Structural investigation of a 2:1 co-crystal between diflunisal and isonicotinamide based on terahertz and Raman spectroscopy.

In order to characterize molecular structure changes of drugs upon co-crystallization by means of spectroscopic techniques, vibrational spectra of solid-state diflunisal (DIF), isonicotinamide (ISO) and their 2:1 co-crystal have been investigated by using terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy. A 2:1 DIF-ISO co-crystal between DIF and ISO has been synthesized by slow solution crystallization from ethanol. The experimental THz spectroscopy shows that the co-crystal has a few significantly different absorption peaks compared with raw parent materials within the frequency region from 0.2 to 1.6 THz. Likewise, some differences of vibrational spectra between the co-crystal and starting compounds could also be characterized by Raman spectral results. Density functional theory (DFT) was used to simulate optimized structures and vibrational modes of two kind of possible co-crystal theoretical forms (form I and II) between DIF and ISO. Theoretical co-crystal form I is shown with 2:1 theoretical binary-adduct formed by carboxylic acid-amide and carboxylic acid-pyridine under inter-molecular hydrogen bonding. Theoretical co-crystal form II has a similar structure as form I, meanwhile the only difference is that O63 atom simultaneously forms hydrogen bond with H33 and H64. Also the hydroxyl -OH and carboxyl group -COOH establish molecular heterocycle under intra-molecular hydrogen bonds in both forms. The theoretical results show that both THz and Raman spectra of co-crystal form II between DIF and ISO is more consistent with the experimental observations than those of co-crystal form I. These results provide us with a wealth of information and unique method for characterizing the composition of co-crystal structures and also inter-molecular hydrogen bonding interactions shown within pharmaceutical co-crystallization at the molecular level.