Enabling mechanical separation of enantiomers through controlled batchwise concomitant crystallization : digital design and experimental validation

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Dunn, Andrew S. and Szilagyi, Botond and ter Horst, Joop H. and Nagy, Zoltan K. (2020) Enabling mechanical separation of enantiomers through controlled batchwise concomitant crystallization : digital design and experimental validation. Crystal Growth and Design, 20 (12). pp. 7726-7741. ISSN 1528-7483 (https://doi.org/10.1021/acs.cgd.0c00974)

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Abstract

In the pharmaceutical industry the separation of chiral molecules is important due to the different physiochemical properties that the enantiomers of a chiral drug possess. Therefore, resolution techniques are used to separate such enantiomers from one another. In particular, preferential crystallization is a common technique used to separate conglomerate-forming compounds, due to its high selectivity. However, the efficient separation of enantiomers in a batchwise preferential crystallization process through seeding with the preferred enantiomer alone is still inefficient, since unwanted nucleation of the counter enantiomer is inevitable. Here, we demonstrate a model-based digital design for the separation of enantiomers for a conglomerate-forming compound (asparagine monohydrate), by using mechanical separation by sieving after crystallization, whereby the separation is enabled by a designed bias in the crystal size distributions of each enantiomer. This bias is created by a concomitant crystallization of both enantiomers using optimized seeding and cooling profiles obtained from a population balance model. In this way, a high level of control is achieved over a batchwise preferential crystallization process, since the crystallization of both enantiomers is controlled. We show that, through this separation method, material with impurity levels as low as 6 wt % can be obtained. To our knowledge this is the first demonstration of modeling such a process to separate enantiomers of a conglomerate-forming compound.

ORCID iDs

Dunn, Andrew S. ORCID logoORCID: https://orcid.org/0000-0002-8417-8468, Szilagyi, Botond, ter Horst, Joop H. ORCID logoORCID: https://orcid.org/0000-0003-0118-2160 and Nagy, Zoltan K.;
CORE (COnnecting REpositories)