Investigation into polymorphism within ethenzamide-ethylmalonic acid cocrystal using Raman and terahertz vibrational spectroscopy.

Two cocrystal polymorphs of ethenzamide (ETZ) and ethylmalonic acid (EMA) were synthesized by solvent evaporation. Crystal structure analysis revealed that the main amide - carboxyl heterosynthon in ETZ-EMA cocrystal Form I and Form II are the same, but the crystal structure of these two polymorphs are different. Terahertz (THz) and Raman vibrational spectroscopy were used to characterize ETZ, EMA, ETZ-EMA cocrystal polymorph Form I and Form II respectively. The experimental results showed that ETZ, EMA, ETZ-EMA cocrystal Form I and ETZ-EMA cocrystal Form II exhibited completely different characteristic peaks. Both THz and Raman vibrational spectroscopy can be used to distinguish ETZ-EMA cocrystal Form I from Form II. Furthermore, the investigation of phase transition induced by temperature and solid-state grinding was also performed. In the temperature phase transition experiments, when the powder sample was heated to a temperature range of 80-82 °C, the metastable ETZ-EMA cocrystal Form I transformed into the more stable ETZ-EMA cocrystal Form II. Solid-state grinding analysis revealed that the results of the ETZ-EMA cocrystal polymorph synthesis in grinding experiments depended on the polarity of the solvents used. Grinding without solvent or with high polarity solvents tended to result in the stable ETZ-EMA cocrystal Form II. Moreover, the metastable ETZ-EMA cocrystal Form I would transform into Form II after further grinding process. These results demonstrate that THz and Raman vibrational spectroscopy have high sensitivity and accuracy in the detection of both cocrystal synthesis and cocrystal polymorph phase transitions.