| Summary: | 博士 === 臺灣大學 === 化學工程學研究所 === 96 === In this study, measurement and correlation of solid solubility for pharmaceutical compounds in supercritical carbon dioxide was investigated. Measurement of solid solubility for non-steroidal anti-inflammatory drug (NSAID) was accomplished. The solubilities for three NSAIDs of nabumetone, phenylbutazone, and salicylamide in supercritical carbon dioxide were measured using a semi-flow type apparatus. The experimental data were taken at 308, 318 and 328 K, over the pressure range from 10 to 22 MPa. The measured results were then correlated using semi-empirical equations presented by Chrastil, and that presented by Mendez-Santiago and Teja. With optimally fitted parameters, these two equations yielded satisfactory results.
Besides the solubility measurement, correlation of solubility data for sixty pharmaceutical systems was attempted using solution model approach. The infinite dilution activity coefficient for pharmaceutical compound is described by regular solution model coupled with Flory-Huggins equation. Data correlation, parameters simplification and generalization were investigated in our research. A revised generalized equation between model parameter and physical properties of pharmaceutical compounds was proposed. Prediction of solid solubility for
pharmaceutical compounds in supercritical carbon dioxide was demonstrated. In addition, in order to improve the ability for solubility prediction using the generalized correlation equation. Further classification for pharmaceutical systems was suggested.Correlation of solubility data for phenolic compounds was attempted. Similar procedure for parameter generalization was employed. A new generalized correlation equation for phenolic compounds was proposed in this study. Solubility prediction for phenolic compounds was improved by applying the new generalized correlation equation. Furthermore, prediction of solid solubility using only one data point was attempted. Reasonable prediction for solid solubility using solution model was observed when only single data point was available. Finally, the solid solubilities of three NSAIDs measured in this study and seven other NSAIDs in supercritical carbon dioxide were correlated by applying the solution model. The parameters in the solution model could be generalized for the specific drug of NSAIDs. Predicted solubilities of ten NSAIDs in supercritical carbon dioxide were demonstrated to be reliable.
In our research, micronization of two pharmaceutical compounds with higher solid solubility in supercritical carbon dioxide, nabumetone and phenylbutazone, using the rapid expansion of supercritical solution process (RESS) was investigated. For the phenylbutazone, the crystal habit and polymorphism behavior were modified after the RESS process. Irregular particle with polymorph conversion from δ-form to β-form was obtained. For the nabumetone, effect of process parameters was discussed by design of experiment (DOE) for extraction temperature, extraction pressure, pre-expansion temperature and post-expansion temperature. Results from analysis of variance (ANOVA) showed that the effect of post-expansion temperature is most significant. Lower post-expansion temperature favor the production of small particle. In addition, interaction effect between extraction pressure and post-expansion temperature was confirmed from the results of analysis of variance. Further investigation for micronization of nabumetone was demonstrated. The smallest particle obtained from the RESS process is 3.3 μm in this study. Further study on dissolution profile for original and processed nabumetone was investigated. After the RESS process, dissolution rate of nabumetone was improved significantly.
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