From Molecular Interactions to Solubility in Deep Eutectic Solvents: Exploring Flufenamic Acid in Choline-Chloride- and Menthol-Based Systems

This study explores how intermolecular interactions govern the composition of saturated solutions of influence flufenamic acid (FlA) in deep eutectic solvents (DESs). Using choline chloride (ChCl) or menthol (Men) as the HBAs and various polyols as the HBDs, FlA solubility was measured in different DES systems. The experimental values along with intermolecular interactions quantified via COSMOtherm-derived Gibbs free energies were used in the determination of component distributions for varying DES formulations. It was inferred that DES systems primarily consist of molecular complexes (dimers and hetero-pairs) rather than monomers due to their high association propensity. In the case of ChCl-based DESs, the HBA–HBD hetero-pairs are favored and strongly dominate. In contrast, Men-based DESs exhibited a strong attraction to HBDs; however, their self-association led to the predominance of HBD dimers. Solubility of FlA correlated with solute-containing hetero-pairs, peaking at optimal HBA–HBD ratios. These insights support in developing a rationale for DES design for pharmaceutical applications. The conclusions of this study were inferred from a novel crafted physically constrained iterative algorithm that reliably determines molecular composition from the equilibrium constants, overcoming the limitations of conventional numerical solvers in highly associated systems.