Combined Effect of Polymorphism and Process on Preferential Crystallization:  Example with (±)-5(4‘-Methylphenyl)-5-methylhydantoin

Abstract

The structural data of two varieties of the title compound as well as the corresponding irreversible polymorphic transition are detailed. Although extensive structural analogies are pointed out, the transition is of destructive/reconstructive type with a poor rate requiring days or even weeks for completion. Without seeding, evidence of epitaxial nucleation is given. The genuine impact of polymorphism on the preferential crystallization is highlighted. The greater the departure from thermodynamic equilibrium the greater the differences between the courses of the entrainments initiated with a given polymorph. The best result in terms of robustness, yield, and conditions for up-scaling is obtained by using a combination of (i) a smooth crystallization process (auto-seeded and polythermic: AS3PC), (ii) the use of the stable polymorph, (iii) a pretreatment of the solid particles designed to enlarge the surface of the solid phase ready for the crystal growth as soon as the cooling program is launched.