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The objectives of this dissertation’s studies were to determine the effects of different additives on biomass wood pellets’ physical properties and the production energy required to produce each treatment. Chapter II was completed using a pneumatic pelletizer as a small scale test to determine effects of different additives. The pneumatic pelletizer was a good indicator of which additives can be successfully pelletized. The results of this chapter show that using bio-oil can significantly increase calorific value, without significantly decreasing durability and significantly increasing production energy required. Corn starch, in a 4% treatment, was shown to not hinder durability or calorific value significantly, but significantly lower production energy. Biochar was shown to be an additive insignificant in production due to such a low durability. Chapter III is a scaled up pelleting study, which takes additives from Chapter II as well as multiple new additives to determine each one’s effects on the physical properties and production energy effects. The larger scale, Sprout Walden pelletizer gave much different results than that of the pneumatic pelletizer. The results tend to prove beneficial to durability, calorific value, and bulk density with multiple of the treatments. Vegetable oil was a treatment shown to be less beneficial with each increase in additive and would not be recommended in a production setting at such levels. Chapter IV focused on the economic effect of the pellets produced in Chapter III. Equations were made to determine the possible marginal revenue using each of the treatments. The marginal revenue equations take into account the changes in durability and calorific value. Biochar 4%, and vegetable oil at 1% and 2% show that an increase in marginal revenue could be possible with these treatments.

O intumescimento é um dos fatores decisivos que influenciam o comportamento de desintegração de formas farmac6uticas compactadas e, consequentemente, o perfil biofarmacêutico de substancias ativas. Entre os diversos adjuvantes empregados para promover a desagregação daquelas formas farmac6uticas nas suas partículas primarias originais, são utilizadas varias substancias, abrangidas pelo conceito de desintegrantes intumescedores. A escolha do adjuvante mais adequado nestes casos pode ser vista como uma atividade que exige o gasto considerável de tempo e de custos elevados. Além disto deve ser levada em consideração a existência de vários produtos similares no mercado. A questão da equival6ncia representa portanto um desafio importante na fase de formulação. Com o objetivo de aumentar os conhecimentos nesta área, foi desenvolvido equipamento para a avaliação dinâmica do intumescimento de pês. Inicialmente foram considerados fatores de construção do aparelho, tais como a porosidade, espessura e área do filtro de vidro sintetizado. Foram tamb6m avaliadas variações metodológicas, entre as quais a temperatura de realização do teste e o meio liquido empregado. Croscarmelose, um superdesintegrante, foi utilizada como adjuvante-modelo no teste do equipamento. A alteração do meio liquido de ensaio foi o fator que causou a maior influ6ncia sobre os resultados, embora a espessura dos filtros de vidro sintetizado tenha causado alguma alteração quer no tempo como no volume final de intumescimento. intumescimento. Já a mudança de temperatura não provocou diferenças significativas nas observações. Numa segunda fase foi investigada a influência deste desintegrante sobre as características de intumescimento de quatro celuloses microcristalinas (CMCr) isoladas ou adicionadas com um lubrificante. Para tanto elaborou-se um planejamento fatorial 4 X 2 X 2. A presença do desintegrante, como esperado, provocou aumento do volume final de intumescimento das CMCr, que apresentaram, no entanto, comportamentos diferenciados frente ao adjuvante. Já a presença do lubrificante conduziu a resultados totalmente dependentes do tipo de CMCr testada. A análise comparativa entre estes produtos demonstrou que somente num caso houve simitaridade de comportamento. / Swelling is one of the decisive factors influencing the disintegrant behavior of compacted pharmaceutical dosage forms and consequently the biopharmaceutical profile of drug substances. Among the various excipients used to promote the disintegration of such dosage forms in its originally primary particles, several substances, classified as swelling disintegrants, are employed. The choice of the most appropriate excipient in this case can be a time and cost consuming enterprise. Additionally it must be considered that the same substance can be delivered in the market by different producers. The question of equivalence represents also an important challenge in the formulation phase. In order to provide more knowledge in this area an apparatus to analyze the dynamic swelling of powder admixtures was developed. Construction factors such as filter porosity, thickness and area were considered. Methodological variants including essay temperature and liquid medium were also evaluated. Croscarmelose, a superdisintegrant, was used as model excipient to test the self built equipment. The change of the test fluid was the determinant factor on the results, although the thickness of the sintered glass filter showed some influence on both swelling volume and swelling time of this adjuvant. As a second step, the influence of this disintegrant on the swelling behavior of four microcrystalline celluloses (MCC) alone or added with a lubricant were investigated by using a 4 X 2 X 2 factorial design. The presence of the disintegrant was able to increase the swelling volume. Both final swelling volume and time were dependent of the MCC type. The lubricant showed different influences on the four tested MCC. A comparative study demonstrated that only in one case these products presented similarly swelling behavior.

