial para utilização no tratamento tópico das DII.

The preparation of multiple unit tablets was investigated in this thesis with the intention of gaining a deeper understanding of some of the factors that influence the properties of such tablets.

Initially, three different types of pellets (drug, soft and disintegrant pellets) were combined as a model to investigate the ability of the mixture to form disintegrating tablets. The proportions of the different pellets and the type of disintegrant used were factors that independently influenced the tablet properties. Furthermore, the properties of tablets containing drug pellets barrier-coated with an aqueous polymer dispersion were also found to depend on the coating thickness and the compaction pressure.

When compacting pellets barrier-coated with a solvent-based polymer solution without incorporating excipient particles in the tablet formulation, a high pellet porosity was advantageous to preserve the original drug release profile, even though highly porous pellets became more densified and deformed than pellets of lower porosity.

The influence of the properties of excipient particles on the deformation of the reservoir pellets was also studied and, although the amount of flattening of the pellets was only slightly affected, changes in the pellet shape (irregularity) with alterations in the porosity and size of the excipient particles were more substantial. In contrast, the properties of the excipient particles did not affect the pellet densification.

The solvent-based coating used was able to adapt to the changes in volume and shape that the pellets underwent during compaction. The coating structure appears to be changed by compaction and it is proposed that the final structure of the coating is the net effect of two parallel processes, one reducing and one prolonging the transport time of the drug across the coating. Thus, the drug release could be maintained or even prolonged after compaction, despite extensive structural changes of the reservoir pellets.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
As sementes de milho superdoce possuem fino pericarpo e formato irregular dificultando a operação de semeadura. Em função disso, surge a possibilidade de utilizar o processo de peletização para facilitar a semeadura e obter estande uniforme sem a necessidade de desbaste de plantas. Embora essa técnica seja conhecida há muitos anos, pouco se estudou sobre o efeito desse procedimento na plantabilidade e na qualidade fisiológica de sementes de milho superdoce. Sendo assim, este trabalho teve como objetivo avaliar o efeito da peletização na qualidade fisiológica e na ocorrência de falhas e de sementes duplas. A qualidade fisiológica das sementes e péletes foi avaliada pelos testes de germinação, primeira contagem de germinação e teste de frio. Foram avaliados também alguns atributos físicos das sementes e dos péletes por meio dos testes de fragmentação, retenção de peneiras, massa de mil sementes e volume aparente. O recobrimento foi muito eficiente na redução das falhas e da ocorrência de sementes duplas, proporcionando resultados altamente satisfatórios para esses atributos. Não houve efeito do armazenamento no potencial fisiológico nem nos resultados do teste a frio para as sementes nuas. As sementes recobertas foram afetadas negativamente pela peletização a partir dos 90 dias de armazenamento. Durante esse período todos os lotes de sementes peletizadas apresentaram-se dentro do padrão de germinação exigido pelo Ministério da Agricultura Pecuária e Abastecimento, os resultados permitiram concluir que o revestimento melhora a plantabilidade das sementes afetando positivamente a eficiência do processo de semeadura
The supersweet corn seeds have thin pericarps and irregular shape difficulting the sowing operation. As a result, there is the possibility of using the pelleting process to facilitate the seeding and more uniform stand without the need of thinning plants. Although this technique has been known for many years, little has been studied on the effect of this procedure in plantability and in physiological quality of supersweet corn seeds. Thus, this study aimed to evaluate the effect of pelleting on the water content during the storage and the occurrence of double seeds and lack of seeds in the holes during the sowing test. The physiological quality of seeds and pellets was evaluated by germination, first germination and cold test. It also was evaluated other physical attributes of seeds and pellets by means of fragmentation tests, retention sieves, seed weight and apparent volume. The coating was very effective in reducing seed double faults and providing highly satisfactory results for these attributes. There was not effect of storage on physiological potential or in the results of the cold test for naked seeds. The coated seeds were negatively affected by the coating from 90 days of storage. During this period all batches of pelleted seeds were inside the physiological pattern required by the ministry of agriculture. The results showed that the coating improves plantability seeds positively affecting the efficiency of the seeding process. Based on the results it can be concluded that the coating improve seed plantability, positively affecting the efficiency of the seeding process

