Investigation on Solubility and Micronization of Nitrogen-Containing Drugs Using Supercritical Carbon Dioxide Process
Date Issued
2014
Date
2014
Author(s)
Lee, Chen-An
Abstract
Abstract
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 rapid expansion of supercritical solution (RESS) with cyclone separation as collector and supercritical anti-solvent (SAS) processes.
The solid solubilities of three skeletal muscle relaxants of chlormezanone, metaxalone, methocarbamol, and three vasodilators of cinnarizine, pentoxifylline, piracetam 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.
Fampridine is used to cure multiple sclerosis and Alzheimer’s disease. In this study, it was re-crystallized and micronized using rapid expansion of supercritical solution (RESS) process. The mean particle size of fampridine was reduced from its original 532.3 to 0.32 μm under the optimal operation conditions. Its dissolution rate enhanced by 2.90 times after the RESS processed in a simulated gastric buffer (pH6.8).
Finally, re-crystallization and micronization for a thiazide diuretic chlorothiazide was investigated using semi-continuous supercritical anti-solvent (SAS) process. The chlorothiazide DMSO solvate (chlorothiazide: DMSO(mole ration=1:1.2)) was prepared via a SAS process by using DMSO, DMSO:EtAc (1:4),or DMSO:EtOH (1:4) as a solvent. Then the solvent effect of acetone was also used in SAS process. It was the same polymorph (form I) with original. The mean particle size of chlorothiazide was reduced from its original 43.1 to 0.21 μm under the optimal operation conditions. It also presented an enhanced dissolution rate by 1.40 times after the SAS processed. In this study, the kinetic model of MSMPR (Mixed Suspension, Mixed-Product-Removal ) was also developed.
Subjects
溶解度
原料藥
超臨界二氧化碳
關連
微粒化
擬態多晶型
Type
thesis
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