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Thesis (M.S.)--Oregon State University, . / Printout. Includes bibliographical references (leaves 99-103). Also available on the World Wide Web.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

京都大学 / 0048 / 新制・論文博士 / 博士(工学) / 乙第12950号 / 論工博第4126号 / 新制||工||1628(附属図書館) / 32249 / 京都大学大学院工学研究科化学工学専攻 / (主査)教授 長谷部 伸治, 教授 前 一廣, 教授 吉田 潤一 / 学位規則第4条第2項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Over recent years the delivery of nanosized drug particles has shown potential in improving bioavailability. Drug nanosizing is achieved by 'top-down' and by 'bottom-up' approaches. Owing to limitations associated with the top-down techniques, such as high energy input, electrostatic effects, broad particle size distributions and contamination issues, great interest has been directed to alternative bottom up technologies. In this study, the hypothesis that microreactors can be used as a simple and cost-effective technique to generate organic nanosized products is tested using three steroids (hydrocortisone, prednisolone and budesonide). Arrested antisolvent nanoprecipitation using ethanol (solvent) and water (antisolvent) was conducted within the microreactors. To enable experimental design for the microreactor studies, solubility profiles in different ethanol-water combinations at 25 °C were explored. All three drugs' solubility increased with increasing ethanol concentration showing maxima at 80-90 % v/v ethanol-water mixtures. Because of the complex multivariate microfluidic process, artificial neural network modelling was then employed to identify the dominant relationships between the variables affecting nanoprecipitation (as inputs) and the drug particle size (as output). The antisolvent flow rate was found to have the major role in directing drug particle size. Based on these successful findings, the potential of preparing pharmaceutical nanosuspensions using microfluidic reactors was researched. A hydrocortisone (HC) nanosuspension (NS) was prepared by introducing the generated drug particles into an aqueous solution of stabilizers stirred at high speed with a propeller mixer. A tangential flow filtration system was then used to concentrate the prepared NS. Results showed that a stable narrow sized HC NS of amorphous spherical particles 500 ± 64 nm diameter and zeta potential -18 ± 2.84 mV could be produced. The ocular bioavailability of a microfluidic precipitated HC NS (300 nm) was assessed and compared to a similar sized, milled HC NS and HC solution as a control. The precipitated and the milled NS achieved comparable AUC0-9h of 28.06 ± 4.08 and 30.95 ± 2.2, respectively, significantly (P < 0.01) higher than HC solution (15.86 ± 2.7). These results illustrate the opportunity to design sustained release ophthalmic formulations. Going nano via microfluidic precipitation was also exploited to tailor budesonide (BD) NS for pulmonary administration. The in vitro aerosolization by nebulization of a BD NS was studied in comparison with a commercial BD microsuspension. Overall, the fine particle fraction generated from BD NS (56.88 ± 3.37) was significantly (P < 0.05) higher than the marketed BD (38.04 ± 7.81). The mean mass aerodynamic diameter of BD NS aerosol (3.9 ± 0.48 μm) was significantly smaller (P < 0.05) than the microsuspension (6.2 ± 1.09 μm) indicating improved performance for BD NS. In conclusion, findings of this study support the hypothesis of using microfluidic nanoprecipitation as a promising and economical technique of drug nanosizing.

