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

Weronika Kras,Aurora J Cruz-Cabeza,Andrea Carletta,Riccardo Montis,Rachel A Sullivan

doi:10.1038/s42004-021-00473-7

Weronika Kras, Aurora J Cruz-Cabeza + Show 3 more

Open Access

https://doi.org/10.1038/s42004-021-00473-7

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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.

Highlights

Almost 200 years ago, benzamide was reported as polymorphic with two of its forms (II and III) found to be difficult to crystallise
At concentrations of NCM above 30 mol%, diffraction peaks corresponding to solid NCM start appearing suggesting that the solid solubility of NCM in BZM form III lies around that value
In conclusion, we have shown that the relative stability of forms I and III BZM can be inverted by using a selective impurity (NCM) able to form solid solutions

Summary

Introduction

Almost 200 years ago, benzamide was reported as polymorphic with two of its forms (II and III) found to be difficult to crystallise. Along the journey towards a final drug product, it is common to observe the appearance of metastable polymorphs first which eventually transform to other more stable polymorphs This solid form evolution has often been linked to an increase in chemical purity. Whilst crystallisation is a very selective process ( widely used as a purification technique), sometimes the tiniest amount of impurities can have a significant impact on the outcome This is especially true when the impurity has a close molecular similarity with the compound under development. We explore a different molecular route of action: rather than blocking the nucleation and growth of the stable form, we explore how other impurities may be able stabilise the metastable polymorph through the formation of solid solutions

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