Screening of High-Solubility Ionic Liquid Excipients for Ketoconazole Based on COSMO-RS and Molecular Mechanisms: A Preliminary In Vitro Cytotoxicity Evaluation

In this study, we screened preliminarily safe, high-solubility ionic liquids (ILs) for ketoconazole (KCZ) using the conductor-like screening model for real solvents (COSMO-RS) based on the logarithmic infinite dilution activity coefficient (lnγ∞) and molecular mechanism analysis. Across all tested temperatures, the experimental solubility of KCZ follows the order: [EMPYR][DCA] > [OMIM][PF6] > [BMPYR][Tf2N] > [BMPYR][l-lactate], consistent with COSMO-RS predictions. [EMPYR][DCA] showed a solubility of 18.86 mg/mL at 25 °C, being 470-fold higher than the corresponding solubility in water. HaCaT cell tests revealed [OMIM][PF6] was more toxic, while the other three ILs had acceptable cytotoxicity, suggesting preliminary safety potential. Moreover, the IL-KCZ mixtures displayed lower cytotoxicity than the neat ILs, and no increase in cytotoxicity was observed under the tested conditions. Quantum chemical calculations and molecular dynamics simulations showed that strong IL-KCZ hydrogen bonding enhances solubility, with [EMPYR][DCA] having optimal HB properties. This study provides preliminary insights for screening IL excipients for KCZ and structurally analogous BCS Class II drugs.