A RESS (rapid expansion of supercritical solution) process for the preparation of ultra-fine drug particles with no organic solvent has been developed with supercritical CO 2 . Three drug substances with different solubility in supercritical CO 2 were used, and orifice disks and capillary tubes were adapted as an expansion device. The solubilities of drug substances in supercritical CO 2 and the effects of various operating parameters on the characteristics of the particles prepared by RESS process were experimentally investigated. The solubility of the drug substance in supercritical CO 2 had a major effect on the average diameter of the particle prepared by RESS process, and the particle diameter decreased with the solubility for all the drugs and operating conditions. The particle diameter also decreased with preexpansion temperature and increased with the hole diameter of the orifice nozzle and aspect ratio (L/D) of the capillary tube.