Vibrational spectral and structural characterization of multicomponent ternary co-crystal formation within...

Ternary co-crystal, as a novel co-crystal design strategy developed on the basis of binary co-crystal, could be used to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently. However, it is difficult to obtain specific ternary co-crystals since such ternary one involves complex assembly of three different molecules. There are few reports on the micro-molecular structure respect of specific ternary co-crystal systems. In present work, 1:1:1 ternary co-crystal between acetazolamide (ACZ), nicotinamide (NAM) and 2-pyridone (2HP) has been synthesized successfully by mechanical grinding approach, and their structures are investigated by terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy combined with theoretical calculation at the molecular level. The experimental THz spectral results showed that ACZ-NAM-2HP ternary co-crystal and the starting parent materials exhibited a few distinct spectral features in frequency-domain absorption spectra. Likewise, the Raman spectral result also shows some difference between the co-crystal and starting raw materials. Through density functional theory (DFT) calculations, the theoretical THz/Raman spectra and vibrational modes of two kind of possible ternary co-crystal theoretical forms (form I and II) between ACZ, NAM and 2HP were obtained. By comparing experimental and theoretical spectral results, the most suitable structure and vibrational modes of ACZ-NAM-2HP ternary co-crystal were determined. These results provide a wealth of information and unique method for studying molecular assembly and also inter-molecular interactions in specific ternary co-crystals at the molecular level in the emerging pharmaceutical co-crystal fields.