O intumescimento é um dos fatores decisivos que influenciam o comportamento de desintegração de formas farmac6uticas compactadas e, consequentemente, o perfil biofarmacêutico de substancias ativas. Entre os diversos adjuvantes empregados para promover a desagregação daquelas formas farmac6uticas nas suas partículas primarias originais, são utilizadas varias substancias, abrangidas pelo conceito de desintegrantes intumescedores. A escolha do adjuvante mais adequado nestes casos pode ser vista como uma atividade que exige o gasto considerável de tempo e de custos elevados. Além disto deve ser levada em consideração a existência de vários produtos similares no mercado. A questão da equival6ncia representa portanto um desafio importante na fase de formulação. Com o objetivo de aumentar os conhecimentos nesta área, foi desenvolvido equipamento para a avaliação dinâmica do intumescimento de pês. Inicialmente foram considerados fatores de construção do aparelho, tais como a porosidade, espessura e área do filtro de vidro sintetizado. Foram tamb6m avaliadas variações metodológicas, entre as quais a temperatura de realização do teste e o meio liquido empregado. Croscarmelose, um superdesintegrante, foi utilizada como adjuvante-modelo no teste do equipamento. A alteração do meio liquido de ensaio foi o fator que causou a maior influ6ncia sobre os resultados, embora a espessura dos filtros de vidro sintetizado tenha causado alguma alteração quer no tempo como no volume final de intumescimento. intumescimento. Já a mudança de temperatura não provocou diferenças significativas nas observações. Numa segunda fase foi investigada a influência deste desintegrante sobre as características de intumescimento de quatro celuloses microcristalinas (CMCr) isoladas ou adicionadas com um lubrificante. Para tanto elaborou-se um planejamento fatorial 4 X 2 X 2. A presença do desintegrante, como esperado, provocou aumento do volume final de intumescimento das CMCr, que apresentaram, no entanto, comportamentos diferenciados frente ao adjuvante. Já a presença do lubrificante conduziu a resultados totalmente dependentes do tipo de CMCr testada. A análise comparativa entre estes produtos demonstrou que somente num caso houve simitaridade de comportamento. / Swelling is one of the decisive factors influencing the disintegrant behavior of compacted pharmaceutical dosage forms and consequently the biopharmaceutical profile of drug substances. Among the various excipients used to promote the disintegration of such dosage forms in its originally primary particles, several substances, classified as swelling disintegrants, are employed. The choice of the most appropriate excipient in this case can be a time and cost consuming enterprise. Additionally it must be considered that the same substance can be delivered in the market by different producers. The question of equivalence represents also an important challenge in the formulation phase. In order to provide more knowledge in this area an apparatus to analyze the dynamic swelling of powder admixtures was developed. Construction factors such as filter porosity, thickness and area were considered. Methodological variants including essay temperature and liquid medium were also evaluated. Croscarmelose, a superdisintegrant, was used as model excipient to test the self built equipment. The change of the test fluid was the determinant factor on the results, although the thickness of the sintered glass filter showed some influence on both swelling volume and swelling time of this adjuvant. As a second step, the influence of this disintegrant on the swelling behavior of four microcrystalline celluloses (MCC) alone or added with a lubricant were investigated by using a 4 X 2 X 2 factorial design. The presence of the disintegrant was able to increase the swelling volume. Both final swelling volume and time were dependent of the MCC type. The lubricant showed different influences on the four tested MCC. A comparative study demonstrated that only in one case these products presented similarly swelling behavior.

