Milling induces disorder in crystalline griseofulvin and order in its amorphous counterpart

Abstract

This study investigates two apparently similar thermal signatures, shaped as bimodal exotherms, observed when either the crystalline or the amorphous from of the drug are subjected to milling. Crystalline griseofulvin was cryomilled and the (quenched-melt) amorphous form was subjected to either cryomilling or grinding. The thermal and surface properties of the resulting samples were analyzed using differential scanning calorimetry (DSC) and surface energy analysis. After milling, both the crystalline and the amorphous material revealed visually similar bimodal exothermic events when the heating rate was 20 C min À1 . Under different heating rates, the pair of DSC peaks for the bimodal exotherm of each material behaved entirely different from each other. The two peaks of the bimodal event, as well as the glass transition, can be kinetically resolved for the ground amorphous form using standard mode DSC. In contrast, similar analysis was unable to resolve the bimodal exotherm or a glass transition in the case of the cryomilled crystals. Furthermore, cryomilled crystals do not exhibit a glass transition even when analyzed using modulated DSC. Synchrotron sourced X-ray analysis revealed that grinding the amorphous material results in the nucleation and growth of the crystalline form. Milling thus induces disorder in the crystals of griseofulvin but induces order in the amorphous form of the drug. The surface of the two milled systems consistently exhibited different energetics under a wide range of relative humidity conditions. These findings suggest that cryomilling induces both bulk and surface disorder, specifically, a certain level of dislocations on the crystal. In contrast, grinding the amorphous material lowers the activation energy for crystal formation, inducing nuclei formation and growth throughout the amorphous matrix.

Solid-State Transformations of Sulfathiazole Polymorphs: The Effects of Milling and Humidity

“…The PCA scores and the corresponding loadings plots for the NIR spectra of the milled samples in the regions 6980-5800 and 5130-4000 cm -1 are shown in Figure 4. Mechanical activation induced solid-state polymorphic transitions and amorphizations have been reported in many cases such as gabapentin [1], famotidine [26], fananserine [27] trehalose [28] and griseofulvin [29]. In general it is not clear if polymorphic transformations are direct crystal-crystal transformations or if an intermediate stage of transient amorphization or a transient unstable crystal phase is generated which is followed by a rapid recrystallization process to a known polymorph [27].…”

Structural Characterization of Amorphous Solid Dispersions

“…Interestingly, the first crystallization event originates from surface that is followed by bulk process beyond T g . Highest surface crystal growth rates around T g were confirmed for APIs exhibiting surface crystallization (Otte et al 2012).…”

Amorphous Solid Dispersions

“…Interestingly, the first crystallization event originates from surface that is followed by bulk process beyond T g . Highest surface crystal growth rates around T g were confirmed for APIs exhibiting surface crystallization (Otte et al 2012). Experimental conditions such as thermal contact with the DSC pan, sample particle size, heating rate, etc.…”