Processing of ketoconazole–4-aminobenzoic acid cocrystals using dense CO2 as an antisolvent

Abstract The aim of this work was to improve the dissolution rate of a poorly water–soluble antifungal drug, ketoconazole (KET), by forming cocrystal with 4-amino benzoic acid (PABA). Gas Anti-Solvent (GAS) technique with the use of dense carbon dioxide as an anti-solvent was applied for cocrystallization. The effects of KET to PABA molar ratio (1:2, 1:1 and 1:0.5), temperature (25–45 °C) and solvent type (methanol, ethanol, acetone and a solvent mixture of methanol and ethanol) on drug content and dissolution rate were investigated. It was found that the drug content of the produced cocrystal via GAS was approximately 77%, which was equivalent to 1:1 molar ratio, irrespective of the drug to coformer molar ratio used at the starting. Cocrystal synthesized by GAS using KET to PABA molar ratio of 1:2 in methanol at 25 °C exhibited the fastest dissolution rate compared to unprocessed drug, physical mixture and cocrystal prepared by slow evaporation.