Les mini-granules enrobées offrent un grand potentiel pour la libération contrôlée de médicament par voie orale. Cependant, les mécanismes de libération impliqués ne sont pas toujours élucidés et compris. Ainsi, l’impact de certains paramètres de formulation peut être surprenant. Par exemple, il a été démontré dans ce travail :- La libération du propranolol HCl à partir de mini-granules enrobées avec du Kollicoat SR est plus lente si les mini-granules sont composées de noyaux de sucre comparé à des noyaux de cellulose microcristalline (CMC).Généralement, la tendance inverse est observée, car les noyaux de sucre ont une activité osmotique attirant plus rapidement l’eau à l’intérieur du système et entrainant ainsi, une dissolution et diffusion de la substance active. Ce résultat inattendu est dû à une association de 2 phénomènes : (i) l’effet plastifiant dû au sucre sur le film de Kollicoat SR et (ii) la diminution de la solubilité de cette SA dans le milieu de dissolution en présence de sucre dissous.De plus, le Kollicoat SR 30 D [dispersion aqueuse de poly(vinyl pyrrolidone)] offre des possibilités intéressantes de formulation par sa haute flexibilité et ses propriétés mécaniques stables. En revanche, les mini-granules composées de noyaux de sucre ont tendance à gonfler de par le cumul de l’activité osmotique du noyau et de la SA jusqu’à l’apparition de « cracks », révélés par des images obtenues par micro tomographie à rayons X.- Lorsqu’on augmente la quantité en propranolol HCl dans le système, la cinétique de libération est augmentée, particulièrement avec les mini-granules composées de noyaux de CMC.L’opposé est souvent constaté car accroitre la quantité de SA nécessite un plus grand apport en eau afin de pouvoir tout dissoudre. Les mini-granules à base de CMC présentent probablement des « cracks » malgré un faible gonflement du système, et sont accentués par l’augmentation de la concentration en propranolol HCl.En conclusion, des nouvelles connaissances sur les mécanismes de libération à partir de mini-granules enrobées avec du Kollicoat SR ont été apportées et l’importance du type de SA et la nature du noyau composant le système ont été élucidées.- Dans une deuxième partie, des mini-granules enrobées avec un mélange de polymère (Aquacoat ECD et Eudragit NM 30 D) ont été formulées dans le but de libérer la diprophylline, SA modèle, par diffusion à travers le film de polymère et de pouvoir modéliser sa cinétique à partir de modèles mathématiques
Polymer coated pellets offer a great potential for control drug delivery system. Nevertheless, the underlying drug release mechanisms can be complex and are not fully understood. Thus, the impact of formulation parameters can be surprising. For example, it has been demonstrated during this thesis that:- The release of propranolol HCl was slower from sugar-based pellets coated with Kollicoat SR compared to microcrystalline cellulose (MCC)-based pellets.Generally, the opposite was observed because the sugar cores are osmotically active attracting more and more water into the system leading to a fast dissolution and diffusion of the drug, especially with high water-soluble drug. This unexpected result is due to a combination of two phenomena: (i) The plasticizing effect of sugar for the film coating and (ii) Decrease in drug solubility in the release medium due to the presence of co-dissolved sugar.In addition, Kollicoat SR 30 D [an aqueous dispersion of poly(vinyl acetate) also containing small amounts of poly(vinyl pyrrolidone) and sodium lauryl sulfate] is a very interesting polymer owing to its high flexibility and stable mechanical properties. However, sugar-based pellets tend to swell by the osmotic pressure created by the high water-soluble API and the sugar until crack formation, clearly visible on the images obtained by X-ray micro tomography.- Propranolol HCl release in phosphate buffer pH 7.4 increases by increasing the drug loading into the system, especially from MCC-based pellets.The opposite was often observed since the amount of water within the drug reservoir might not be sufficient to dissolve all drug. MCC-based pellets likely presented also cracks despite a low swelling of the system, accentuated by the increase of propranolol HCl concentration.To conclude, new insights on the underlying drug release mechanisms from Kollicoat SR coated pellets were provided. The importance of the type of drug and the nature of starter cores were elucidated.- In the second part, diprophylline loaded pellets coated with a polymer blend composed of Aquacoat ECD and Eudragit NM were prepared in order to control the drug release only by diffusion through the intact polymeric film and to predict the drug kinetics using mathematical models

