Temperature Cycling Induced Deracemization (TCID) is a promising route to obtain enantiomerically pure suspensions of conglomerate-forming compounds, yet the role of primary nucleation (PN) remains poorly quantified. Here we develop a population balance equation (PBE) model of TCID for the compound NMPA that combines measured growth and dissolution, racemization and primary nucleation kinetics, as reported in the literature. With the model, we quantify how primary nucleation can perturb the evolution of the enantiomeric excess under temperature cycling programs of practical interest. For typical TCID conditions reported for NMPA, primary nucleation has no detectable impact at the process scale. In contrast, when the process is designed to increase productivity, by (i) widening the temperature span, (ii) increasing the cooling rate, (iii) lowering the suspension density or (iv) enhancing secondary nucleation, the effect of primary nucleation becomes visible, leading to run-to-run variability and a measurable loss in the final enantiomeric excess. These results can help rationalize why primary nucleation is often negligible in TCID processes, while identifying operating regimes where it must be explicitly accounted for in design and scale-up. • Mechanistic PBE model for TCID coupling growth, dissolution, racemization and primary nucleation. • Model validation against experiments for NMPA deracemization. • Assessment of effects of temperature span, cooling rate, suspension density, secondary nucleation and racemization catalyst concentration. • Trade-off between robustness to primary nucleation and process productivity.
Chen et al. (Sun,) studied this question.