Ketoconazole ionic liquids with citric and tartaric acid: Synthesis, characterization and solubility study

Solid forms of drugs have some potential problems such as low solubility, slow dissolution rate, variable bioavailability and polymorphism. One of the strategies to overcome these problems is the preparation of ionic liquid forms of drugs. Recently, active pharmaceutical ingredient (API) was employed to produce an ionic liquid, using a counter-ion. Ketoconazole (KTZ) (synthetic imidazole antifungal drug), which is a practically insoluble drug, citric acid (CA), and tartaric acid (TA) were chosen as counter-ions for preparing the ionic liquid. Different molar ratios (1:1, 1:2.5, 1:5) of KTZ–CA and KTZ–TA were prepared applying solvent evaporation method with methanol as the solvent. The viscosity and the solubility in phosphate buffer (0.1 M) (pH = 6.8 at 37 °C of KTZ–CA and KTZ–CA) were measured. More than three unit differences between pKa of KTZ and the studied carboxylic acids, characterization by different instrumental analysis methods, and previous studies on imidazole ring and carboxylic acid confirm the formation of ionic hydrogen bond between the imidazole functional group of KTZ and the carboxyl group of CA and TA. The findings of this study indicated that as molar ratio of CA and TA increases, the apparent solubility of the IL improves, while the solubility of the physical mixtures has a minor difference with non-processed KTZ. These results could be utilized in overcoming the disadvantages of KTZ solid form and increasing its solubility.