O segmento farmacêutico demonstra um crescente interesse no processo de peletização, o qual consiste na aglomeração por via úmida de pós finos compostos de ativos e excipientes em pequenas unidades esféricas, com excelentes vantagens tecnológicas e terapêuticas. O objetivo do presente trabalho envolve o estudo de processos de incorporação de suspensões em péletes inertes, compostas de ativos e excipientes, utilizando dois tipos de processos: 1. Drageadeira Modificada e 2. Leito Fluidizado nas configurações top spray e bottom spray. Os ativos utilizados foram besilato de anlodipino nas concentrações de 2.5% e 5% em massa, e cloridrato de benazepril em 15% em massa, presentes nas formulações das suspensões e aplicadas em quantidades iguais nos dois processos, em um total de 9 lotes. Os indicadores de desempenho de processo utilizados para incorporação do ativo nos péletes inertes foram tempo de aplicação da suspensão (min) e taxa de aplicação da suspensão (g/min). Os péletes finais obtidos foram avaliados por meio das análises das propriedades físico-químicas: teor de umidade (%), teor de princípio ativo (%), uniformidade de conteúdo (%) e dissolução (%). Dentre os lotes testados, os processos em drageadeira e leito pelo sistema bottom spray apresentaram o menor tempo de aplicação (120 min) para a suspensão com o ativo anlodipino na concentração de 2.5%, enquanto que pelo sistema top spray apresentou um tempo de aplicação de 300 min, uma vez que este sistema foi projetado originalmente para processo de granulação. O processo em drageadeira apresentou a maior taxa real de aplicação, igual a 6.24 g/min, seguida pelo sistema bottom spray com 4.91 g/min, e o sistema top spray com 1.62 g/min, para suspensão com o ativo benazepril na concentração de 15%. Para os processos em drageadeira e leito pelo sistema bottom spray, todas as propriedades físico-químicas dos péletes deste estudo se apresentaram dentro dos padrões recomendados pela indústria farmacêutica, o que não aconteceu para o sistema top spray com relação à propriedade teor de princípio ativo (benazepril), cujo valor apresentado ficou em 12.90%, abaixo do limite inferior de 13.50%; o que não garantirá a eficácia do fármaco de acordo com a ação esperada. Os resultados apresentados ratificam os processos de peletização em drageadeira e leito pelo sistema bottom spray como os ideais pela técnica de incorporação de princípio ativo em péletes inertes.
The pharmaceutical industry has shown a growing interest in pelletization process, which consists of wet agglomeration of fine powders composed of active ingredients and excipients into small spherical unities, with excellent technological and therapeutic advantages. The objective of this work involves the study of processes of incorporation of suspensions in inert pellets, composed of active ingredients and excipients, using two types of processes: 1. Modified Coating Pan and 2. Fluid Bed in top spray and bottom spray systems. The active ingredients used were amlodipine besylate in concentrations of 2.5% and 5% by mass, and benazepril hydrochloride 15% by mass, included in the formulations of suspensions and applied in equal amounts in both processes, in a total of 9 batches. The process performance indicators used for incorporation of the active ingredient in inert pellets were time of application of the suspension (min) and rate of application of the suspension (g/min). The final pellets were evaluated by means of analyses of the physicochemical properties: water content (%), assay of active ingredient (%), uniformity content (%) and dissolution (%). Among the batches tested, the processes in coating pan and fluid bed by bottom spray system had the shortest application time (120 min) for the suspension with amlodipine besylate active with concentration of 2.5%, while the top spray system had an application time of 300 min, since this system was originally designed for granulation process. The process in coating pan showed the highest real rate of application, equal to 6.24 g/min, followed by the bottom spray system with 4.91 g/min, and the top spray system with 1.62 g/min to the suspension with benazepril hydrochloride with concentration of 15%. For the processes in coating pan and fluid bed by the bottom spray system, all physicochemical properties of the pellets of this study are presented within the standards recommended by the pharmaceutical industry, which has not happened for the top spray system with respect to property "assay of active ingredient (benazepril), whose value present was in 12.90%, below the lower limit of 13.50%, which does not guarantee the efficacy of the drug according to the expected action. The results presented confirm the processes of pelletization in coating pan and fluid bed by the bottom spray system as the ideal technique for incorporation of the active ingredient in inert pellets.

