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

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)