In situ investigation of controlled polymorphism in mechanochemistry at elevated temperature

Mechanochemistry routinely provides solid forms (polymorphs) that are difficult to obtain by conventional solution-based methods, making it an exciting tool for crystal engineering. However, we are far from identifying the full scope of mechanochemical strategies available to access new and potentially useful solid forms. Using the model organic cocrystal system of nicotinamide (NA) and pimelic acid (PA), we demonstrate with variable temperature ball milling that ball milling seemingly decreases the temperature needed to induce polymorph conversion. Whereas Form I of the NA:PA cocrystal transforms into Form II at 90 °C under equilibrium conditions, the same transition occurs as low as 65 °C during ball milling: a ca 25 °C reduction of the transition temperature. Our results indicate that mechanical energy provides a powerful control parameter to access new solid forms under more readily accessible conditions. We expect this ‘thermo-mechanical’ approach for driving polymorphic transformations to become an important tool for polymorph screening and manufacturing.