Performance of Rapid Expansion of Supercritical Solution (RESS) process, under different operation conditions, was conditions were evaluated through the analysis of the drug particle characteristics. The original particles of Lynestrenol with average size of 10 mu m as a drug material were dissolved in supercritical CO2 and then expanded rapidly through a nozzle with 0.6 mm diameter. The effect of temperature, pressure and fraction of solid co-solvent (menthol) was investigated by a two-level factorial experimental design. Our results showed that the pre-expansion pressure, temperature and solid co-solvent can significantly affect the morphology and size of the precipitated particles. In addition, the binary interaction effects of temperature-pressure and pressure-cosolvent were observed to apparently influence the size of outlet particles. In the temperature range from 45 to 60 degrees C, pressures from 15 to 30 MPa and the menthol fraction of 0 to 5 wt.%, the RESS process produced ultrafine Lynestrenol particles (from 58 to 326 nm) from its original particles as reflected by SEM and zetasizer analysis. (C) 2012 Elsevier B.V. All rights reserved.