Additive-assisted preferential crystallization of racemic component: A case of norvaline

[Display omitted] •A preferential crystallization process of norvaline performed near the eutectic composition was established.•Additive-assisted preferential crystallization boosts purity up to 98% with 56% yield.•Tailor-made additives selectively suppress crystallization of racemate not enantiomer.•Molecular mechanism of selective inhibition by tailor-made additives was elucidated. Herein, we report a successful resolution of L-norvaline, a racemic compound system, performed near the eutectic composition by coupling preferential crystallization with tailor-made additives. The structures of enantiomer and racemate were characterized by PXRD, DSC, and the enantiomeric purity were measured by Chiral HPLC. The preferential crystallization process was designed and established from binary melting phase diagram and ternary solution phase diagram. The effects of supersaturation, solution enantiomer composition, and seed quantity on the preferential crystallization process were investigated. However, the significant improvements of enantiomeric purity and product yield were demonstrated by additive-assisted preferential crystallization approach using tailor-made additives. These additives bearing similar structure motifs to norvaline a highly selective binding to the racemate rather than enantiomer and remarkably suppress nucleation of DL-norvaline, the key factor determining the resultant enantiomer purity and separation efficiency. The underly inhibition principle was revealed due to the centrosymmetric packing of the racemate while the polarity of enantiomer leads to only partial or slight crystallization suppression. The interesting inhibition mode by tailor-made additives is also believed to be applicable for other racemic crystallization systems. Our established additive-assisted preferential crystallization has showed great potential in the development of separation technology and resolution of enantiomer from racemic compounds.