Switching polymorph stabilities with impurities provides a thermodynamic route to benzamide form III

• Published in: Communications chemistry 2021-03, Vol.4 (1), p.38-38, Article 38
• Main Authors: Kras, Weronika, Carletta, Andrea, Montis, Riccardo, Sullivan, Rachel A., Cruz-Cabeza, Aurora J.
• Format: Article
• Language: English
• Subjects: 639/638/440/951; 639/638/541/961; Benzamide; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Crystallization; Nicotinamide; Solid solutions; Switching
• ISSN: 2399-3669; 2399-3669
• DOI: 10.1038/s42004-021-00473-7

Almost 200 years ago, benzamide was reported as polymorphic with two of its forms (II and III) found to be difficult to crystallise. In a recent study, it was shown that benzamide form I can easily convert into benzamide form III using mechanochemistry in the presence of nicotinamide. Here we show, experimentally and computationally, that this transformation is the result of a thermodynamic switch between these two polymorphic forms driven by the formation of solid solutions with small amounts of nicotinamide. The presence of nicotinamide in the crystallisation environment promotes the robust and exclusive crystallisation of the elusive form III. These results represent a promising route to the synthesis and utilisation of elusive polymorphs of pharmaceutical interest. The formation of solid solutions can result in changes of relative stabilities of crystal polymorphs. Here, the elusive form III of benzamide is stabilized through solid solution formation with nicotinamide. It is shown, experimentally and computationally, how such thermodynamic switching allows for consistent and facile crystallization of the otherwise elusive benzamide form III.