Novel Approaches for Crystallization-Based Enantioseparation

Since Pasteur’s famous experiments of separating the sodium ammonium tartrate enantiomers by direct crystallization, extensive activities have been devoted to study and to apply crystallization processes for enantioseparation. Substantial progress has been achieved both in understanding the thermodynamic and kinetic fundamentals behind selective crystallization and also in exploiting this knowledge to develop suitable methods. In general, crystallization techniques are straightforward, cost-efficient and facilitate high purities. Further, they offer attractive synergism in combination with other chiral separation methods or not fully selective synthesis, allowing for improvements in the overall process performance (e. g. in terms of productivity or yield). Although the design of such integrated processes is challenging, it generally widens the access to single enantiomers. In the contribution, various integrated approaches to pure enantiomers will be presented and discussed. Thereby, crystallization is usually applied subsequently to a previous enantiomeric enrichment step that provides a solution containing the enantiomers in a non-racemic ratio. Enrichment techniques studied are biocatalytic synthesis, pertraction and liquid chromatography. In dependence on the particular phase diagram characteristics of the chiral system and the enantiomeric excess achieved by the enrichment step, different crystallization schemes can be exploited to provide the desired enantiomer. They involve e.g. preferential crystallization and a novel 2-step crystallization process. The feasibility and potential of such integrated approaches will be demonstrated also on industrially relevant substances studied in the frame of the European Collaborative Project “INTENANT”, successfully running from 2008 to 2011 (http://www.intenant.eu/)