(394f) Continuous Separation of Enantiomers By Combined Crystallization-Distillation Systems: A Proof of Concept Study for Continuous Viedma Ripening

The separation of chiral molecules is of key importance in major industries, such as the pharmaceutical industry, where different enantiomers of a chiral compound can have markedly different biological effects. For instance, only one of the enantiomers of a drug might provide the therapeutic effect, while the other enantiomer shows little effect, no effect, or even harmful effects. Hence, the pharmaceutical industry is driven towards processes that allow separating enantiomers in a cost- and material-efficient way [1]. For systems of enantiomers that crystallize as conglomerates, the process of Viedma ripening has attracted considerable attention by the crystallization community [2,3]. In this process, a racemization reaction in solution (which may be catalyzed) and a complex interplay of crystal growth, dissolution, breakage and agglomeration lead to an enantiomerically pure product [4]. While the mechanism behind the process and how its performance can be improved were intensively investigated, a truly continuous process configuration of Viedma ripening has not been presented so far in the open literature.

In this work, we present such a continuous process configuration that relies on a combination of continuous crystallization, milling and distillation. Specifically, the process involves a mixed suspension mixed product removal crystallizer that is fed with a racemic solution of the substance. A suspension mill, operating in a loop around the crystallizer, serves as an attrition source. The outflow of the crystallizer is put forward to a continuous filtration unit where enantiopure crystals and the mother liquor are separated. The mother liquor is then subjected to a continuous distillation step in which part of the solvent is removed selectively, i.e., without the loss of chiral product or racemization catalyst. The remaining, concentrated mother liquor is recycled back to the crystallizer. Thus, the process allows obtaining enantiopure solids at a theoretical yield of 100%.

By using extensive process simulations based on population balance equation models [4], we show the start-up behavior (e.g., seeding requirements) and under which operating conditions (residence times in the crystallizer and the mills, feed concentration, milling intensity etc.) the process yields enantiopure solids in a continuous steady-state. We also present proof of concept experiments involving the amino acid asparagine in water as a model system including a racemization catalyst.

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