Direct design of crystallization-induced deracemization through direct nucleation control (DNC)

Abstract

This paper investigates the feasibility of direct nucleation control (DNC) for the rapid design of conglomerates’ temperature cycling induced deracemization (TCID) to obtain enantiopure products in a particle size-controlled way in a single, well-operated crystallization step. The operation is supported by enantiopure seeding in amount and size distribution that translates to the desired product size according to the material balance and McCabe’s ΔL law, assuming that there are no distomer crystals in the product. The DNC ensures that in the case of any nucleation (the target enantiomer or the distomer), the newly formed crystals are dissolved, and the solids’ enantiopurity and size distribution integrity are preserved. In this context, a routinely used in-line tool, e.g., imaging or laser back-scattering-based, can help to control the deracemization in an inferential way that would be difficult to monitor directly. The simulation studies performed based on population balance-based modeling indicated the feasibility of the approach, and the thorough parametric study revealed that there is a correlation between the DNC settings and kinetic properties of the crystallization and the racemization. A SHAP interpretation of an extreme gradient boosting-based classifier allowed us to draw practical conclusions about the desired DNC operation, including working in a high-temperature range, minimizing the stirring rate, and using broader DNC count ranges. The experimental validation of the concept has yet to be performed, and it can be guided by leveraging the knowledge generated in this paper.