Chromatography and Crystallization: Competitors and Partners to Provide Pure Enantiomers and Plant Ingredients

The development of efficient separation processes is an important task for chemical engineers. The widely used and well-understood “working horse” distillation is not always applicable. For isolating and purifying fine chemicals selective crystallization and chromatography offer potential for resolution under mild conditions. These two techniques are often seen as competitors. However, due to the difficulty of many separation tasks, it is frequently not possible to solve separation problems exploiting just a single technology. The presentation will describe two types of problems, where joining forces is attractive.

At first we will introduce the different types of phase diagrams of chiral compounds as the basis for a rational development of enantioselective separation processes. In the simplest but rare case that the enantiomers crystallize as a conglomerate, it is possible and attractive to apply exclusively preferential crystallization. A productive new continuous process exploiting two coupled fluidized beds will be described in more detail. However, enantiomers can frequently form racemic compounds. Thus, enriched feed solutions are required for enantioselective crystallization. Enrichment can be provided by a partial selective synthesis or by a suitable preliminary separation process. We will describe for an industrially relevant drug component an efficient combination of preparative chromatography with subsequent selective crystallization.

In a second part we will focus on mixtures, which contain a target component together with a larger number of other components. We will consider as an example the provision of artemisinin, which can be extracted from sweet wormwood (Artemisia Annua). Artemisinin and several of its derivatives are currently the basis for the most effective drugs to cure the malaria disease. To improve the overall yield of artemisisin a continuous photo-catalytic synthesis from the co-extracted precursor dihydroartemisinic acid is available. Purification using direct crystallization and center-cut simulated moving bed chromatography have been investigated, together with continuous synthesis of artesunate as one of the mentioned derivatives. A particular complex separation problem arises for feed solutions originating after applying longer extraction times in order to co-extract also sufficient amounts of chlorophyll, recently found to be an efficient green photo-catalyst.

Finally, we will consider recycling concepts required to develop efficient processes. Enantioseparation combined with racemization and recycling of the counter-enantiomer will serve for illustration.