Coupling Achiral and Chiral Chromatography for Efficient Separation of Enantiomeric Mixtures

Chiral chromatography (CCh) is often a cost driver in the large-scale separation of enantiomers. To improve the economics of the separation process, we developed the concept of coupling CCh with achiral chromatography (ACh). In this concept, the CCh step is used to enrich the enantiomeric mixture with the target enantiomer, while in the ACh step, the enriched mixture is separated to obtain the product with a desired purity. The ACh separation is driven by the phenomenon of self-disproportionation of enantiomers (SDE), which relies on formation of homochiral and heterochiral associates that can be separated in an achiral environment, whereas the CCh separation occurs in the presence of a chiral stationary phase (CSP). The coupled ACh-CCh process is operated in a cyclic mode for which cyclic steady state is attained. To demonstrate the concept of the process and develop a generic methodology for its design, a model mixture consisting of enantiomers of methyl p-tolyl sulfoxide was used, with S-p-tolyl sulfoxide as the target enantiomer. For both ACh and CCh, the influence of the operating variables, including mobile phase composition, loading density, and enantiomeric excess (ee) of the feed mixture, on the separation performance was examined. On the basis of the experimental data, a dynamic model was formulated, calibrated, and used to support the process design and assess the performance of both the standalone ACh and CCh as well as their coupling in various configurations. The amount of product obtained in a single cycle of ACh-CCh was markedly higher compared to that obtained in the standalone CCh, which provided the benefit of reducing consumption of the costly CSP. This benefit was enhanced with increasing ee of the feed mixture. For example, for racemic mixtures, the mass of the product per cycle of ACh-CCh was 1.5 times higher, for mixtures with ee = 70% it was 4 times higher, and for mixtures with ee = 85% it was 5.7 times higher compared to the standalone CCh. Furthermore, for mixtures with a high ee, a marked improvement in process productivity was obtained, e.g., for mixtures with ee = 70%, the productivity of ACh-CCh was twice higher, for ee = 85% it was 2.5 times higher compared to the standalone CCh.