Structure and spectroscopic characterization of pharmaceutical co-crystal formation between acetazolamide and 4-hydroxybenzoic acid

Co-crystals have great potential for drug research and development because the formation of co-crystal is accompanied by changes inter-molecular interactions between starting materials that enable to improve both physical and chemical properties of active pharmaceutical ingredients. In order to provide a more profound insight into the structural changes of specific drugs upon co-crystallization, spectroscopic characterization of solid-state acetazolamide (ACZ), 4-hydroxybenzoic acid (4HBA) and their co-crystal prepared by mechanical grinding approach has been performed with spectral techniques including terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy. Experimental THz spectra show that the ACZ-4HBA co-crystal has a few significantly different absorption peaks in 0.82, 1.16, 1.28 and 1.64 THz respectively compared with parent materials in the frequency region from 0.2 to 1.8 THz. Likewise, such differences between the co-crystal and starting compounds could also be characterized by Raman vibrational spectra. Moreover, density functional theory (DFT) calculations were performed to simulate optimized structures and vibrational modes of three kind of possible co-crystal theoretical forms (form I, II and III) between ACZ and 4HBA. Theoretical results and THz/Raman vibrational spectra of ACZ-4HBA co-crystal show that the 4HBA links to the thiadiazole acetamide fragment of ACZ via the double-bridged heterodimeric synthon C(N)NH⋯HOOC inter-molecular hydrogen bonding interaction establishing the theoretical form I, which is more consistent with experimental observations than other two possible theoretical co-crystal forms. These results provide rich information and unique method for characterizing the composition of co-crystal structures and also inter-molecular interactions shown within pharmaceutical co-crystallization process at the molecular level.