Milling-Induced Phase Transformations, Underlying Mechanisms, and Resulting Physical States in an Enantiotropic System: The Case of Bezafibrate

The mechanisms driving the milling-induced transformations of an enantiotropic polymorph system, bezafibrate, are depicted. The phase transformations promoted by milling at two different temperatures and the resulting physical states were carefully investigated by the cross-use of structural (X-rays powder diffraction), thermodynamic (differential scanning calorimetry), and dynamic (dielectric relaxation spectroscopy) techniques. Our results highlight that milling of the commercial α phase at Tg─50 °C (−10 °C) leads to a complete amorphization (Tg ∼ 40 °C), whereas at Tg─15 °C (25 °C), it leads to the stable β phase. We establish that, as for monotropic situations, the solid–solid conversion is mediated by a transient amorphous state resulting from a milling-induced disordering of the crystalline structure partly counterbalanced by a slower re-crystallization. However, the monitoring of the transformation kinetics (phase ratio and crystallites’ size) reveals that at least 10% amorphous phase is required to trigger the re-crystallization to the stable β form instead of the metastable α form. For the first time, the molecular mobility of the physical states resulting from milling is finely investigated by dielectric relaxation spectroscopy. Strikingly, it evidenced, for the crystalline phases produced by milling, a residual mobility (detection of localized intra-molecular motions but absence of wide-amplitude motions characterizing the amorphous state), which originates through the mobility of part of molecules on the surface of crystallites. This outstanding result emphasizes and unravels the highly defective nature of the crystalline phases generated by milling.