Distinguishing Polymorphs of Ethenzamide-Saccharin Cocrystal Based on Terahertz and Raman Vibrational Spectroscopic Techniques

In this article, two kinds of pharmaceutical crystallized polymorphs of ethenzamide (ETZ) and saccharin (SAC) cocrystal were synthesized by both solution crystallization and solid-state grinding methods. Crystal structure analysis revealed that the primary hydrogen-bonding heterosynthon of amide–imide in the form I and form II of ETZ-SAC cocrystal was the same, but the secondary interactions in the extended hydrogen-bonding network were different. In addition, ETZ, SAC, their physical mixture, the form I and form II of ETZ-SAC cocrystal were characterized using terahertz (THz) and Raman spectroscopy. The experimental spectra of THz and Raman showed that ETZ, SAC, and two kinds of polymorphs of ETZ-SAC cocrystal exhibited different characteristic peaks, and THz spectroscopy could distinguish the form I and form II of ETZ-SAC cocrystal, but could not be identified by Raman spectroscopy. Solvent phase transition analysis showed that the result polymorphism of ETZ-SAC cocrystal was not dependent on the polarity of the solvent in the solvent drop grinding experiments, neat grinding and most of solvent drop grinding experiments formed the metastable form II of ETZ-SAC cocrystal. These results indicate that with the in-depth study of pharmaceutical polymorphs of cocrystal, it can be reasonably predicted that polymorphs of cocrystal will have great significance in the development of pharmaceutical cocrystals in the future.