From Hydrogen Bonding to Hydrophobic Control: The Shifting Solvation Mechanism of Ibuprofen in Deep Eutectic Solvents

This study investigates the solvation of ibuprofen in deep eutectic solvents (DESs) composed of the hydrogen bond acceptor (HBA) betaine (BET) and hydrogen bond donors (HBDs) ethylene glycol (EG), propylene glycol (PG), or 1,2-butanediol (BD). Molecular dynamics simulations were performed using the Drude polarizable model with a custom-implemented Tang-Toennies damping function designed to resolve short-range polarization artifacts. The structure and thermodynamics of solvation were characterized with minimum-distance distribution functions (MDDFs) and the Kirkwood-Buff (KB) theory of solutions. Betaine forms strong hydrogen bonds with the carboxylic group of ibuprofen, whereas alcohols, especially EG, are largely excluded from the first solvation shell. Decomposition of solvent MDDFs reveals that hydrophobic groups from ibuprofen promote the accumulation of both betaine and HBDs, with the preferential solvation shifting from betaine to the HBD as the alkyl chain increases. Betaine preferentially binds ibuprofen with greater preference in the BET-EG system, while in the BET-BD system, the hydrogen-bond donor is preferentially accumulated around the solute. Beyond characterizing these specific interactions, this work demonstrates the application and usefulness of MDDF-based KB analysis in anhydrous, highly viscous media, extending its application from traditional aqueous protein systems to the complex, glass-like dynamics of deep eutectic environments.