Crystallization Resolution of a Racemic Compound (R,S)-Sulpiride Promoted by Chiral Ionic Liquids: Insight into the Effect on Selective Nucleation

This study systematically investigates the influence of chiral ionic liquids (CILs) on the enantiomeric resolution efficiency of chiral drugs via crystallization. Four CILs―1-pentyl-3-methylimidazolium-R-mandelate ([Pmim][R-MA]), 1-pentyl-3-methylimidazolium-R-pyroglutamate ([Pmim][R-PgA]), 1-pentyl-3-methylimidazolium-S-mandelate ([Pmim][S-MA]), and 1-pentyl-3-methylimidazolium-S-pyroglutamate ([Pmim][S-PgA])―previously synthesized and characterized in prior research were employed in a methanol-based system to evaluate their effects on the nucleation kinetics and crystallization resolution of the model drug RS-sulpiride (RS-Sul). Nucleation probability analysis revealed that R-enantiomeric CILs (R-CILs) preferentially facilitated the nucleation of S-sulpiride (S-Sul), exhibiting intermolecular interactions with S-Sul that are significantly stronger than those with R-sulpiride (R-Sul). Furthermore, a CIL-based cosolvent mixture (CCM) with a mass fraction (ω) of 0.7 (CCM-0.7) was identified as a highly effective nucleation inhibitor, selectively suppressing the crystallization of enantiomers with identical chiral configurations while promoting the nucleation of their opposite enantiomers. In a methanol-based system containing 7 wt % R-CILs, variations in solvent composition and seeding concentrations significantly influenced the crystallization resolution efficiency of RS-Sul. The chiral recognition mechanism between CILs and Sul enantiomers was revealed by an independent gradient model based on Hirshfeld partition (IGMH) analysis as well as binding energy (BE) calculations, which further demonstrated that [Pmim][R-PgA] exhibited superior chiral recognition compared to [Pmim][R-MA], elucidating the molecular-level mechanism of CIL-mediated stereoselective nucleation. Additionally, cyclic stability assessments revealed that after six reuse cycles, the CILs retained a 93.8% recovery efficiency and structural integrity, highlighting their potential for practical applications in chiral resolution.