Eutectic Composition of a Chiral Mixture Containing a Racemic Compound

Abstract

The enantioseparation process is of great interest to the pharmaceutical industry since more than 50% of the pharmaceutically active ingredients are known to be chiral and one enantiomer is usually preferred over the racemic mixture. Crystallization is widely used as the final step to reject the enantiomeric impurity from a mixture. Yet, a fundamental guidance on developing a purification procedure for systems forming racemic compounds (which account for more than 90% of all chiral systems) is not available. In this work, it is shown that the enantiomeric excess (ee) of the eutectic point is the key information needed to assess the feasibility of a crystallization process and to predict the purity and the yield of the product. In a dilute solution, the eutectic ee is determined solely by a eutectic constant (Keu), a new parameter introduced in this paper. Keu is defined as the ratio of the activity of the major enantiomer to that of the minor enantiomer. A eutectic constant equation was derived from the basics of thermodynamics, and for the first time, it was shown that the Keu is independent of solvent if no solvates are formed but varies with temperature. With an understanding of how the eutectic ee changes with solvent and temperature, the time and material required in developing a crystallization procedure for ee enhancement can be dramatically reduced. This theory was supported by experimental data, and its application was demonstrated on a system of pharmaceutical interest.