Rapid expansion of supercritical solutions (RESS) was applied to tolbutamide and barbital. The solubility in supercritical CO2 was determined to estimate the extraction efficiency roughly by a simple method and accurately by a direct spectrophotometric technique. The latter revealed that the solubility of tolbutamide was a function of applied pressure and temperature and was proportional to the pressure. No significant difference in solubility between polymorphic Forms I and II of tolbutamide was detected. Tolbutamide and barbital particles produced by the RESS were characterized by size distribution measurement, polymorph identification and morphological evaluation. Significant size reduction to micron or sub-micron level with narrow size distribution was achieved, while conventional mechanical grinding had only slight effect. The particle size was greatly affected by both extraction and expansion conditions. The lower the extraction temperature was, the smaller was the mean particle size. Higher extraction pressure resulted in smaller mean particle size when compared at the same extraction temperature. The mean particle size was reduced by lowering the spray nozzle temperature, by lowering the expansion chamber temperature, by increasing the CO2 amount per spray, and by increasing the exhaust gas flow rate. The RESS processing realized the polymorphic conversion as well. As for tolbutamide, three polymorphs (Forms I, II, and IV) out of four could be produced by changing the extraction conditions, and in the case of barbital, one polymorph (Form II) out of three was produced consistently.