Structural insights into the hexamorphic system of an isoniazid derivative

Abstract

Crystal polymorphism is the capacity of a crystalline solid to exist in more than one structural arrangement. The variation in the crystalline forms often induces different mechanical, thermal, and chemical properties. These changes can markedly influence the bioavailability, hygroscopicity, stability and other performance characteristics of the active pharmaceutical ingredient. Isoniazid, a well-known pharmaceutical, is used as a first-line treatment against Mycobacterium tuberculosis (TB). Derivatives of isoniazid were developed in response to TB drug resistance. One such derivative synthesized, isonicotinic acid (E)-(1-phenylethylidene)hydrazide (IPH), was found to exhibit complex polymorphic behaviour. To date, only one crystal structure of IPH has been reported in the literature. We have discovered and isolated an additional five polymorphs of IPH from various crystallization techniques, namely slow cooling, rapid evaporation, sublimation, as well as from hot-stage experiments. All of the polymorphs display hydrogen bonding through the carbonyl acceptor and hydrazide donor. Structural information about the polymorphs was obtained by single crystal and powder diffraction, while characterisation included infrared spectroscopy and Raman spectroscopy. The thermal properties of these polymorphs were also investigated using differential scanning calorimetry and hot stage microscopy.