Agomelatine–hydroquinone (1:1) cocrystal: novel polymorphs and their thermodynamic relationship

Abstract

Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine–hydroquinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des. 16, 1063–1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339 K for the pair form (IV)–(II) and 352 K for the pair form (II)–(III).