Vibrational Spectral Detection And Analysis About The Pharmaceutical Cocrystal Structures Of Typical Ternary Cocrystals

Pharmaceutical cocrystal is defined as a combination of two or more solid components in a fixed stoichiometric ratio through non-covalent interactions,which can effectively improve the active pharmaceutical ingredients by changing the structure of the drug molecule through non-covalent interactions.Some physicochemical properties and clinical properties of active pharmaceutical ingredient(active pharmaceutical ingredient,API).The chemical structure of the drug molecule itself does not change,and the biological activity and pharmacological activity of the API itself are not affected in most cases,so the solubility and bioavailability of the drug can be improved through drug co-crystals.In order to have a deeper understanding of the structural changes before and after the formation of pharmaceutical cocrystal,it is very important to obtain accurate molecular structure information of cocrystals through detection methods.However,traditional detection techniques lack spectral detection in the range of molecular fingerprints.In this paper,the terahertz time domain is used.Terahertz Time Domain Spectroscopy(Terahertz Time Domain Spectroscopy,THzTDS)and Raman Spectroscopy(Raman Spectroscopy)were used to detect and analyze a variety of ternary eutectic system drugs,obtain the spectral map of the corresponding structure,and use density functional theory(Density Functional Theory,DFT)simulated the theoretical structure of the eutectic,and obtained rich vibrational mode information.The most reasonable form of the cocrystal was obtained by comparing the experimental spectral results.By combining these two vibrational spectroscopy techniques,ternary co-crystals can be accurately detected and rich intramolecular and intermolecular structural information can be obtained.The obtained information can lay a good data foundation for the development and production of ternary drug cocrystals in the future.The main research contents of the paper are as follows:(1)Drug-drug cocrystal is an important part of pharmaceutical cocrystal,which improves the physicochemical properties of each component under the premise of synergistic therapy.When two or more APIs can’t form cocrystals,it can be considered to introduce new drugs as "bridges" to connect the target APIs to form co-crystals.For example,acetazolamide and nicotinamide cannot directly produce drug-drug cocrystals,and need to be combined with 2-pyridone to induce ternary cocrystal.Two vibrational spectroscopy techniques,THz-TDS and Raman spectroscopy,were used to detect and analyze the structures of the raw materials and co-crystals,and the spectral effect diagrams of the corresponding structures were obtained.The theoretical structure of the ternary cocrystal was simulated by DFT,and rich vibrational mode information was obtained.(2)The starting components in the ternary cocrystal may form binary cocrystal in pairs,and the synthesis of the binary cocrystal plays a crucial role in the formation of the ternary cocrystal.Glutaric acid can form binary cocrystal with isonicotinamide and pyrazinamide,respectively,and the three can also form ternary cocrystal together.Through the analysis of the hydrogen bond formation mode of binary cocrystal,the hydrogen bonds of ternary cocrystal are further discussed.(3)THz spectroscopy is very sensitive to changes in molecular lattice structure.This technique can be applied not only to the analysis of binary and ternary cocrystal structures,but also to qualitative and quantitative analysis of ternary cocrystal.In this paper,the ternary cocrystal system of isoniazid-nicotinamide-succinic acid,which has a large number of cocrystal types,is selected as the research object.