(545c) Modeling, Simulation and Design Strategies to Efficiently Apply Preferential Crystallization in a Continuous Process

Preferential crystallization (PC) is a strong technique capable to resolve mixtures of enantiomers that crystallize as a conglomerate forming system [1, 2]. It involves preferentially crystallizing a target enantiomer by adding pure seed crystals into a supersaturated solution at racemic composition. The non-target enantiomer crystallization is inhibited kinetically for a certain period, which is expressed in this study as a stop time (t_stop). After this period, crystallization of the counter enantiomer takes place and the purity of the solid phase drops. Due to unavoidable spontaneous nucleation of the non-target enantiomer, the classical approach of a single batch process has limitations. Therefore, it is desirable to delay the counter enantiomer nucleation and to benefit from a longer operation time window to harvest more pure product. One of the methods to achieve this is based on using racemization in the liquid phase.

Population Balance Models (PBMs) are a powerful tool to describe crystallization processes [3]. Due to the consideration of many details, the resulting set of equations is rather difficult to solve and expensive when applied for simulation and optimization. In this work, a shortcut model (SCM) is introduced, which is based on the assumptions of equally sized spherical particles and a single lumped kinetic mechanism [4]. The analysis considers as a case study of the enantiomers of DL-asparagine (DL-Asn) in water crystallizing as a monohydrate under used conditions. An evaluation of Key Performance Indicators (KPI) for the process (i.e. productivity and yield) is performed using the shortcut models. This model is found to be capable to describe main features of batch PC with and without racemization using only three differential equations, which are formulated from the mass balances of the preferred enantiomer in the liquid and solid phases (Figure 1). A systematic theoretical study of design strategies of PC in classical single batch crystallization with and without racemization in one-pot and also in two connected pots is performed using the shortcut model. Finally, a possible extension of the shortcut model to simulate preferential crystallization carried out in continuous mode and for resolving racemic compound forming systems will be discussed in the presentation.

1. Jacques (1994): Enantiomers, Racemates and Resolutions. Krieger Publishing Company Malabar, FL.
2. Coquerel (2007): Preferential Crystallization. Top Curr Chem 269, 1-51
3. Ramakrishna (2000): Population Balances. Theory and Applications to Particulate Systems in Engineering. Academic Press, London
4. T. Carneiro, S. Bhandari, E. Temmel, H. Lorenz, A. Seidel-Morgenstern (2019): Shortcut Model for Describing Isothermal Batch Preferential Crystallization of Conglomerates and Estimating the Productivity. Cryst. Growth Des. 19, 9, 5189-5203