The nature of crystal disorder in milled pharmaceutical materials

Abstract

The purpose of this study was to study the nature of disorder in milled crystalline materials. Specifically to elucidate if the induced disorder represents crystal defects or amorphous regions. Felodipine and griseofulvin were chosen as model drugs and subjected to milling. Cryomilling was chosen in order to mitigate the influence of heat generated by the process. Amorphous drug samples were produced by quenching the melt. Crystalline, amorphous and cryomilled drug samples were characterized by powder X-ray diffraction (PXRD), thermal analysis (DSC), thermal polarization (thermally stimulated polarization current), and surface energy (inverse gas chromatography). The PXRD analysis shows that cryomilling reduces the crystallinity of the two drugs, while maintaining the same crystal form. Heat capacity measurements (DSC) show that milled material for either drug does not exhibit a glass transition but shows instead an exothermic (crystallization like) event. The thermal polarization profiles revealed that none of the modes of molecular motion (polarization peaks) characteristic of the amorphous form were observed in either the unmilled crystalline or milled forms for either drug. For each drug, the polarization spectra of milled forms were similar, but not identical, to those of the corresponding unmilled crystalline materials. Inverse gas chromatography (IGC) measurements showed that the surface energy of cryomilled samples was higher than those of the unmilled and amorphous forms for both drugs. The polarization and heat capacity measurements show that the disorder induced by milling either griseofulvin or folodipine consists of crystal defects rather than amorphous regions. The exothermic event in the milled samples is attributed to the crystallization of defects in the crystal. These results when combined with the IGC measurements indicate that the milled material retains its crystalline character, making it more stable (at the core) than the amorphous form. However, the milled material has also the most active surface, making it the more interactive with other surfaces as an activated powder.