- 學位論文
利用超臨界快速膨脹法進行Gemfibrozil、Lidocaine、Ethosuximide及Tolbutamide藥物微粒化之研究
Micronization of Gemfibrozil, Lidocaine, Ethosuximide and Tolbutamide by Rapid Expansion Supercritical Technique
摘要
藥物粒徑的大小，對於生物可利用率有非常大的關係。本研究中，利用超臨界快速膨脹法( RESS )，各別進行藥物Gemfibrozil，Lidocaine和Ethosuximide的微小化實驗。針對藥物Gemfibrozil，於特定操作條件下，微粒化過程會發生的分相( heterogeneous )現象，本研究以相平衡的觀點出發提出合理解釋，並藉由改變其萃取壓力、膨脹前溫度等操作條件，成功完成微粒化程序。對於二氧化碳中溶解度較高的藥物，如Lidocaine和Ethosuximide，進行萃取溫度、萃取壓力、膨脹前溫度、膨脹後溫度、噴嘴孔徑等參數效應的探討。研究發現藥物Ethosuximide，經RESS處理後，晶型結構有所轉變。最後，選定於二氧化碳中溶解度較低的藥物Tolbutamide，以添加固態共溶劑的方法，提高其溶解度，並進行微粒化操作，膨脹期間因固態共溶劑的存在，避免目標藥物析出時的互相堆疊，成功獲取更小平均粒徑的分散微粒，其晶型結構也由form I轉為form II。最後將其微粒化前後藥物，進行溶離試驗分析，發現經快速膨脹法處理過後藥物，其溶離能力均有顯著的提升。
並列摘要
The particle sizes of the pharmaceutical substances are important for their bioavailability, which can be improved by size reduction. In this study, Gemfibrozil, Lidocaine, and Ethosuximide were micronized using the rapid expansion of supercritical solution (RESS) technique. It is found that Gemfibrozil were heterogeneous under certain operational conditions of the RESS process. This phenomenon was explained by phase equilibrium theory. Under modified conditions, the dispersible and micronized gemfibrozil particles were successfully obtained. The effects of extraction temperature, extraction pressure, pre-expansion temperature, post-expansion temperature, and nozzle diameter on the size and morphology of the micronized Lidocaine and Ethosuximide which were further investigated. The crystal habit and polymorphism behavior for Ethosuximide were modified after the RESS process. Finally, Tolbutamide was studied which had an extremely low solubility in supercritical carbon dioxide. Solid co-solvent menthol was used for the micronization of Tolbutamide. The solid co-solvent hindered the particle growth and results in Tolbutamide particle with smaller mean size and polymorphism behavior from form I to form II. Evaluation and comparison of dissolution profile for the original and RESS processed pharmaceutical compounds were investigated. Significant enhancement of dissolution rates for all micronized pharmaceutical compounds was observed.