New Kinetic Investigations to Better Understand the Mechanism of Polymorphic Transformations of Pharmaceutical Materials Induced by Milling.

Objective: The aim of this work is to improve the understanding of the mechanisms underlying the polymorphic transformations of pharmaceutical materials during milling. Elucidating these mechanisms is essential for controlling the polymorphism of active pharmaceutical ingredients and thereby improving their performance. Method: The structural evolution of various pharmaceutical compounds (sulfamerazine, glycine, mannitol, and famotidine) upon milling was followed using ex situ laboratory X-ray diffraction and in situ synchrotron measurements, complemented by DSC analyses. Results: For each compound, the kinetics of the polymorphic transformation was found to be sigmoidal and the presence of an intermediate amorphous phase during the transition from the initial to the final polymorphic form was also identified. Conclusions: The kinetic data obtained for sulfamerazine and glycine, together with the detection of an amorphous intermediate during the transformations of mannitol and famotidine, support the conclusion that milling-induced polymorphic transformations in pharmaceutical materials generally proceed via an amorphization-recrystallization mechanism.