Crystal engineering to improve the physicochemical properties of ketoconazole in the presence of saccharin

Crystal engineering is a novel approach to modify the physicochemical characteristics of an Active Pharmaceutical Ingredient (API) molecule while preserving its structural integrity. Crystal engineering is a technique toward modifying various pharmaceutically related properties of APIs, especially solubility and bioavailability. In this investigation, both strategies were applied to ketoconazole (KTZ), a synthetic imidazole antifungal drug, which is practically insoluble, with saccharin (SAC) in a 1:1 M ratio. A new crystalline form of KTZ with SAC was prepared through the solvent evaporation method. In addition, the spray-dry method was used to prepare the co-amorphous form. The prepared samples were characterized by differential scanning calorimetry, powder X-ray diffraction and Fourier transform infrared spectroscopy. The kinetic solubility of them was determined in phosphate buffer solution (0.1 M) (pH =6.8 at 37 °C). Powder analysis confirmed the formation of new solid crystalline forms and co-amorphous forms via solvent evaporation and spray-drying methods, respectively. The solubility of both synthesized multi-component forms showed a significant increase compared to crystalline KTZ. Findings from this study indicate that the preparation of multi-component crystalline forms of KTZ using SAC markedly improves its solubility.