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Tese (Doutorado em Tecnologia Nuclear)
IPEN/T
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

碩士
中國醫藥大學
製藥碩士學位學程
106
Coat hydrochloric acid doxycycline enteric-coated pellets with different dissolution characteristics enteric coating, HPMC-P and EUDRAGIT® L30D-55, in different coating process; identify their dissolution, roundness, and friability in 0.06M HCl solution and pH 5.5 buffer solution as well as impact of intense light, high temperature and high humidity on the product and its accelerated stability. Initial results suggest HPMC-P and EUDRAGIT® L30D-55 based products make no significant difference in acid and pH5.5 buffer solution in terms of dissolution. Particles coated by fluid bed granulation end up with better acid dissolution, roundness, and friability than their side granulation counterparts. We then take samples made by bed granulation and different formula for stability and puncture tests. Test results suggest EUDRAGIT® L30D-55 based pellets outperm the HPMC-P ones with respect to substance and concentration while maintaining the same good stability in environment of intense light, high temperature and high humidity as well as less than 2% dissolution in 0.06M HCl solution. EUDRAGIT® L30D-55 is then poised the optimum prescription. Coating EUDRAGIT® L30D-55 enteric material with fluid bed granulation is the best option in terms of reliable quality, lower costs and environment friendliness.

The use of vacuum coating is mostly limited to production of high fat containing extruded aqua and pet diets. The physical characteristics of extrudates are favourable for vacuum coating due to their high porosity and durability. However, with pelleted feed for broilers, there are potentially several opportunities, but there are also challenges; these are explored here. The opportunities identified were inclusion of high level of oils, protected delivery of feed additives (e.g., enzymes, probiotics, vaccines, etc.), improved and safe use of offensive feed additives and improvement of shelf-life of feed and additives. Challenges include the relatively high density of pellets (low porosity) which limits liquid infusion, increased processing cost and decreased feed throughput. However, feed ingredients selection and alternating processing variables (temperature, moisture, die specifications etc.) were deemed to overcome the challenges of low porosity. Three experiments were conducted to evaluate the use of vacuum coating in pelleted feed. In the first experiment, the effect of particle size on post-pellet oil absorption (OA), porosity, pellet durability index (PDI) and bulk density were investigated. The three particle sizes for three grains (wheat, barley and corn) were pelleted using a 4.7 mm die to get whole grain (WP), coarse (CP), and fine (FP) grind pellets. The pellets were coated with 15% canola oil without (VC-) and with (VC+; 0.3 bar) vacuum coating. The grain type was found to have a significant effect on the particle size when ground through either fine (3.2 mm) or coarse (6.4 mm) screen. With coarse grinding, the mean particle size was 1896, 1290 and 1057 µm, respectively for barley, wheat and corn; with fine grinding, the mean particle size was 1153, 767 and 732 µm, respectively. Porosity of CP from wheat and corn was significantly (P<0.01) higher than WP and FP. For barley, there was no difference in porosity of CP and FP but both were significantly higher than WP. For wheat, OA of CP was highest (P<0.01), but no significant difference was found between FP and WP. However, for barley, higher OA was found in FP followed by CP and WP. In corn, OA of CP was higher than for FP or WP. Vacuum coating (VC+) improved (P<0.01) OA of all pellets compared to VC-. Porosity was positively correlated with OA and negatively correlated to PDI and bulk density. Overall, the first experiment suggested that alteration of particle size and grain type could be the options for improving the oil absorption by vacuum coating. A second experiment was conducted to observe the effect of enzyme addition method (EAM; E-, without enzyme; PreE+, Pre-pellet addition of enzyme; PosE+, post-pellet addition of enzyme), conditioning temperature (CT; 65 or 95°C) and coating method (CM; VC- or VC+) on broiler performance when fed wheat-rye-based diets. Enzyme addition (pre or post-pellet addition in comparison to without enzyme) significantly improved (P<0.01) the body weight at 21 and 35d. Higher CT (95°C) improved feed conversion ratio (FCR) in both starter (P<0.01) and grow/finish phase (P=0.04) and PDI of both starter and grow/finish pellets (P<0.01) when compared to low CT (65°C). Vacuum coating did not have any effect on the diet extract viscosity, animal performance or digesta viscosity in either of the phases. However, with post-pellet vacuum coating, there was high retention of xylanase activity after processing. Vacuum coating significantly (P<0.05) reduced the relative length of small intestine of broilers at 21d but not at 35d. In the third experiment, broiler grow/finish diets were stored in an incubator (37°C) to see if vacuum coating can improve the shelf-life of feed. The results showed post-pellet vacuum-coated pellets retained higher enzyme activity after 15 days of storage. Although no effect of vacuum coating on animal performance was observed, vacuum coating was able to protect the enzyme during processing and storage. Further work needs to be done to translate these benefits to improve animal performance, which might be achieved using various vacuum coating and processing conditions, and bioactives.

