Bridging Macroscopic Thermodynamics with Microscopic Solvation Structure: Solubility of Mesalamine in Novel Polyol-Based Deep Eutectic Solvents

-diethylethanolammonium chloride (DEAC) as the hydrogen-bond acceptor and ethylene glycol (EG) or 1,2-propanediol (PD) as hydrogen-bond donors. The solid-liquid equilibrium of mesalamine, chosen as a representative pharmaceutical solute, was measured over the temperature range of 283.15-323.15 K. A pronounced enhancement in solubility was observed, with up to a 53-fold increase in pure DESs relative to water. Analysis of the temperature dependence of solubility reveals an endothermic dissolution process, with entropic contributions becoming increasingly significant in DES-rich systems. The experimental data were accurately correlated using the modified Apelblat and Buchowski-Książczak (λh) equations, while local-composition activity-coefficient models reproduced the nonideal behavior, with the NRTL model yielding the best overall agreement. Segment-based models (NRTL-SAC and UNIQUAC-SAC) further demonstrated reasonable predictive capability for solubility trends. To resolve the molecular origins of the observed thermodynamic behavior, molecular dynamics simulations were performed at 298.15 K. Radial distribution functions, coordination numbers, and hydrogen-bond statistics reveal the preferential accumulation of polyol hydrogen-bond donors in the vicinity of mesalamine, leading to a locally ordered solvation environment and reduced solute-solute association. These structural features provide a molecular interpretation of the enhanced solubility and nonideal mixing behavior. Importantly, interaction energies and local compositions extracted from the simulations show quantitative consistency with fitted NRTL parameters, while activity coefficients derived from Kirkwood-Buff integrals agree with macroscopic model predictions within approximately 7%. Excess Gibbs energies obtained from simulation further support the thermodynamic trends. Together, these results demonstrate how the microscopic solvation structure in DESs governs macroscopic solubility, offering a physically grounded framework for rational solvent design.