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

Abstract

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.

Biogenic Guanine Crystals Are Solid Solutions of Guanine and Other Purine Metabolites

“…A similar effect was recently observed when the metastable benzamide form III was stabilized upon forming solid solutions with the nonisostructural additive nicotinamide. 63 Since the replacement of guanine by hypoxanthine involves replacement of an −NH 2 group by H on the N2 of guanine ( Figure 6 b), we expect that hypoxanthine inclusion should result in lattice contraction within the bc plane and a decrease in the unit cell volume. As predicted, the b and c axes and unit cell volume of synthetic β-guanine–hypoxanthine mixed crystals are lower than those of the synthetic β-guanine standard.…”

A New Curcuminoids‐Coumarin Derivative: Mechanochemical Synthesis, Characterization and Evaluation of Its In Vitro Cytotoxicity and Antimicrobial Properties

“…In addition, some mechanochemical reactions can lead to different products in the absence of solvent, or even do not form the product. [20][21][22][23][24][25][26][27][28][29][30][31] Therefore, a screening was performed using the ball milling process in the synthesis, which was carried out under different conditions to obtain the best synthesis conditions.…”

Cannabinoid crystal polymorphism

“…One can only imagine their amazement as they surprisingly observed the fine needles of one benzamide crystal polymorph convert to the rhombic crystals of another polymorph. Almost two centuries later, benzamide crystal polymorphism continues to fascinate current researchers (Kras et al 2021 ). A myriad of crystal forms have now been characterized for many substances and thousands of them have been archived as X-ray crystal determinations in the voluminous Cambridge Structural Database (van de Streek 2006 ).…”