Micronization by rapid expansion of supercritical solutions to enhance the dissolution rates of poorly water-soluble pharmaceuticals

The dissolution of a drug into the biological environment can be enhanced by reducing the particle size of the drug. In this study the rapid expansion of supercritical solutions (RESS) process was employed to micronize racemic ibuprofen, and the dissolution rate of the micronized product in a buffered solution was examined. The chiral nonsteroidal antiinflammatory, racemic ibuprofen, was used as a model drug because its dissolution rate is limited by its poor solubility in water. The phase behavior of the ibuprofen-CO2 binary system was investigated prior to the solubility measurements being undertaken. The solubility of racemic ibuprofen in supercritical CO2 was measured using a dynamic apparatus at pressures between 80 and 220 bar and temperatures of 35, 40, and 45 degreesC. The solubility data was modeled using the Peng-Robinson equation of state with van der Waals mixing rules. The ratio of It and S isomers in the extract was found to be the same as that in the original material. The solubility of pure optical isomers of ibuprofen, namely, (S)-ibuprofen and (R)-ibuprofen, were also determined at 35 degreesC within the pressure range of 80-200 bar. It was found that (S)-ibuprofen exhibited solubility in CO2 similar to (R)-ibuprofen, and the solubility of the pure isomers was at least 60% higher than that of the racemic ibuprofen at all pressures. The RESS experiments involved studying the effect of spraying distance, the pre-expansion pressure, and nozzle length on the particle size. The median particle size of ibuprofen precipitated by RESS was less than 2.5 mum. Although the particles obtained were aggregated, they were easily dispersed by ultrasonication in water. The pre-expansion pressure and nozzle length had no effect on the particle size and morphology within the range of operating conditions studied. An increase in spraying distance resulted in a slight decrease in particle size and degree of aggregation. The powder dissolution rate of racemic ibuprofen was enhanced as the particle size decreased. The degree of crystallinity of the processed ibuprofen was slightly decreased; as a result, the micronized product exhibited a higher disk intrinsic dissolution rate. The increase in dissolution rate of ibuprofen was hence due to both the reduction in particle size and the degree of crystallinity.