A ampliação de escala na produção de fármacos é um dos principais gargalos na indústria químico-farmacêutica. A Tecnologia de Microrreatores (TMR) soluciona este problema através da perspectiva de desenvolver uma metodologia dentro do laboratório que facilmente pode ser implementada em escala de produção industrial através do aumento do número de microrreatores arranjados em paralelo ou numbering-up. Além disso o uso do microrreator apresenta diversas vantagens, tais como excelente controle de troca térmica, homogeneização mais eficiente, aumento da velocidade da reação, alta conversão e seletividade, segurança ao se trabalhar com reagentes e produtos tóxicos, além da redução da geração de resíduos. O objetivo deste trabalho foi transpor a reação de síntese de um derivado da tiazolidina-2,4-diona, um intermediário para produção de fármacos no combate à diabetes, do processo batelada para microrreator em fluxo contínuo. Através dos resultados foi determinado que não existe a necessidade de mais de 5,5h para se obter o rendimento máximo (96%) da reação em batelada com o n-propanol como melhor solvente a uma velocidade inicial de 1,25 mmol/L.min e utilizando piperidina como melhor base na concentração ideal de 0,053 M. A transposição para o microrreator mostrou que os processos apresentam resultados semelhantes quando utilizada a temperatura de ebulição normal do solvente. Porém, como o microrreator possibilita o aumento da temperatura, foi obtido um rendimento de 76% a 160°C em 20 min de tempo médio de residência utilizando n-propanol como solvente, mostrando um aumento nominal de rendimento de 47%, se comparado com o processo batelada. Esses resultados contribuíram para uma produção cerca de 3 vezes maior atingindo o valor de 3,47 mg/min. Pôde-se concluir que o uso de microrreator deve ser melhor difundido nas indústrias químico-farmacêuticas podendo suprir as produções dos reatores batelada, com maior segurança e eficiência, gerando menos resíduos e ocupando uma área física muito menor. / Scaling-up in drug production is one of the main bottlenecks in the chemical-pharmaceutical industry. Microreactor Technology (MRT) solves this problem from the perspective of developing a methodology within the laboratory that can easily be implemented on an industrial scale by increasing the number of microreactors arranged in parallel or numbering-up. In addition, the use of microreactor has several advantages, such as excellent thermal exchange control, more efficient homogenization, increased reaction rate, high conversion and selectivity, safety when working with reagents and toxic products, as well as reduction of waste generation. The main objective of this work was to transpose the reaction of a thiazolidine-2,4-dione derivative, an intermediate for the production of drugs against diabetes, from the batch process to the microreactor in a continuous flow. From the results it was determined that there is no need for more than 5.5h to obtain the maximum yield (96%) in the batch reaction with n-propanol as the best solvent and with an initial reaction rate of 1.25 mmol/L.min using piperidine as the best basis at the optimum concentration of 0.053 M. Transposition to the microreactor showed that the processes show similar results when used at the normal boiling temperature of the solvent. However, as the microreactor enables operation with increased temperature, yield of 76% at 16 °C in 20 min of mean residence time was obtained using n-propanol as the solvent, showing a nominal yield increase of 47% when compared to the batch process. These results contributed to about 3 times higher production reaching a value of 3.47 mg/min. It could be concluded that the use of microreactor should be better disseminated in the chemical-pharmaceutical industries, being able to supply batch reactor productions with greater safety and efficiency, generating less waste and occupying a much smaller physical area.

Hydrotreating reaction of vegetable oil is an alternative method for the production of renewable biodiesel fuel. This reaction involves conversion of triglycerides into normal alkanes, leads to a deoxygenated and stable product, which is fully compatible with petroleum derived diesel fuel. The hydrotreating process uses hydrogen to remove oxygen from triglyceride molecules at elevated temperature in the presence of a solid catalyst. This work focused on the development of microtechnology-based chemical reaction process for liquid biofuel production from oil-based biofuel feedstock. A hydrotreating reaction of oleic acid and triolein as model compounds and jatropha oil as real feedstock was studied in a continuous flow microchannel reactor of inner diameter 500 ��m and of varied length; 1.5 - 5 m. The microchannel reactor was fabricated from SS-316. The walls of the microreactor were coated with a thin Al���O��� film, which was then impregnated with Ni-Mo catalyst containing phosphorus as promoter. The reactions were carried out in the temperature range of 275-325 ��C, residence time in the range of 11-40 s and at constant system pressure of 500 psig. The results showed that the microchannel reactor was suitable for the hydrotreating process. Complete conversion of the fatty acid hydrotreating reaction was achieved at a reaction temperature of 325 ��C. Hydrotreating of fatty acids occurred primarily via hydrodeoxygenation and the main liquid products were octadecane and heptadecane. Fatty alcohol, fatty acid and long chain esters were formed as reaction intermediates. Hydrotreating of triglycerides proceeded via the hydrocracking of triglycerides into diglycerides, monoglycerides and fatty acids. Then fatty acids were subsequently deoxygenated to hydrocarbons. The conversion of fatty acids and triglycerides increased with increasing temperatures. A detailed mathematical model was developed to represent this two-phase chemical reaction process. The mathematical model was entirely based on first principles, i.e. no adjustable or correlation parameters were used. Kinetic parameter estimation was performed and the predicted results were in good agreement with experimental results. / Graduation date: 2013 / Access restricted to the OSU Community, at author's request, from Sept. 17, 2012 - Sept. 17, 2013

Microchannel process technology (MPT) components are chemical unit operations which exploit highly-parallel arrays of microchannels to process large fluid volumes for portable and distributed applications. Microchannel heat exchangers (MCHXs) have demonstrated 3 to 5 times higher heat fluxes when compared to conventional heat exchangers resulting in proportionate reductions in size and weight. The most common fabrication approach for producing MPT components is microchannel lamination, or microlamination, in which thin layers of metal or polymer are patterned with microchannel features, registered, and bonded to produce monolithic components. Currently, the most common microlamination architecture involves the photochemical machining and diffusion bonding of metal foils. Prior work has established that the yields in diffusion bonding often drive the costs of MCHXs. Laser keyhole welding has been proposed as an alternative bonding technology providing the potential for faster cycle times, smaller weld widths and layer-to-layer evaluation of hermeticity leading to higher yields. Furthermore, laser weldments have small heat-affected zones providing excellent mechanical strength. In this study, efforts are made to evaluate the feasibility of using laser welding in the microlamination of a high-temperature counter-flow heat exchanger made of a Ni superalloy. Preliminary efforts were focused on the development and validation of weld strength estimation models. These models were then used to narrow down the range of process parameters and a final set of process parameters was determined through the use of a full factorial experiment with weld strength, joining efficiency and weld gap as response variables. The most acceptable parameter set was used to demonstrate the fabrication of a Haynes 214 microchannel array with adequate bond strength and hermeticity and minimal thermal warpage. / Graduation date: 2013

