Application of crystallization inhibitors to chiral separations. 1. Design of additives to discriminate between the racemic compound and the pure enantiomer of mandelic acid

In the context of the potential use of crystallization for spontaneous separation of racemates, it is well-known that the frequent appearance of racemic solid forms (racemic compounds) is a serious obstacle. Given previous studies on the selective inhibition of centric versus noncentric polymorphic structures, we report here the application of a similar rationale for the selective crystallization inhibition of a racemic compound compared to a pure enantiomer. We have chosen the system R,S-mandelic acid (MA) in water which, from racemic solutions, crystallizes as two polymorphs of a racemic compound. The selection of potential additives is described and from the effects of additive concentration on the crystallization of (R,S)-MA compared to (S)-MA, at various crystallization temperatures, it is shown that while none of the additives dramatically inhibit the crystallization of (S)-MA even at 3% they significantly inhibit the crystallization of the racemate. With 10% additive, the crystallization of (A,S)-MA is totally inhibited for over 4 months. This leads the way to a new potential crystallization process for chiral enrichment discussed in the accompanying paper in this issue. © 2007 American Chemical Society.