Ketoconazole: Solving the Poor Solubility via Cocrystal Formation with Phenolic Acids

Ketoconazole (KTZ) is an imidazole derivative that is used to treat a wide variety of fungal infections and other human diseases. As a class II compound in the biopharmaceutics classification system, KTZ has low aqueous solubility. To improve this disadvantage, five phenolic acids were employed to form cocrystals with KTZ. The antifungal and anti-inflammatory activity of the phenolic acids may bring an enhanced therapeutic effect and reduce the risk of hepatotoxicity at the same time. The structural information on these five crystalline samples and KTZ were fully disclosed by single-crystal X-ray diffraction. In addition to a previously reported carboxylic acid center dot center dot center dot imidazole N interaction, hydroxyl center dot center dot center dot imidazole N hydrogen bonding also appears in the KTZ cocrystals as a main supramolecular heterosynthon. The short strong hydrogen bonds were observed in two cocrystal structures, which contain slightly longer carboxylic O-H length. N-15 solid-state NMR also provided valuable clues for the confirmation of the molecular/ionization states. The dissolution tests revealed that all the newly obtained cocrystals exhibit significantly improved solubility compared to KTZ.