O intumescimento é um dos fatores decisivos que influenciam o comportamento de desintegração de formas farmac6uticas compactadas e, consequentemente, o perfil biofarmacêutico de substancias ativas. Entre os diversos adjuvantes empregados para promover a desagregação daquelas formas farmac6uticas nas suas partículas primarias originais, são utilizadas varias substancias, abrangidas pelo conceito de desintegrantes intumescedores. A escolha do adjuvante mais adequado nestes casos pode ser vista como uma atividade que exige o gasto considerável de tempo e de custos elevados. Além disto deve ser levada em consideração a existência de vários produtos similares no mercado. A questão da equival6ncia representa portanto um desafio importante na fase de formulação. Com o objetivo de aumentar os conhecimentos nesta área, foi desenvolvido equipamento para a avaliação dinâmica do intumescimento de pês. Inicialmente foram considerados fatores de construção do aparelho, tais como a porosidade, espessura e área do filtro de vidro sintetizado. Foram tamb6m avaliadas variações metodológicas, entre as quais a temperatura de realização do teste e o meio liquido empregado. Croscarmelose, um superdesintegrante, foi utilizada como adjuvante-modelo no teste do equipamento. A alteração do meio liquido de ensaio foi o fator que causou a maior influ6ncia sobre os resultados, embora a espessura dos filtros de vidro sintetizado tenha causado alguma alteração quer no tempo como no volume final de intumescimento. intumescimento. Já a mudança de temperatura não provocou diferenças significativas nas observações. Numa segunda fase foi investigada a influência deste desintegrante sobre as características de intumescimento de quatro celuloses microcristalinas (CMCr) isoladas ou adicionadas com um lubrificante. Para tanto elaborou-se um planejamento fatorial 4 X 2 X 2. A presença do desintegrante, como esperado, provocou aumento do volume final de intumescimento das CMCr, que apresentaram, no entanto, comportamentos diferenciados frente ao adjuvante. Já a presença do lubrificante conduziu a resultados totalmente dependentes do tipo de CMCr testada. A análise comparativa entre estes produtos demonstrou que somente num caso houve simitaridade de comportamento. / Swelling is one of the decisive factors influencing the disintegrant behavior of compacted pharmaceutical dosage forms and consequently the biopharmaceutical profile of drug substances. Among the various excipients used to promote the disintegration of such dosage forms in its originally primary particles, several substances, classified as swelling disintegrants, are employed. The choice of the most appropriate excipient in this case can be a time and cost consuming enterprise. Additionally it must be considered that the same substance can be delivered in the market by different producers. The question of equivalence represents also an important challenge in the formulation phase. In order to provide more knowledge in this area an apparatus to analyze the dynamic swelling of powder admixtures was developed. Construction factors such as filter porosity, thickness and area were considered. Methodological variants including essay temperature and liquid medium were also evaluated. Croscarmelose, a superdisintegrant, was used as model excipient to test the self built equipment. The change of the test fluid was the determinant factor on the results, although the thickness of the sintered glass filter showed some influence on both swelling volume and swelling time of this adjuvant. As a second step, the influence of this disintegrant on the swelling behavior of four microcrystalline celluloses (MCC) alone or added with a lubricant were investigated by using a 4 X 2 X 2 factorial design. The presence of the disintegrant was able to increase the swelling volume. Both final swelling volume and time were dependent of the MCC type. The lubricant showed different influences on the four tested MCC. A comparative study demonstrated that only in one case these products presented similarly swelling behavior.

