With increasing awareness for the need of pure enantiomer drugs, strong emphasis has been focused on the research of chiral drug separation. Compared with other separation methods, crystallization is a simple and economical method, and the metastable zone width (MSZW) is a very important factor for the entire crystallization process. In this paper, the effects of the metastable zones of (R,S)- and (S)-ketoprofen and a 0.94 mole fraction of (S)-ketoprofen in order to enhance the MSZW were studied. Four main factors were studied, namely, temperature, cooling rate, stirring rate, and volume ratio of mixed solvent (water/ethanol). Through the L9 fractional experiment design, it was observed that all samples' MSZWs would increase with an increase in cooling rate and decrease with an increase in the ethanol volume ratio and temperature. The ethanol ratio may have the strongest effect on the process and can greatly enhance the metastable zone, and the other three factors influence the MSZW only slightly. In conclusion, the these four factors for enhancing MSZW have been optimized: water-to-ethanol volume ratio, 1:0.6; temperature, 20 degrees C; stirring rate, 700 rpm; and cooling rate, 12.0 degrees C/h. All of these results will be helpful for the following chiral separation of ketoprofen by crystallization.

Compared to simulated moving bed (SMB) chromatography, fractional crystallization is a simple and economical method for enantioseparation. Therefore, the coupling of SMB chromatography and fractional crystallization is suggested for enantioseparation of racemic compounds. In this work, a nonsteroidal antiinflammatory drug, ketoprofen (Kp), was chosen to be studied. Kp was verified as a racemic compound by FTIR, PXRD, and thermodynamic calculations. To derive the condition where pure (S)-Kp could be crystallized from a solution, which was previously enantiomerically enriched, the binary melting phase diagram and the ternary solubility phase diagram in the mixed solvent of ethanol and water over a temperature range of 15-30 degrees C were obtained. From these phase diagrams the eutectic point was determined as 91.6% mole percent (S)-Kp from the binary phase diagram and 91% from the ternary phase diagram. The results may provide valuable experiment data for the possibility of coupling fractional crystallization with SMB for Kp separation.