Application of preferential crystallization for racemic compound integrating thermodynamics, kinetics and optimization

Abstract

Typically, the preferential crystallization was used for enantioseparation of a racemic conglomerate. However, racemic compounds occupy 90-95% of all racemates. Therefore, we attempted to extend and modify the concept of critical supersaturation control for preferential crystallization and applied this strategy to two kinds of racemic compound systems: mandelic acid and ketoprofen. System thermodynamic aspects such as binary and ternary phase diagram were measured. The metastable zone widths under different cooling rates were determined. The crystal nucleation and growth kinetics were measured with s-plane analysis. Based on the solubility and metastable zone width diagram, the maximal limit of practicable operating range to conduct preferential crystallization to obtain pure enantiomer product was defined. Different operating profiles were applied and the solution supersaturation was analyzed for the crystallization processes. The final productb s optical purity, yield and crystal size distribution were examined and compared.