Study On Micronizing Process Of Bezafibrate By Supercritical Technology

Bezafibrate(BZ), also named bezalip, is mostly insoluble in water, but is soluble in methanol and slightly soluble in ethanol. The phenoxy acid derivative BZ, is a common used cholesterol-lowering drug. It is also used for treatment for hypercholesterolemia and mixed hyperlipidemia patients because of its cholesterol-lowering effect. Supercritical fluid granulation technique is a new technique of particle micronization. In the paper, bezafibrate was chosen as model medicine and the effects of process parameters on preparation of drug particles by gas anti-solvent(GAS) and rapid expansion of supercritical solution(RESS) were studied.The solubility of BZ in pure supercritical carbon dioxide and supercritical carbon dioxide with cosolvent was measured by dynamic method. The experimental temperature was from 308.15 K to 328.15 K and experimental pressure was from 10 MPa to 30 MPa. Ethanol, acetone and ethyl acetate were chosen as cosolvents respectively. The results showed that solubility of BZ increased with the increase of operating pressure and temperature. In addition, solubility of BZ in supercritical carbon dioxide increased with cosolvent used and the solubility increased with the increase of concentration of cosolvent. The solubility of BZ was different when different cosolvents with same concentration were used. The solubility was highest when ethanol was used as cosolvent and the solubility was higher with ethyl acetate used as cosolvent than that with acetone used as cosolvent. Christal model was applied to correlate BZ solubility and the result was desirable.BZ particles were recrystallized by GAS process. The effect of process parameters such as crystallizing temperature and pressure, concentration of BZ, solvent type and the rate of gas(CO2)discharge on the particle size and crystal habit was evaluated. The result showed that needle-like(about 150 mm long, about 1.5 mm in diameter) particles were obtained by GAS process. Shorter particles with lesser length-diameter ratio were obtained at higher crystallizing temperature and lower pressure. When the concentration of BZ increased, the particle length and length-diameter ratio decreased. Particle size was also different when using different solvents. But when the flow rate of CO2 increased, particle size did not show significant change. The particles before and after GAS were analyzed by light microscope, SEM, FT-IR, XRD, and TG-DSC. The result showed a relative polymorph conversion of BZ after GAS process.BZ particles were micronized by RESS process. The effect of process parameters such as extraction temperature, extraction pressure, collecting temperature, nozzle temperature and nozzle diameter on particle size and morphology was investigated. The experimental results demonstrated that mean particle diameter of BZ precipitated by RESS was about 1.4mm and particle size was narrow distribution. An increase in extraction temperature and extraction pressure resulted in a decrease in particle size. The particle size increased with nozzle temperature, nozzle diameter and collecting temperature increased.