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

Andrew S. Dunn, Botond Szilagyi, Joop H. ter Horst, Zoltan K. Nagy

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)7726-7741
Number of pages16
JournalCrystal Growth and Design
Volume20
Issue number12
Early online date28 Oct 2020
DOIs
Publication statusPublished - 2 Dec 2020

Keywords

  • preferential crystallization
  • mechanical separation
  • concomitant crystallization
  • digital design of crystallization
  • crystallization control
  • enantioseparation
  • asparagine monohydrate

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