Molecular and Thermodynamic Evaluation of Ibuprofen and Mefenamic Acid Solubility in Choline Chloride–Propylene Glycol Deep Eutectic Solvent

Abstract Understanding drug–solvent interactions at the molecular level is crucial for improving the solubility of poorly water-soluble pharmaceuticals. In this work, we computationally investigate the solubility behavior of ibuprofen (IBU) and mefenamic acid (MFA) in a choline chloride–propylene glycol (CHL–PG) deep eutectic solvent (DES) compared to water, using a hybrid approach that integrates PM3 semi-empirical conformer screening with ωB97X-D density functional theory calculations including dispersion and basis-set superposition error corrections. The DES is shown to form a stable dual hydrogen-bonded network (O–H and Cl–H), resulting in enhanced reactivity and favorable solute–solvent orbital interactions compared to aqueous media. Solubility strength (SS and solvation-corrected SScorr) and liquid-phase Gibbs free energy (ΔG) analyses reveal that IBU interacts favorably with the DES (SS = − 0.75 eV; SScorr = − 0.15 eV; ΔG = − 0.147 eV), in agreement with experimental solubility (204.52 mg/g), whereas MFA exhibits weaker and non-spontaneous association (SS = − 0.57 eV; SScorr = 0.46 eV; ΔG = 0.432 eV; LSS = 1.06 mg/g). Thermodynamic parameters further confirm the spontaneous, exothermic nature of IBU–DES solubilization and the comparatively unfavorable MFA–DES interaction. These results demonstrate the selective solubilization capability of CHL–PG DES and provide quantitative insights for rational design of DES-based drug delivery systems.