Solid-state deracemization of a chiral compound: Considerations on scale, solvent and degradation

Solid-state deracemization of N-(2-methylbenzylidene)-phenylglycine amide (NMPA), a conglomerate-forming model compound was investigated under nominally isothermal conditions to assess its robustness and scalability in practical crystallization environments. We demonstrate successful deracemization in a 2 L laboratory crystallizer at 30 °C without attrition enhancement, extending previous milliliter-scale studies and confirming theoretical analysis reported earlier in literature. When operated at elevated temperature (40 °C), the process exhibited an unexpected loss of enantiomeric excess due to the formation of a previously unidentified degradation product, 2-(2-methylphenyl)-5-phenyl-imidazolidin-4-one, arising from cyclization reaction of NMPA in a 95/5 (w/w) isopropanol–acetonitrile solvent mixture. Although deracemization continued in its presence at low concentrations, the by-product formation highlights a temperature-dependent degradation pathway. Interestingly, this byproduct was absent in pure acetonitrile; however, this solvent system suffered from crystal fouling and impaired mixing, negatively affecting deracemization. These findings reveal a trade-off between chemical stability and process performance, emphasizing the need to optimize solvent composition and operating conditions. Overall, the study provides key insights into solvent-dependent degradation mechanisms and practical considerations for scaling up solid-state deracemization in industrial crystallization systems. • Deracemization of NMPA is scaled-up to 2 L under nominally isothermal conditions. • NMPA undergoes cyclization reaction in mixture of isopropanol and acetonitrile. • Deracemization proceeds provided the byproduct remains in solution at low concentration. • When byproduct crystallizes, the enantiomeric excess declines unexpectedly. • No byproduct forms in pure acetonitrile, but crystal fouling impairs mixing.