京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19936号 / 農博第2186号 / 新制||農||1044(附属図書館) / 学位論文||H28||N5009(農学部図書室) / 33022 / 京都大学大学院農学研究科森林科学専攻 / (主査)教授 木村 恒久, 教授 西尾 嘉之, 教授 髙野 俊幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

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)

No description available.

High deposition rates on large areas are industrial needs for mass production of microcrystalline silicon (μc-Si:H) solar cells. This doctoral work aims at exploring the usefulness of Matrix Distributed Electron Cyclotron Resonance (MDECR) plasmas to process the intrinsic layer of μc-Si:H p-i-n solar cells at high rates. With the high dissociation of silane achieved in MDECR plasmas, deposition rates as high as 6nm/s and 2.8nm/s have been demonstrated in our lab for amorphous and microcrystalline silicon respectively, without hydrogen dilution. This technique is also promising because it can be easily scaled up on large areas, just by extending the matrix of elementary microwave applicators. This subject was a unique opportunity to cover the whole chain of this field of research : A new MDECR reactor has been specially designed and assembled during this project. Its maintenance and its improvement have been important technical challenges : for example, the addition of a load-lock enabled us to lower the oxygen concentration in our films by a factor of 10. The impact of the deposition parameters (e.g. the ion energy, the substrate temperature, different gas mixtures, the microwave power) has been explored in extensive parametric studies in order to optimize the material quality. Great efforts have been invested in the characterization of the films. Our strategy has been to develop a wide range of diagnostics (ellipsometry, Raman spectroscopy, SIMS, FTIR, XRD, electrical characterizations etc.). Finally, p-i-n cells have been processed with the selected interesting materials. The successive successful improvements in the material quality (e.g. diffusion lengths of holes parallel to the substrate as high as 250 nm) did unfortunately not result in high efficiency solar cells. Their limited performance is in particular due to a very poor response in the red part of the spectrum resulting in low current densities. Consequently, the potential sources of limitation of the reactor, the material and the device have been studied : e.g. the presence of “cracks” prone to post-oxidation in the highly crystallized materials and the risk of deterioration of the ZnO substrate or of the p-doped layer by a too high process temperature or by hydrogen diffusing from the plasma.

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.

Compared to wafer based solar cells, thin film solar cells greatly reduce material cost and thermal budget due to low temperature process. Monolithically manufacturing allows large area fabrication and continuous processing. In this work, several photovoltaic thin films have been developed by rf-PECVD including a-Si:H and μc-Si, both intrinsic and doped on Corning 4 inch glass substrate at low temperature. The conductivity of n type and p type μc-Si at 180ºC was 17S/cm and 7.1E-2S/cm, respectively. B dopants either in a-Si:H or μc-Si films require higher plasma power to get active doping. The B2H6-to-SiH4 flow ratio for p type μc-Si lies from 0.01 to 0.025. Chamber conditions have critical effect on film quality. Repeatable and superior results require a well-established cleaning passivation procedure. Moreover, μc-Si films have been deposited from pure silane on glass substrate by modified rf-ICP-CVD. The deposition rate has been dramatically increased to 5Å/s due to little H2 dilution with crystalline fraction was around 69%, and 6.2Å/s with crystalline fraction 45%. Microstructure started to form at 150ºC with a thin incubation layer on the glass substrate, and became fully dense conical conglomerates around 300nm where conductivity and crystallinity saturated. Additionally, a-SiGe:H films have been developed by modified rf-ICP-CVD. The optical band gaps have been varied from 1.25 to 1.63eV by changing SiH4-to-GeH4 ratio. Also high temperature resulted in low bandgap. Cross-section TEM showed some microcrystllites appeared near interface region. Heterojunction solar cells on p type c-Si wafer have been fabricated using films developed in this thesis. Interference fringes in EQE disappeared on either textured substrate or cells with lift-off contacts. Maximum EQE was 87% around 700nm. I-V curves have also been studied where the interesting kink suggests a counter-diode has formed between emitter region and contacts.

Compared to wafer based solar cells, thin film solar cells greatly reduce material cost and thermal budget due to low temperature process. Monolithically manufacturing allows large area fabrication and continuous processing. In this work, several photovoltaic thin films have been developed by rf-PECVD including a-Si:H and μc-Si, both intrinsic and doped on Corning 4 inch glass substrate at low temperature. The conductivity of n type and p type μc-Si at 180ºC was 17S/cm and 7.1E-2S/cm, respectively. B dopants either in a-Si:H or μc-Si films require higher plasma power to get active doping. The B2H6-to-SiH4 flow ratio for p type μc-Si lies from 0.01 to 0.025. Chamber conditions have critical effect on film quality. Repeatable and superior results require a well-established cleaning passivation procedure. Moreover, μc-Si films have been deposited from pure silane on glass substrate by modified rf-ICP-CVD. The deposition rate has been dramatically increased to 5Å/s due to little H2 dilution with crystalline fraction was around 69%, and 6.2Å/s with crystalline fraction 45%. Microstructure started to form at 150ºC with a thin incubation layer on the glass substrate, and became fully dense conical conglomerates around 300nm where conductivity and crystallinity saturated. Additionally, a-SiGe:H films have been developed by modified rf-ICP-CVD. The optical band gaps have been varied from 1.25 to 1.63eV by changing SiH4-to-GeH4 ratio. Also high temperature resulted in low bandgap. Cross-section TEM showed some microcrystllites appeared near interface region. Heterojunction solar cells on p type c-Si wafer have been fabricated using films developed in this thesis. Interference fringes in EQE disappeared on either textured substrate or cells with lift-off contacts. Maximum EQE was 87% around 700nm. I-V curves have also been studied where the interesting kink suggests a counter-diode has formed between emitter region and contacts.