Solution enhanced dispersion by supercritical CO2 (SEDS) was modified to prepare poly (L-lactic acid) (PLLA) microparticles used for controlled release of water soluble drugs. The preparation conditions of the water involved micronization process were explored. Results showed that the modifier (ethanol) promoted the mutual miscibility between water and supercritical CO2. The flow rates ratio (R) of the aqueous solution, ethanol and methylene chloride solution significantly affected the morphology of the microparticles and the optimized R was 1/7.5/2.5. Morphine loaded PLLA (MF-PLLA) spheroid microparticles with a mean diameter of 2.45 mu m were also prepared under the optimum conditions, and their drug loading was 4.73 +/- 0.34%. The in vitro release profile showed a burst increase in the first 4 h followed by a slow sustained release over a period of about 168 h, suggesting that the modified SEDS method could be used to prepare the water soluble drug-loaded microparticles with sustained release profile. (c) 2012 Elsevier B.V. All rights reserved.