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)

Neste trabalho avaliou-se o comportamento coloidal de suspensões nasais contendo micropartículas de celulose (MCC-NaCMC) com o objetivo de desenvolver um produto genérico compatível com o produto referência de mercado. As propriedades reológicas destas formulações possuem alta influência nos atributos críticos de qualidade do produto, como uniformidade de dose, devido sedimentação durante estocagem em prateleira, e também na performance in-vitro/ in-vivo. Realizaram-se testes com diferentes concentrações de MCC-NaCMC e diferentes parâmetros de processo (tempo e taxa de cisalhamento) utilizando um planejamento de experimentos (DoE) de superfície de respostas através de um modelo composto central. As respostas avaliadas foram tamanho de partículas (quantidade em porcentagem de partículas menores que 1&#181;m e D90) através da técnica por difração a laser e viscosidade/tixotropia através de um reômetro rotacional. Influências significativas dos três fatores e efeitos sinérgicos entre eles nas respostas analisadas foram observadas. Desta maneira foi possível obter respostas próximas ao do produto referência de mercado através deste mapeamento. Observou-se também uma alta correlação entre as respostas, pois este estudo mostrou que o tamanho das partículas coloidais controla a viscosidade e tixotropia das dispersões coloidais. Este trabalho mostrou a significativa influência das etapas de processo no comportamento coloidal das formulações. Idealmente o processo deveria ser monitorado por medidas reológicas, porém este controle é inviável devido ao tempo para a reestruturação do sistema (24 horas). Portanto, a melhor alternativa seria o monitoramento do processo por análise de tamanho de partículas online. / In this work, the colloidal behavior of nasal suspensions containing cellulose microparticles (MCC-NaCMC) was evaluated, in order to develop a generic product compatible with the brand-name product. The rheological properties of these formulations have high influence on the critical quality attributes of the product, such as dose uniformity, due to sedimentation during shelf life, and also on in-vitro/in-vivo performance. Tests were performed with different concentrations of MCC-NaCMC and different process parameters (time and shear rate) using a Design of Experiments (DoE) with response surface by central composite design. The responses evaluated were particle size (amount in percentage of particles smaller than 1m and D90) by means of laser diffraction, and viscosity / thixotropy using a rotational rheometer. Significant influences of the three factors and synergic effects among responses were observed. Through this mapping it was possible to obtain nearby responses to the brand-name product. There was also a strong correlation between the responses, because the size of colloidal particles controlled the dispersion viscosity and thixotropy. This study showed the significant influence of the process steps on the colloidal behavior of the formulations. Ideally the process should be monitored by rheological measurements, but this control is not feasible due to the time required for the system rebuilding (24 hours). Therefore, the best alternative would be monitoring the process by the online particle size analysis.

Neste trabalho avaliou-se o comportamento coloidal de suspensões nasais contendo micropartículas de celulose (MCC-NaCMC) com o objetivo de desenvolver um produto genérico compatível com o produto referência de mercado. As propriedades reológicas destas formulações possuem alta influência nos atributos críticos de qualidade do produto, como uniformidade de dose, devido sedimentação durante estocagem em prateleira, e também na performance in-vitro/ in-vivo. Realizaram-se testes com diferentes concentrações de MCC-NaCMC e diferentes parâmetros de processo (tempo e taxa de cisalhamento) utilizando um planejamento de experimentos (DoE) de superfície de respostas através de um modelo composto central. As respostas avaliadas foram tamanho de partículas (quantidade em porcentagem de partículas menores que 1&#181;m e D90) através da técnica por difração a laser e viscosidade/tixotropia através de um reômetro rotacional. Influências significativas dos três fatores e efeitos sinérgicos entre eles nas respostas analisadas foram observadas. Desta maneira foi possível obter respostas próximas ao do produto referência de mercado através deste mapeamento. Observou-se também uma alta correlação entre as respostas, pois este estudo mostrou que o tamanho das partículas coloidais controla a viscosidade e tixotropia das dispersões coloidais. Este trabalho mostrou a significativa influência das etapas de processo no comportamento coloidal das formulações. Idealmente o processo deveria ser monitorado por medidas reológicas, porém este controle é inviável devido ao tempo para a reestruturação do sistema (24 horas). Portanto, a melhor alternativa seria o monitoramento do processo por análise de tamanho de partículas online. / In this work, the colloidal behavior of nasal suspensions containing cellulose microparticles (MCC-NaCMC) was evaluated, in order to develop a generic product compatible with the brand-name product. The rheological properties of these formulations have high influence on the critical quality attributes of the product, such as dose uniformity, due to sedimentation during shelf life, and also on in-vitro/in-vivo performance. Tests were performed with different concentrations of MCC-NaCMC and different process parameters (time and shear rate) using a Design of Experiments (DoE) with response surface by central composite design. The responses evaluated were particle size (amount in percentage of particles smaller than 1m and D90) by means of laser diffraction, and viscosity / thixotropy using a rotational rheometer. Significant influences of the three factors and synergic effects among responses were observed. Through this mapping it was possible to obtain nearby responses to the brand-name product. There was also a strong correlation between the responses, because the size of colloidal particles controlled the dispersion viscosity and thixotropy. This study showed the significant influence of the process steps on the colloidal behavior of the formulations. Ideally the process should be monitored by rheological measurements, but this control is not feasible due to the time required for the system rebuilding (24 hours). Therefore, the best alternative would be monitoring the process by the online particle size analysis.

