Molecular interactions, solubility, and cytotoxic activity of 4‑hydroxycoumarin in choline chloride‑based acidic deep eutectic solvents.

This study systematically investigated the solubility enhancement of 4-hydroxycoumarin (4HC), a poorly water-soluble pharmaceutical compound, in three novel acidic deep eutectic solvents (ADESs) prepared from choline chloride (ChCl) and acidic hydrogen bond donors encompassing propionic acid (Pro), acetic acid (Ace) and lactic acid (Lac). The solubility measurements were conducted Appling the shake-flask method at 298.15-313.15 K. The ChCl/Pro system exhibited unprecedented more than 500-fold solubility improvement over the pure water, with solubility Increasing in the order: ChCl/Pro > ChCl/Ace > ChCl/Lac. Hansen Solubility Parameters (HSPs) analysis confirmed hydrogen bonding and acidity as dominant dissolution factors. In addition, advanced thermodynamic models (Wilson, e-NRTL, UNIQUAC) accurately correlated experimental solubility data, with the Wilson model achieving ARD percentage values as low as 0.10%. Thermodynamic analysis revealed the dissolution process is endothermic and enthalpy-driven. MTT cytotoxicity assays on HT29 colon cancer cells demonstrated IC₅₀ values in the 20-100 µg/mL range, with differential cytotoxicity correlated to solvent composition. These findings identify ChCl/Pro as the optimal ADES candidate (500-fold solubility enhancement, IC50 20-100 µg/mL range) for preformulation development of 4HC, establishing a data-driven foundation for green solvent-based pharmaceutical applications.