Vibrational Spectroscopic Investigation into Novel Ternary Eutectic Formed between Pyrazinamide, Fumaric Acid, and Isoniazid

[Image: see text] To improve the efficacy of anti-tuberculosis (anti-TB) therapy, drug–drug co-crystallization stands for an alternative approach to settle the tuberculosis problem. Directly co-crystallizing two typical parent anti-TB drugs (pyrazinamide, PZA and isoniazid, INH) into a single binary co-crystal could not be obtained successfully. Multicomponent eutectic are highly effective and useful for enhancing the dissolution rate, bioavailability, and physical stability of the poorly water-soluble active pharmaceutical ingredient (API) drugs, when the attempts of forming a binary co-crystal have failed. Therefore, the ternary eutectic composition conception was proposed in this study, in which fumaric acid (FA) was chosen as the molecule to connect two first-line anti-tubercular drugs. First of all, three starting materials (including PZA, INH, and FA) were grinded at a 1:1:1 molar ratio, the eutectic composition was investigated through vibrational spectroscopic techniques, including terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy. Additionally, the density functional theory (DFT) was utilized to simulate the optimized structures and vibrational modes of two possible theoretical eutectic composition forms. The THz absorption spectrum of the theoretical form I shows much more consistency with the experimental results than that of form II. Raman spectra also help to characterize the differences in vibrational modes between the eutectic composition and the starting parent compounds. The results provide us with both structural information and intermolecular hydrogen bonding interactions within specific multicomponent eutectic composition formulations based on Raman and terahertz vibrational spectroscopic techniques in combination with theoretical calculations.