Unraveling prothionamide solubility enhancement by ionic liquids: from molecular screening to microscopic insights

This study tackles the poor aqueous solubility of prothionamide (PTO), a poorly water-soluble anti-tuberculosis drug, and innovatively proposes utilizing ionic liquid (IL) technology to enhance its solubility. First, the conductor-like screening model for real solvents (COSMO-RS) was utilized with the logarithm of the activity coefficient at infinite dilution (ln γ^∞) serving as the core evaluation basis for the systematic screening of ILs with application potential. Based on a combination of experimental data and COSMO-RS screening results, [BMIM][TfO] exhibited the best solubilization effect on PTO: at 25 °C, the solubility of PTO in [BMIM][TfO] reached 21.02 mg mL^-1, which was 214.5 times higher than its solubility in water, and the solubility increased significantly with temperature elevation. In addition, cytotoxicity experiments confirmed that the selected ILs exhibited no significant toxicity within the effective solubilization concentration range and possessed good bio-safety. Finally, with the aid of quantum chemical (QC) calculations and molecular dynamics (MD) simulations, the dissolution mechanism was explored in depth, and the strong hydrogen bond interaction between PTO and the IL was the key driving force for achieving efficient solubilization. Furthermore, for other class II poorly soluble drugs with similar structures, this article can serve as an important guiding basis for their related research or development work.