2-Steps Chiral Separation by Crystallization

The number of chiral compounds used in pharmaceuticals, agrochemicals, flavors, and personal care has been growing rapidly over the last years and hence the demand for asymmetric synthesis and efficient chiral separation techniques has increased. One commune, costly and time consuming pathway towards optically pure enantiomers from a racemic mixture consists of coupling a chiral pre-enrichment step using chromatographic columns with a subsequent selective crystallization step. Additionally, crystallization techniques require a comprehensive knowledge of the underlying solid–liquid phase equilibria (SLE) of the chiral compound.

In a study published by H. Lorenz et al was investigated bicalutamide, a chiral active pharmaceutical ingredient for the treatment of prostate cancer (1). The drug is manufactured at a scale of several metric tons per annum as a racemate. The initial process targeted manufacture of the pure (R)-enantiomer of bicalutamide due to its slightly higher bioavailability. The method included SMB-HPLC for full enantiomeric separation of the racemic material. Hence, an alternative separation route based on the selective crystallization of asymmetric mixtures of bicalutamide enantiomers was of high need and evaluated a few years ago by H. Lorenz et al. Their aim was to produce the pure target enantiomer with an acceptable yield using a two-step crystallization process.

A comprehensive solvent/antisolvent screening was carried out based on the COSMO-SAC model and a solvent database of 1432 compounds. Ternary and quaternary phase diagrams of the enantiomers and promising solvent candidates were derived and compared to experimental data. Solid–liquid equilibrium (SLE) model based chiral separation of bicalutamide enantiomers was conducted and the process performance was evaluated in terms of yield and product purity (2-5). Determination of solubility was performed by using both the equilibrium and polythermal dissolution method (also known as temperature variation method) using a Crystal16® instrument. Predefined amounts of mixtures of the enantiomers were dissolved in a solvent (mixture) at high temperature, cooled and recrystallized and then completely dissolved again. The cloud and the clear points were determined in the Crystal16® by turbidity and the corresponding temperatures were recorded. The advantage of the polythermal dissolution method with the Crystal16® is the quick acquisition of solubility data. The process was balanced and a model was derived for estimating the theoretical yield based on calorimetric properties of the enantiomer and the racemic compound. H. Lorentz et al claim that chiral separation of an asymmetric mixture of bicalutamide enantiomers was implemented in a two-step crystallization process. In the first step, the initial purity was increased from 70% to 97.7%. In the 2nd process step this was increased even further to 99.2%. The design of both process steps was based on the solid–liquid phase equilibria models (SLE).


(1). H. Kaemmerer, M.J. Jones, H. Lorenz, A. Seidel-Morgenstern, Fluid Phase Equilibria 296 (2010) 192–205.
(2). S.R. Perrin, W. Wauck, E. Ndzie, J. Blehaut, O. Ludemann-Hombouger, R.-C. Nicoud, W.H. Pirkle, Org. Proc. Res. Dev. 11 (2007) 817–824.
(3). K. Gedicke, M. Kaspereit, W. Beckmann, U. Budde, H. Lorenz, A. Seidel-Morgenstern, Chem. Eng. Res. Des. 85 (7) (2007) 928–936.
(4). A.M. Chen, Y. Wang, R.M. Wenslow, Org. Process Res. Dev. 12 (2) (2008) 271–281.
(5). D. Polenske, H. Lorenz, A. Seidel-Morgenstern, Cryst. Growth Des. 7 (9) (2007) 1628–1634.