A new adhesive bonding method is introduced for microlamination architectures, for producing low-temperature microchannel arrays in a wide variety of metals. Sheet metal embossing and chemical etching processes have been used to produce sealing bosses and flow features, resulting in approximately 50% fewer laminae over traditional methods. These lamina designs are enabled by reduced bonding pressures required for the new method. An assembly process using adhesive dispense and cure is outlined to produce leak-free devices. Feasible fill ratios were determined to be 1.1 in general and 1.25 around fluid headers, largely due to gaps between faying surfaces caused by surface roughness. Bond strength investigation reveals robustness to surface conditions and a bond strength of 5.5-8.5 MPa using a 3X safety factor. Dimensional characterization reveals a two sigma (95%) post-bonded channel height tolerance under 10% (9.6%) after bonding. Patterning tolerance and surface roughness of the faying laminae were found to have a significant influence on the final postbonded channel height. Leakage and burst pressure testing on several samples has established confidence that adhesive bonding can produce leak-free joints. Operating pressures up to 413 kPa have been satisfied, equating to tensile pressure on bond joints of 1.9 MPa. Higher operating pressures can be accommodated by increasing the bond area of devices. A two-fluid counterflow microchannel heat exchanger has been redesigned, fabricated and tested to demonstrate feasibility of the new method. Results show greater effectiveness and higher heat transfer rates, suggesting a smaller device than the original heat exchanger. A maximum effectiveness of 82.5% was achieved with good agreement between theoretical and experimental values. Although thermal performance was improved, higher pressure drops were noted. Pressure drops were predicted with a maximum error of 16% between theoretical and experimental values. Much of the pressure drop was found to be in the device manifolds, which can be improved in subsequent designs. Fluid flow simulation results show a 45-65X reduction in fluid leakage velocity past sealing bosses, thereby mitigating adhesive erosion concerns. Theoretical models indicate that the worst-case adhesive erosion rate is 1/12th the rate of aluminum and 1/7th the rate of stainless steel, implying satisfactory reliability in high fluid velocity applications. Economic comparison indicates an 83% reduction in material cost and 71% reduction in assembly cost with the new adhesive bonding process, when compared to diffusion bonding for the recuperator investigated in this study. Adhesive compatibility with common refrigerants is reviewed through literature references, with no adverse compatibility issues noted. The findings of this research suggest a fairly quick path to commercialization for the new bonding method. Future studies required to pursue commercialization are liquid and gas permeability evaluations, and long term strength and performance testing of adhesives in targeted applications. / Graduation date: 2012 / Access restricted to the OSU Community at author's request from Mar. 26, 2012 - Mar. 26, 2013

This thesis is devoted to the study and application of gas-liquid segmented flow microfluidic reactors. In the most common configuration, these devices facilitate mixing and reaction of liquid-phase constituents by the introduction of non-participating gas bubbles in a microchannel flow. In this work, segmented flow microreactors are modelled, designed, fabricated, tested and applied. Residence time distribution (RTD) within the reactors is employed as a measure to quantify reactor performance. In order to narrow the residence time distribution, a novel microreactor with hybrid surface properties is developed. The injector channel is made wetting to the liquid phase to assure stable segmentation while the reaction channel is rendered less wetting to eliminate the lubricating film surrounding the gas bubbles. It is demonstrated through RTD testing that the hybrid microreactor shows up to 63% gain in performance over the fully-wetting reactor. A numerical model is developed to study the feasibility of shear-induced breakup of nanoparticles within gas-liquid segmented flow reactors. The critical shear rate required for breakup is calculated from literature and is compared to the maximum shear rate value found through modeling to give a prediction for the possibility of particle breakup. Previous experimental data support the existence of shear-induced particle breakup. Here, the transition region where the liquid film meets the liquid plug is found to exhibit relatively high shear stresses. With these results, the potential role of shear-induced processing of nanoparticle systems is discussed. Lastly, fabricating devices with long microchannel lengths, as required in this work, necessitates the ability to densely pattern microfluidic channels on a substrate with minimal defects. The fabrication methods developed and employed here for densely patterned, high surface area microchips are presented in detail. These microchips were employed in this thesis work and also in other collaborative works.