Improved dissolution of ketoconazole by coprecipitation with nicotinamide using gas anti-solvent process

Abstract

The gas anti-solvent (GAS) process utilizing compressed carbon dioxide as an anti-solvent was applied to prepare coprecipitated particles between ketoconazole (KET), a poorly water-soluble drug substance, and nicotinamide (NIC), a water-soluble carrier. KET-NIC solid dispersion was also prepared by solvent evaporation and compared with the coprecipitated particles obtained from GAS process. DSC results indicated that KET formed eutectic with NIC at a weight ratio of 7:3. The results showed that the KET-NIC coprecipitated particles prepared by the GAS process, at an initial weight ratio of 1:1.5 in ethanolic solution, had suitable particle morphology and exhibited a remarkably higher dissolution than solid dispersion, physical mixture, and unprocessed KET. The formation of a simple eutectic mixture between KET and NIC in the coprecipitates prepared by both processes was confirmed by DSC, FTIR spectroscopy and powder X-ray diffraction. The enhanced dissolution of the GAS coprecipitated particles might be attributed to the eutectic formation, the improved wettability and hydrophilic microenvironment by the water-soluble carrier, the lower crystallinity, and the smaller size of the drug crystals.