Naproxen Drug Solubility: Enhancement and Thermodynamic Modeling by Surface-Active Ionic Liquids Based on 2-Hydroxyethylamine

Surface-active ionic liquids (SAILs) have garnered increasing attention as potential solubility enhancers for poorly soluble drugs. Naproxen often encounters solubility limitations that hinder its effective pharmaceutical application. This study investigates the enhancement of naproxen (NAP) solubility through the utilization of various 2-hydroxyethylamine-based SAILs at experimental temperatures of (298 to 318) K with 5 K intervals. The solubility of NAP in the presence of aqueous (2-hydroxyethyl)ammonium octanoate [2-HEA][Oc], bis(2-hydroxyethyl)ammonium octanoate [BHEA][Oc], and tris(2-hydroxyethyl)ammonium octanoate [THEA][Oc] SAILs was explored. Experimental results revealed that [THEA][Oc] provided the most substantial solubility enhancement, achieving a 46-fold increase in naproxen solubility compared to pure water at 298 K. The electrolyte-nonrandom two liquid (e-NRTL), Wilson, and Jouyban–Acree models were implemented to correlate the experimental solubility data of naproxen in aqueous media containing SAILs. The van’t Hoff and Gibbs equations were employed to examine the thermodynamic characteristics of the dissolution process in the studied systems. Additionally, conductor-like screening model (COSMO) calculations were performed to further investigate the behavior of naproxen in the presence of SAILs. According to the COSMO results the [THEA][Oc] by possessing the most surface cavity volume values potentially can show the most interaction with NAP in aqueous media.