Effect of Novel Surface-Active Ionic Liquids Based on 2-Hydroxyethylammonium Oleate on the Solubility and Thermodynamic Properties of Drug Ibuprofen

Abstract Ibuprofen (IBU), a BCS Class II drug, poses significant challenges in pharmaceutical formulation due to its poor aqueous solubility and low bioavailability. In this study, renewable surface-active ionic liquids (SAILs) based on (2-hydroxyethyl)amine were investigated as green solubilizing agents for enhancing the aqueous solubility of IBU. Three SAILs, (2-hydroxyethyl)ammonium oleate ([2-HEA][Ole]), bis(2-hydroxyethyl)ammonium oleate ([BHEA][Ole]), and tris(2-hydroxyethyl)ammonium oleate ([THEA][Ole]), were synthesized. The equilibrium solubility was determined in aqueous SAIL solutions at various SAIL mass fractions and temperatures (298.15–313.15 K) using the saturation shake-flask method, followed by UV–vis spectrophotometry. The experimental data were correlated using the Wilson and electrolyte nonrandom two-liquid (e-NRTL) activity coefficient models. Density functional theory (DFT) calculations with the DMol3 module and COSMO solvation model were performed to investigate intermolecular interactions. The results show IBU solubility increased with increasing SAIL concentration and temperature, indicating an endothermic and entropy-driven dissolution process. Solubility followed the order [2-HEA][Ole] < [BHEA][Ole] < [THEA][Ole], with [THEA][Ole] providing up to a 34-fold enhancement. The Wilson model correlated the experimental data more accurately than the e-NRTL model, with average relative deviations of approximately 0.20% and 5.34%, respectively.