碩士
中國醫藥大學
藥學系碩士班
95
Lansoprazole is the proton pump inhibitor of a kind of benzimidazoles，It last coat of the stomach the cells not secreting uniqueness not all right ferment of hydrochloric acid in gastric juice (H + /K + the - ATPase) ，Make it activate，reduce the secretion of the hydrochloric acid in gastric juice。Apply to such various kinds of treatment resisting acid and secreting as the gastric ulcer、duodenal ulcer、adverse current esophagitis、Zollinger-Ellison disease groupetc。 Pellet can hit into the lozenge or pack into the capsule pharmaceutical， but the characteristic of the round one can overcome the time that the intestines and stomach shift difference，transformation in intestines and stomach to transport food influence of law，influence not emptied by the stomach either。The round one can be distributed evenly in the intestines and stomach，increase the area of absorbing in addition，improvement body availability on can big，can reduce between medicine and stimulus， intestines and stomach of mucous membrane. Prepare Lansoprazole into the intestines to dissolve the destruction in order to avoid the hydrochloric acid in gastric juice of round grains of form of a drug，use Wooster type flow bed is it prepare intestines dissolve round grain，is it design and act as content determining and relevant assessment with excipient so as to HPLC to fill a prescription to go on to utilize to come。Found by the experimental result，in the medicine floor， use Polyvinyl Alcohol (PVA) The best as binding the pharmaceutical result。 Because Lansoprazole easy to destroy PVA have stable result can prevent Lansoprazole from destroy among solution。In the casing floor， postpone medicines and justify one oneself to release with increase of the thickness of Eudragit® L30 D-55 different proportions。 When the thickness of floor of casing is too high，will influence and dissolve and leave the release that the speed suppresses the medicine。Make round grains of thing in addition，capsule thing assessment determine，including particle density，particle grain distribute directly，for a time content，water content of particle and dosage of unit。It is and then by body dissolve from testing,assess proportion thickness，the casings of layer not different dissolve to Lansoprazole from influence。Because the bag formed will postpone medicines to release to cover the thickness too thick，even prevent the medicine from releasing，but too thin to will release early too， make medicine destroy hydrochloric acid in gastric juice，can stimulate stomach too。

