| Summary: | 博士 === 國立臺灣大學 === 化學工程學研究所 === 105 === In this study, measurement and correlation of solid solubility for active pharmaceutical ingredients （APIs） in supercritical carbon dioxide were investigated. And re-crystallization and micronization for APIs were also investigated using supercritical anti-solvent （SAS） processes. The preparation of pharmaceutical co-crystals were also investigated using supercritical anti-solvent processes.
The solid solubilities of three components of 4-Aminopyridine, Edaravone and Monobenzone in supercritical carbon dioxide were measured using a semi-flow apparatus. Total 63 data points were obtained. These experimental results were correlated by three semi-empirical models : Mendez-Santiago-Teja, Chrastil and Bartle model. The measured data satisfied the self-consistency test, and the parameters in the semi-empirical models are feasible for data extrapolation.
Fumaric acid is used as drug to treat of psoriasis, and also as food additive. In this study, it was re-crystallized and micronized using supercritical anti-solvent（SAS）process. The operating parameter of temperature and pressure were 308.2~328.2 K and 10~20 MPa respectively. Total 9 data points were obtained. The mean particle size of Fumaric acid was reduced from its original 136.3 ± 74.99 μm to 2.84 ± 1.58 μm under the lowest operation conditions. The mean size of products and the recovery of products were involved to the operating parameters: the smallest mean size and 57.95 % of largest recovery operating at lower temperature and pressure, and the largest mean size and 30.84 % of smallest recovery operating at higher temperature and pressure. For pharmaceutical process, the results of the smallest mean size and largest of recovery indicate that the feasibility and potential to alternating the traditional excipient.
Finally, the drug for Alzheimer’s disease: piracteam, and salicylic acid were choose as API and co-former re-crystallization and micronization for a thiazide diuretic chlorothiazide was investigated using semi-continuous supercritical anti-solvent （SAS） process. In this study, piracetam and salicylic acid were chosen as API and co-former respectively and synthesized by prepared various molar ratio of piracetam-salicylic acid-acetone solution operating at supercritical state. Molar ratio solution, temperature and pressure were setting as operating parameters and 1:1~1:4 molar ratio solution was prepared and operating at 35~55 °C of temperature and 10~12 MPa of pressure. After SAS process, co-crystal products was collected and analyzed by SEM, PXRD, ATR-FTIR, DSC, TGA and 1H-NMR respectively. For low recovery of co-crystal products, DSC was a judgment and was firstly introduced to conform the reaction is completed or uncompleted; Then ATR-FTIR was introduced to conform the existing of hydrogen bonding of co-crystal products. The ATR-FTIR spectra of co-crystal products show that piracetam and salicylic acid were bonded with each other; Thermal analysis results such as DSC and TGA show that the good thermal stability of co-crystal products, and the residual solvent containing in co-crystal products were not observed; Morphology of co-crystal products shown on the PXRD pattern indicates that the characteristic of co-crystal products might be near single crystal form. Finally, the 1H-NMR result was illustrated that the stoichiometric ratio of a co-crystal is invariant weather the molar ratio changed at same operating condition for low recovery of product, and it can also be double conformed by TGA curve. This result of double checking has not been reported by other publication using supercritical technique. This novel screening process will further check the ideal co-crystals for developing of pharmaceutical processing.
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