A tunable additive strategy for enantioseparation of hydrophobic racemic ibuprofen through agarose-based hydrogels.

Chiral drugs often exhibit stereoselective pharmacological activity, yet their separation remains challenging due to virtually identical physicochemical properties. Here, we propose a tunable additive strategy using agarose hydrogels (AG) as chiral enantioseparation scaffolds, where non-covalent interactions between drug and additives enable chiral recognition. Using racemic ibuprofen (Ibu) as a model compound, Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction analyses revealed the enhanced loading, modified morphology, and altered crystallinity of hydrophobic Ibu induced by additives. Non-covalent interactions between the additives and Ibu, revealed by molecular docking, quantum chemical calculation, and IRI analysis, promote the dispersion of Ibu within the matrix and preferentially release the pharmacologically active enantiomer. Notably, while additive free AG afforded an enantiomeric excess of 1.7 %, the cyclodextrin-modified hydrogel achieved up to 15.6 %, a more than 9 times improvement, highlighting the potential of this strategy for the adjustable enantioseparation at the biointerface.