Vemurafenib: A Tetramorphic System Displaying Concomitant Crystallization from the Supercooled Liquid

Abstract

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 α, β, γ, and δ. The thermodynamic stability is α > β > γ or δ. Isothermal crystallization between 120 and 240 °C resulted in concomitant polymorphs with samples containing either 2 or 3 of t...