Supercritical fluid technology for particle size reduction
Abstract
The broad objective of this research is to test the hypothesis that crystallization using supercritical fluid technology is a potentially superior method for size reduction of pharmaceutical solids compared with mechanical milling. The specific aims of this study are (1) To determine the critical process variables affecting particle size, particle size distribution, yield and level of residual carrier solvent, (2) To consistently obtain average particle sizes of 5 μm or less, and (3) To determine the effect of the drug solution composition on particle size. In this study, supercritical carbon dioxide (CO2) is used as a non-solvent to cause precipitation of methylprednisolone acetate from various organic solvents resulting in a finely divided powder. The process variables include temperature and pressure of the CO2, agitation rate, CO2 flow rate, drug solution flow rate, and drug solution temperature. The effect of drug solution composition was examined by adjusting the drug concentration, by using different carrier solvents, and by comparing six different steroids after precipitation from tetrahydrofuran. Carrier solvents were chosen based on their dielectric constant and vapor pressure. Results show that yield and level of residual carrier solvent are not affected by the process variables examined in this study, while particle size and particle size distribution are most dependent upon adequate dispersion of the drug solution into the supercritical fluid. Finely dispersing the drug solution, decreasing its rate of addition, and increasing the agitation rate results in the smallest average particle size and narrowest particle size distribution. Concentration of the drug solution does not affect the particle size or particle size distribution, while using carrier solvents possessing a high dielectric constant and/or low vapor pressure results in a larger average particle size. Methylprednisolone acetate resulted in the largest average particle size when compared to the other steroids tested. It was determined that the slightly higher solubility of methylprednisolone acetate in the CO 2/solvent mixture lead to the increase in particle size. Under carefully controlled processing conditions, average particle sizes of 5 μm or less are produced.
Degree
Ph.D.
Advisors
Nail, Purdue University.
Subject Area
Pharmaceuticals
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