Vibrational Spectral Detection And Analysis About The Pharmaceutical Cocrystal Formation Of Typical Anti-tubercular Drugs

Pharmaceutical cocrystal refers to crystal formed by intermolecular non-covalent bond between cocrystal coformer(CCF)and active pharmaceutical ingredient(API)according to certain stoichiometric ratio.Its obvious feature is to improve the bioavailability and solubility of the drug without changing the API.The specific contents are as follows:(1)Pyrazinamide(PZA)and 3-hydroxybenzoic acid(3hBA)based on Terahertz(THz)and Raman detection were studied.And they were prepared by solution evaporation and grinding methods.THz spectroscopy is extremely sensitive to intermolecular interactions.Raman spectroscopy is more manifested in intramolecular interactions and functional group vibration modes.Raman and THz spectra were used to detect and analyze the cocrystal and the corresponding spectra were obtained.In the experimental THz spectra,the characteristic peaks of the cocrystal around 0.81,1.47 and 1.61 THz are completely different from the raw materials,and the Raman spectra also shows significant difference from the raw materials.Density functional theory(DFT)simulation results are compared with experimental vibrational spectra to determine the PZA-3hBA cocrystal's vibration modes.(2)Then another typical anti-tuberculosis drug isoniazid(INH)were selected as the research object with 3hBA.The vibrational spectra of INH,3hBA and its 1:1cocrystal were studied by THz and Raman spectroscopy techniques.The experimental results show that the absorption peak of the cocrystal is significantly different from the raw materials in the frequency range of 0.2~1.4 THz.Similarly,Raman spectroscopy can also be used to characterize the difference in vibrational spectra between the cocrystal and the raw materials.The optimized structure and vibration mode of the cocrystal theory were simulated by DFT.The verification of the cocrystal structure by THz and Raman spectra were realized.(3)The ternary cocrystal structure is designed and connect with experiment verification.The anti-tuberculosis drugs PZA and INH cannot directly form cocrystal.Fumaric acid(FA)can connect PZA and INH to form ternary cocrystal.Ternary cocrystal has good solubility and bioavailability.The raw materials and ternary cocrystal detected by THz and Raman spectroscopy were compared with the simulated spectra,and the coincidence between them was good.Under the control of THz and Raman,the ternary cocrystal was well detected and analyzed.