Characterization and crystal structure of two polymorphic forms of racemic thalidomide

Abstract

There are two polymorphic forms of racemic thalidomide. The α-polymorph was formed by crystallization from 2-ethoxyethanol, methanol or dichloromethane, while the β-polymorph was formed by crystallization from a supersaturated solution in refluxing 2-ethoxyethanol. The two polymorphs were characterized by IR spectra, differential scanning calorimetry (DSC), melting points, powder X-ray diffraction patterns, and X-ray crystallography. They were easily differentiated by IR (KBr) in which the α polymorph absorbed at 3196, 3098 and 859 cm^–1 and the β at 3276 and 755 cm^–1. DSC scans of the α and β forms showed endothermic peaks at 272.3 and 275.7 °C, respectively. During this measurement the α form was partially or fully converted into the β form if the rate of temperature change was slow or if the α form contained some β which provided seed crystals for the interconversion. Upon remelting both forms gave one peak corresponding to the β polymorph. The powder X-ray diffraction patterns for the two forms differ significantly. The crystal structures of the two polymorphs differ primarily in their mode of hydrogen bonding. In the α polymorph the molecules form dimers, while in the β the dimers form infinite linear strings linked by bifurcated hydrogen bonds along the b-axis.