Enantioselective separation of ofloxacin in hydrophobic deep eutectic solvent-based aqueous two-phase systems: a molecular dynamics study

Abstract In this work, molecular dynamics (MD) simulations were performed to assess three hydrophobic deep eutectic solvents (HDESs) as green extraction media for the enantioseparation of OFX in aqueous two-phase systems (ATPS). The HDESs were formulated to systematically vary hydrogen-bond chemistry, hydrophobicity, and solvent chirality: DES1 (octanoic acid/decanoic acid, 2:1), DES2 (octanoic acid/dodecanoic acid, 2:1), and DES3 (L-menthol/decanoic acid, 1:2), with hydroxypropyl-β-cyclodextrin (HPβCD) serving as the chiral selector in the aqueous phase. Within the simulated systems, the density profiles indicated partitioning of both enantiomers into the three DES phases, with DES3 showing the highest total OFX population in the DES phase. Partitioning selectivity calculations indicated preferential ( S )-OFX partitioning in DES3 (β = 2.66 ± 0.15), whereas DES1 (β = 0.40 ± 0.05) and DES2 (β = 0.54 ± 0.10) favored ( R )-OFX partitioning. Radial and combined distribution functions, together with hydrogen bond analysis, demonstrated that ( S )-OFX forms stronger and more directionally defined interactions with decanoic acid within the chiral microenvironment of DES3 (3.35 vs. 0.70 hydrogen bonds for ( S )-OFX and ( R )-OFX, respectively). Interaction energy decomposition confirmed that van der Waals forces dominate across all systems, with ( S )-OFX exhibiting the most favorable total interaction energy in DES3, driven by cooperative hydrogen bonding and hydrophobic complementarity mediated by L-menthol. Mean square displacement and diffusion coefficient analyses further corroborated these trends, revealing a consistent anticorrelation between binding strength and enantiomer mobility. These results identify DES3 as a computationally promising candidate for the preferential partitioning of ( S )-OFX and provide molecular-level hypotheses for subsequent experimental investigation.