<p>Cellulose powders from various sources were manufactured and characterized to investigate the influence of their crystallinity index, surface area, and pore volume on sorption phenomena and the relevant pharmaceutical functionality. The influence of the cellulose crystallinity index on moisture sorption was important at low and intermediate relative humidities. At high relative humidities, properties such as surface area and pore volume took precedence in governing the moisture sorption process.</p><p>The theory of physical adsorption of gases onto fractal surfaces was useful for understanding the distribution of water in cellulose and the inner nanoscale structure of cellulose particles. It was found that, as a consequence of swelling, moisture induces a fractal nanopore network in cellulose powders that have a low or intermediate degree of crystallinity. On the other hand, no swelling occurs in highly crystalline cellulose powders and moisture sorption is restricted to the walls of the open pores.</p><p>No correlation was found between the cellulose crystallinity index and the incorporation and release of nicotine in cellulose mixtures. By loading nicotine in highly porous matrices of the Cladophora sp. algae cellulose, higher stability against oxidative degradation, higher loading capacity, and more steady release into an air-stream was achieved than when commercially available microcrystalline cellulose was loaded.</p><p>It was also shown that, by manipulating the structure of cellulose, the undesired hydrolysis of acetylsalicylic acid in mixtures with cellulose can be avoided. It was suggested that a broad hysteresis loop between the moisture adsorption and desorption curves of isotherms at low relative humidities could be indicative of an improved compatibility between acetylsalicylic acid and cellulose.</p><p>In all, this thesis demonstrates how the pharmaceutical functionality of microcrystalline cellulose can be improved via engineering of the structure of native cellulose powders.</p>

Cellulose powders from various sources were manufactured and characterized to investigate the influence of their crystallinity index, surface area, and pore volume on sorption phenomena and the relevant pharmaceutical functionality. The influence of the cellulose crystallinity index on moisture sorption was important at low and intermediate relative humidities. At high relative humidities, properties such as surface area and pore volume took precedence in governing the moisture sorption process. The theory of physical adsorption of gases onto fractal surfaces was useful for understanding the distribution of water in cellulose and the inner nanoscale structure of cellulose particles. It was found that, as a consequence of swelling, moisture induces a fractal nanopore network in cellulose powders that have a low or intermediate degree of crystallinity. On the other hand, no swelling occurs in highly crystalline cellulose powders and moisture sorption is restricted to the walls of the open pores. No correlation was found between the cellulose crystallinity index and the incorporation and release of nicotine in cellulose mixtures. By loading nicotine in highly porous matrices of the Cladophora sp. algae cellulose, higher stability against oxidative degradation, higher loading capacity, and more steady release into an air-stream was achieved than when commercially available microcrystalline cellulose was loaded. It was also shown that, by manipulating the structure of cellulose, the undesired hydrolysis of acetylsalicylic acid in mixtures with cellulose can be avoided. It was suggested that a broad hysteresis loop between the moisture adsorption and desorption curves of isotherms at low relative humidities could be indicative of an improved compatibility between acetylsalicylic acid and cellulose. In all, this thesis demonstrates how the pharmaceutical functionality of microcrystalline cellulose can be improved via engineering of the structure of native cellulose powders.