Overcoming itraconazole limitations via proline cocrystals: improved solubility, dissolution, and antifungal efficacy

Crystal engineering plays a crucial role in the efficient design of pharmaceutical cocrystals, hinging on a deep understanding of intermolecular interactions that influence crystal packing. By leveraging these interactions, researchers can create innovative solid forms with customized physical and chemical properties. This versatile approach is especially valuable for tackling the solubility and bioavailability issues commonly associated with poorly soluble drugs. In this study, we focused on synthesizing cocrystals of itraconazole (ITZ) and proline via the kneading technique, an eco-friendly crystal engineering technique. Our work included comprehensive solid-state characterization, stability assessments, and in vitro efficacy evaluations. We specifically examined how these cocrystals performed in terms of dissolution, solubility, and antifungal activity. Our solid-state characterization results highlighted the formation of significant intermolecular interactions within the cocrystals, particularly hydrogen bonds between ITZ and the functional groups of proline. Notably, the ITZ-proline cocrystals demonstrated superior solubility and faster dissolution rates compared to pure ITZ, alongside increased crystallinity in the newly formed solid state. Additionally, the cocrystals exhibited enhanced antifungal activity and stability. Consequently, our findings have indicated that forming ITZ cocrystals with proline significantly enhances the solubility as well as stability of ITZ, thereby offering a promising antifungal strategy to combat fungal infections.