Application of Supercritical Carbon Dioxide on Solubility and Micronization of Pharmaceutical Compounds

• Main Authors: Yen-Ming Chen, 陳彥銘
• Other Authors: Yan-Ping Chen
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/47020764446909330579

博士 === 臺灣大學 === 化學工程學研究所 === 98 === In this study, measurement and correlation of solid solubility for active pharmaceutical ingredients (APIs) and organic compounds in supercritical carbon dioxide were investigated. And re-crystallization and micronization for APIs were also investigated using rapid expansion of supercritical solution (RESS) and supercritical anti-solvent (SAS) processes. The solid solubilities of three non-steroidal anti-inflammatory drugs (NSAIDs) of antipyrine, 4-aminoantipyrine, 4-dimethylaminoantipyrine, and three antilipemic agents of clofibric acid, fenofibrate, gemfibrozil in supercritical carbon dioxide were measured using a semi-flow apparatus. Total 126 data points were obtained. These experimental results were correlated by three semi-empirical models of Mendez-Santiago-Teja, Chrastil and Bartle. The measured data satisfied the self-consistency test, and the parameters in the semi-empirical models are feasible for data extrapolation. Beside the solubility measurement, the solubility data for nine families of phenolic compounds, naphthalene compounds, nsaids, antilipemic agents, steroids, sulfonamids, vitamins, antioxidant agents and dyes, totally 91 compounds and 2158 data points, were correlated using the solution model in its dimensionless form. This correlation can further be generalized to predict the solubility of complex solid in supercritical carbon dioxide. Furthermore, prediction of the solubility using only single data point was available. The solution model with less parameters yielded comparably satisfactory results to those from commonly used semi-empirical models. The unique prediction ability of the solution model is also demonstrated. Re-crystallization and micronization for an antilipemic agent fenofibrate were investigated using rapid expansion of supercritical solution (RESS) process. The mean particle size of fenofibrate was reduced from its original 19.50 to 3.94 μm under the optimal operation conditions. We also using RESOLV process to formation the fenofibrate particles in aqueous suspension. The mean particle size was further reduced to 2.02 μm after RESOLV treated under the optimal operation conditions. It presented an enhanced dissolution rate for fenofibrate in a simulated gastric fluid that was 2.95 times than the original compound. Finally, re-crystallization and micronization for a sulfonamid sulfathiazole were investigated using semi-continuous supercritical anti-solvent (SAS) process. The mean particle size of sulfathiazole was reduced from its original 42.99 to 2.07 μm under the optimal operation conditions. It was observed that different kinds of solvents resulted in different polymorphisms. The original sulfathiazole had the Form III crystalline. It was re-crystallized and micronized into Form I when acetone was used as the solvent in SAS process. The polymorph changed to Form IV when ethanol was used as the solvents. It also presented an enhanced dissolution rate for sulfathiazle in a simulated intestinal fluid that was 3.19 times than the original compound.