Scientific Publications by FDA Staff

Cryst Growth Des 2016 Oct;16(10):6033-42

Vemurafenib: a tetramorphic system displaying concomitant crystallization from the supercooled liquid.

Lu M, Taylor LS

The current interest in amorphous forms of active pharmaceutical ingredients stems from their increasing use in enabling formulations for the delivery of poorly water-soluble compounds. Because amorphous drugs are metastable and have a tendency to revert to crystalline forms, their crystallization behavior is an important topic. This study reports the observation of concomitant polymorphs of vemurafenib following crystallization from the supercooled liquid, and their subsequent phase transformations. The crystallization behavior of amorphous vemurafenib was evaluated between the glass transition temperature and melting temperature. Six characteristic crystal morphologies were observed. Based on X-ray diffraction and Raman spectroscopic studies, these morphologies were associated with four polymorphic forms, designated alpha, beta, gamma and delta. The thermodynamic stability is alpha > beta > gamma or delta. Isothermal crystallization between 120 and 240 degrees C resulted in concomitant polymorphs with samples containing either 2 or 3 of the 4 polymorphs depending on the specific temperatures, with the alpha-form or beta-form typically dominating. Crystallization at even higher temperature yielded only the alpha-form. A monotropic relationship was inferred between the alpha- and beta-forms based on calorimetric data. beta-to-alpha, gamma-to-beta, and delta-to-beta phase transformations were observed using hot-stage polarized light microscopy, Raman microscopy, and powder X-ray diffraction. The discovery of three new concomitant polymorphs of vemurafenib following crystallization from the supercooled liquid of vemurafenib highlights the rich polymorphic landscape that can be accessed by evaluating crystallization in supercooled liquids, and underscores the complexity in evaluating the crystallization of amorphous drug forms.