特征光谱技术在含氮杂环类药物晶型结构分析中的应用

发布时间：2018-05-17 22:45

本文选题：太赫兹时域光谱 + 傅里叶变换拉曼光谱　；参考：《中国计量学院》2016年硕士论文

【摘要】：太赫兹光谱对物质的分子构型、分子间作用力十分敏感;而拉曼光谱对分子内化学键和官能团的振动更有效。本文依据含氮杂环类药物(呋喃妥因和吡嗪酰胺-异烟肼联用药物)在这两种特征光谱中的特征峰,达到辨别并分析药物晶型结构的目的。结合实验光谱与理论模拟结果研究氢键对该类含氮杂环药物晶型结构的影响以及相关共晶体的结构性质;利用太赫兹波段内联用药物吸收系数、折射率等与其含量的相关性研究,获得其中吡嗪酰胺的含量检出限。呋喃妥因是广谱抗菌药,存在多种晶型,水溶性差。使用傅里叶拉曼(FT-Raman)和太赫兹(THz)光谱技术研究并确认呋喃妥因及其水合物的晶型结构。发现两者在THz光谱中的差异远高于Raman的光谱结果。呋喃妥因共晶体的水溶性高于它本身,选取呋喃妥因和5种典型的共晶形成物(3-氨基苯甲酸、4-氨基苯甲酸、马来酸、富马酸、尿素)制备共晶体,并通过THz技术获得它们的指纹谱。结合DFT理论对模型药物进行光谱模拟,从实验结果与理论模拟的吻合程度判断并确认模型药物的晶型结构。以呋喃妥因与4-氨基苯甲酸的共晶体为例,深入分析研磨时间对共晶体形成的动态过程的影响。共晶体与原料药的拉曼峰和研磨反应时间呈现相关性,结果表明共晶体的动态形成过程可以被特征光谱技术实时监测。人体对吡嗪酰胺和异烟肼容易产生耐药性;而吡嗪酰胺的肝脏毒性较强,应严格控制含量。利用THz光谱分析吡嗪酰胺的两种多晶型,结合理论模拟确认它们以二聚体形态存在。获取异烟肼的THz光谱并验证异烟肼以单分子形态存在。吡嗪酰胺-异烟肼联用药物的吸收系数、折射率与含量之间存在线性相关。本文分别采用一元线性和偏最小二乘回归模型完成了联用药物的定量分析。结果表明吡嗪酰胺的偏最小二乘回归模型的检出极限0.7660%,是一元线性回归的十分之一。说明偏最小二乘回归模型的预估效果更好。
[Abstract]:The terahertz spectrum is very sensitive to the molecular configuration and intermolecular force, while the Raman spectrum is more effective for the intramolecular chemical bond and functional group vibration. Based on the characteristic peaks of nitrogen-containing heterocyclic drugs (furantoin and pyrazinamide isoniazid) in these two characteristic spectra, the crystal structure of the drugs was identified and analyzed. The effect of hydrogen bond on the crystal structure of the nitrogen-containing heterocyclic drugs and the structural properties of the related eutectic were studied by combining the experimental spectra and theoretical simulation results, and the absorption coefficients of the drugs used for inlining in the terahertz band were used. The detection limit of pyrazinamide was obtained by studying the correlation between refractive index and content of pyrazinamide. Furantoin is a broad-spectrum antimicrobial drug with many crystal forms and poor water solubility. The crystal structure of furantoin and its hydrate was studied and confirmed by Fourier Raman spectroscopy (FT-Raman) and terahertz (THz) spectroscopy. It is found that the difference between the two in THz spectra is much higher than that in Raman spectra. The water solubility of furantoin eutectic is higher than that of itself. Furantoin and five typical eutectic formatives, such as 3-aminobenzoic acid, maleic acid, fumaric acid and urea, are selected to prepare eutectic. Their fingerprints were obtained by THz technique. Combined with DFT theory, the model drug was simulated by spectrum, and the crystal structure of the model drug was confirmed by judging the degree of agreement between the experimental results and the theoretical simulation. Taking the eutectic of furantoin and 4-aminobenzoic acid as an example, the effect of grinding time on the dynamic process of eutectic formation was analyzed. The results show that the dynamic formation process of eutectic can be monitored by characteristic spectrum technique in real time. It is easy to develop drug resistance to pyrazinamide and isoniazid in human body, while pyrazinamide is more toxic in liver, so the content of pyrazinamide should be strictly controlled. Two kinds of polycrystalline forms of pyrazinamide were analyzed by THz spectroscopy, and they were confirmed to exist in dimer form by theoretical simulation. The THz spectra of isoniazid were obtained and the existence of isoniazid as a monolayer was confirmed. There is a linear correlation between the absorption coefficient, refractive index and content of pyrazinamide-isoniazid. In this paper, the linear and partial least square regression models were used to analyze the combined drugs. The results show that the detection limit of the partial least square regression model of pyrazinamide is 0. 7660, which is 1/10 of the linear regression. It shows that the prediction effect of partial least squares regression model is better.
【学位授予单位】：中国计量学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R917

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