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Neste trabalho, o leite é proposto como excipiente inovador (agente de revestimento), para formulações pediátricas como agente mascador de sabor. Foram produzidos, por extrusãoesferonização, pellets constituídos por celulose Microcristalina e Paracetamol. O Paracetamol está descrito na literatura como substância ativa segura, integrando a lista de fármacos essenciais para uso pediátrico, elaborada pela Organização Mundial de Saúde. Foram realizadas três formulações distintas de revestimento com diferentes tipos de leite de vaca – leite magro, leite meio gordo e leite gordo – avaliando-se a capacidade de funcionarem como agentes de revestimento. O processo de revestimento foi realizado em equipamento de leito fluidizado, usando a configuração de Wurster. A influência das variáveis do processo - volume e temperatura do ar, pressão de atomização do ar e temperatura do produto- foi investigada pelo seu impacto na qualidade da camada de revestimento formada. As características da superfície dos pellets revestidos, bem como a espessura da camada de revestimento foi analisada qualitativamente por Microscopia de Varrimento (SEM). Características organoléticas, como o odor, cor e sabor foram igualmente avaliadas. Um lote de controlo foi produzido, com a mesma composição e tamanho de partícula, para posterior comparação com os pellets revestidos. Tanto os pellets revestidos como os sem revestimento (controlo) foram caracterizados em termos de teor de substância ativa, perfil de dissolução, aspect ratio, friabilidade e teor de perda por secagem. Durante o processo de revestimento, parâmetros como o volume e temperatura de ar de entrada foram difíceis de manter constantes culminando numa camada de revestimento pouco espessa e heterogénea, com fissuras visíveis nas imagens obtidas por SEM. A proteína do leite, caseína, formou micelas que prenderam a substância ativa e assim, diminuíram o teor de substância ativa. Os resultados dos testes de friabilidade, perda por secagem, aspect ratio e perfil de dissolução não sofreram variações significativas com a camada de revestimento. Os pellets revestidos apresentavam sabor, cheiro e cor característicos do leite, mostrando que o revestimento aderiu à superfície dos pellets. O estudo provou que o leite tem a capacidade de funcionar como agente mascarador de sabor, no entanto a formulação de revestimento tem de ser melhorada, por exemplo adicionando um anti- aderente, como o Talco, e um plasticizante, como o Sorbitol.
In this work, milk is proposed as a novel excipient (coating agent) in paediatric formulations as taste-masking agent. Pellets were conducted with Microcrystalline Cellulose and Paracetamol, a drug with a safety described in literature, part of the World Health Organizations (WHO) lists of essential medicines for children, as nuclei made by extrusion-spheronization. Three coating films were made with different types of cow’s fresh milk - skimmed milk; half-fat milk; fat milk - and its ability to function as film-forming agent were evaluated. The coating process was performed in a fluidized bed system, using the Wurster configuration. The influence of the process variables – volume and temperature of the inlet air, atomization air pressure and temperature of the product - on the quality of the coating layer was investigated. The surface characteristics of the coated pellets and the thickness of the coating film were analysed qualitatively by Scanning Electron Microscopy (SEM). Organoleptic characteristics were also evaluated, such as odour, colour and taste. A control batch, with the same granulometric class, composition and without coating film was made in order to compare the effect of the coating layer. Both coated and uncoated pellets (control) were characterized in terms of drug content, dissolution profile, aspect ratio, friability and loss on drying. During the coating process, parameters like the volume of inlet air and temperature were hard to maintain which led to a thin and heterogenous coating layer full of cracks ,visible in SEM images. Casein, a milk protein, formed micelles and entrapped the drug substance, decreasing the drug content. Friability, loss on drying, aspect ratio and the dissolution rate did not suffer significant variations with the milk film. Coated pellet’s taste, odor and colour was characteristic of milk, proving that milk film adhered to the pellet surface. The study proved that milk is suitable to function as taste-masking agent, however the coating formulation has to be improved by adding, for example, an anti-adherent, as Talc, and a plasticizer, such as Sorbitol.
Faculdade de Farmácia da Universidade de Milão; Hospital Garcia de Orta (Estágio F.Hospitalar); Farmácia Carmo Sobral (Estágio F.Comunitária)