Establishing template-induced polymorphic domains for API crystallisation: the case of carbamazepine

Abstract

Template-induced nucleation of the model compound, Carbamazepine (CBZ), on substrates with different surface chemistries was studied. Supersolubility regions in which CBZ metastable form II or stable form III preferentially nucleated under the influence of cyano-, mercapto- and fluoro-functionalised templates were determined. Analysis of the resulting Template-induced Polymorphic Domain (TiPoD) plots indicated that cyano-functionalised templates promoted nucleation of form II and, in contrast, mercapto and fluoro surfaces favoured nucleation of form III. By comparing the interaction energies between CBZ crystal polymorphs and each template surface using molecular simulations, we propose that intermolecular interactions during the early stages of crystal nucleation selectively favours heterogeneous nucleation and growth of specific polymorphs on the functionalised surfaces. In the light of recent studies relating solvent effects to preferential nucleation of CBZ polymorphs, we further discuss the role of surface chemistry in directing the molecular-assembling process en route template-induced crystal nucleation.