Vibrational Spectral Detection And Analysis About The Pharmaceutical Cocrystal Structures Of Typical Anti-inflammatory Drugs

Co-crystal is defined as a multi-component crystal that is held together by non-covalent interactions in two or more solid components(under preset experimental conditions)at a set stoichiometric ratio.This change in the internal structure of the drug molecule caused by the non-covalent bond can effectively improve the physicochemical properties and final clinical properties of the relevant active pharmaceutical ingredient(API),while the chemical structure,inherent biological activity and API and the corresponding pharmacological activity is almost unaffected in most cases.Therefore,it is essential to obtain high-precision molecular structure information by means of detection.Traditional detection techniques do not provide high-resolution molecular structure fingerprints,while Terahertz Time Domain Spectroscopy(THz-TDs)and Raman Spectroscopy provide spectral information on the internal microstructure of molecules.The main research contents of the thesis are as follows:(1)The typical anti-inflammatory drug diflunisal(DIF)has four crystal forms.The crystal form II is the main ingredient of the commercial DIF due to its structure is the most stable.But the solubility and low magnetic permeability of this form would affect the body’s full absorption of drugs.The DIF and isonicotinamide(ISO)co-crystal prepared by solvent evaporation can improve these deficiencies.Two kinds of vibrational spectroscopy techniques,Terahertz Time Domain spectroscopy(THz-TDs)and Raman spectroscopy,were used to detect and analyze the raw materials and co-crystal structures to obtain the spectral effects of the corresponding structures.Using Density functional theory(DFT)to simulate the theoretical structure of co-crystal,we obtain rich information of vibration modes,and compare the experimental results,successfully obtain a new structural form of DIF-ISO co-crystal instead of the structural form previously reported by the Wang Lianyan group.(2)The process of drug synthesis is accompanied by changes in molecular structure,and researchers often need to quantify the extent of this change in order to obtain information on the process of drug synthesis.Since THz and Raman spectroscopy are very sensitive to weak changes in molecular structure,these two techniques can be applied to the quantitative analysis of binary co-crystal formation process,in addition to being well applied to the qualitative analysis of binary co-crystal.In this paper,acetazolamide(ACZ),which is a typical anti-inflammatory drug,was selected as the research object(ACZ also has shortcomings such as low solubility and bioavailability),and ACZ and 4-hydroxybenzoic acid(4-HBA)were obtained by liquid-assisted grinding,and successfully obtained the qualitative results of ACZ-4HBA co-crystal,while the offline synthesis of THz spectra was performed on the synthesis process of ACZ-4HBA co-crystal during the experiment to obtain THz map data of co-crystal formation process,analysis of the intensity and positional changes of characteristic peaks in THz spectral data,which is beneficial to the pharmaceutical industry to achieve process control of drug production,enabling it to improve drug production effects and quality.(3)Ternary co-crystal is a new type of co-crystal form developed on the basis of binary co-crystal.Compared with binary co-crystal,its synthesis requires non-covalent bond to act on three different component molecules.Crystals have more complex structures and are less prone to be prepared.However,the complex structure determines that such co-crystal has better physical and chemical properties than the binary co-crystal,and can also improve the side effects of the drug to some extent.In order to study the application of THz and Raman detection techniques in the ternary co-crystal microstructure,the ternary co-crystal of ACZ and 2-pyridion(2HP)and nicotinamide(NAM)was successfully prepared by liquid-assisted grinding.The THz and Raman spectra were used to detect the binary and ternary co-crystal samples of the same API,and the corresponding vibrational spectra were successfully obtained.The spectral results well characterized the difference between the co-crystal and the raw materials.At the same time,the DFT is used to calculate the co-crystal theory form and its own vibration mode,and the spectral model of ACZ and its co-crystal structure is obtained.It embodies the superiority of THz and Raman spectroscopy technology not only in the qualitative analysis of binary co-crystal drug structure,but also can be successfully applied to the detection of ternary co-crystal.