RESS 공정을 이용한 의약품 미세입자의 제조 및 특성

Abstract

A supercritical fluid(SCF) is defined as a solvent above its critical temperature and pressure. SCFs are unique and useful as extracting agents because their strong solvent powers can be manipulated over a wide range by adjusting temperature and pressure. Furthermore, SCFs have gas-like viscosities and the diffusion coefficients in SCFs are at least an order of magnitude higher than those in liquids, thus promoting mass transfer. On the benefit of these attractive properties, SCFs have been widely applied in extraction, chemical reactions and materials processing, etc. Carbon dioxide is the most widely used SCF because it has a relatively low critical temperature and a moderate critical pressure. In addition, it is inexpensive, leaves, no toxic residue, and is not flammable. Since the critical temperature of CO₂is near ambient, it is attractive for processing heat-sensitive flavors, pharmaceuticals, labile lipids, and reactive monomers. The advantage of crystallization at supercritical conditions over conventional crystallization is especially clear when non-volatile, thermally labile pharmaceutical substances are to be crystallized. As a non-contaminating solvent at close to ambient temperature, ScCO₂might be an attractive alternative to conventional organic solvents. Rapid expansion of a supercritical solution(RESS) with ScCO₂is an attractive process for the production of small, uniform and solvent free powders of low vapor pressure solutes. The advantage of the RESS process that have great potential for particle formation include its capacity for a wide range of inorganic, organic and polymeric materials, low temperature operation(with CO₂) and single step processing. In this study, RESS process for the preparation of ultra-fine drug particles with no organic solvent has been developed with supercritical CO₂. Three drug substances(griseofulvin, benzoic acid and lidocaine) with different solubility in supercritical CO₂were used, and orifice disks and capillary tubes were adapted as an expansion device. The solubilities of the drug substances in supercritical CO₂and the effects of various operating parameters on the characteristics of the particles prepared by RESS process were experimentally investigated. Experimental apparatus for RESS process consists of three main units( an extraction unit, a pre-expansion unit, and a precipitation unit) and auxiliary facilities. The liquid solvent (CO₂) was compressed to the extraction vessel packed with drug substances and glass wool, and saturated supercritical drug solution flew into the pre-expansion unit to expand through the expansion device. Prior to each run, ScCO₂was purged through the bypass section of the extraction unit and continues to flow through the pre-precipitation unit to remove solute residue. The solubilities of the drug substances in supercritical carbon dioxide increased with extraction pressure and temperature, except those of benzoic acid under 2,500 psi. It has been found that the solubility of drug substances in supercritical CO₂had a major effect on the average diameter and particle size distribution of the drug particles prepared by RESS process. The average particle diameter decreased with the solubility, regardless of the kind of drug substance and other operating conditions. The particle diameter also decreased with pre-expansion temperature and increased with orifice diameter nozzle and aspect ratio (L/D) of capillary tube. Although RESS process with solid co-solvent(menthol) produced very fine griseofulvin particles, additional researches might be preformed to be established.