Characterizing the kinetics of crystal nucleation and thermal degradation of a conglomerate-forming chiral compound for temperature cycling induced deracemization

In this study, we complete the kinetic picture needed for model-based temperature cycling-induced deracemization (TCID) of N-(2-methylbenzylidene)-phenylglycine amide (NMPA) by quantifying primary nucleation and thermal degradation. First-event primary nucleation statistics were measured under controlled polythermal cooling for solutions of racemic and enantiopure NMPA using a probabilistic analysis consistent with Classical Nucleation Theory, showing that enantiopure solutions nucleate earlier than racemic ones under identical per-enantiomer driving force. Isothermal studies show that NMPA degrades by a first-order pathway with Arrhenius temperature dependence, with modest losses over typical TCID timescales. Combined with published racemization and growth/dissolution data, these results provide a complete kinetic set for TCID, enabling selection of cooling profiles that reduce the impact of primary nucleation while limiting thermal exposure, improving robustness and yield in the resolution of enantiopure conglomerate-forming compounds.