药物微量未知成分及降解产物的质谱研究
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摘要
在药物的质量研究中,药物杂质的定性和定量分析极为重要。液质联用技术(HPLC/ESI-MS~n)兼顾了色谱的分离与质谱的定性能力,具有灵敏度高,分析快速简捷,样品消耗量少等优点,并能获得结构信息,已成为应用于药物在线分析的强有力的工具。本论文运用这一技术,成功地对亚胺培南和美罗培南的降解产物及依普罗沙坦和左氧氟羧酸中的微量杂质进行了分析研究及结构鉴定。主要内容包括以下三个部分:
第一部分应用液质联用技术、电喷雾串联质谱法及核磁共振技术分析了亚胺培南和美罗培南在酸性条件下的降解产物的产生过程及化学结构,通过傅里叶变换离子回旋共振质谱(FTICR-MS)离线确定了这些化合物的准确元素组成。并用核磁共振数据进行了确证。同时对其降解的中间产物进行了跟踪检测和分析鉴定。
第二部分应用电喷雾串联质谱探讨并归纳了正离子模式下依普罗沙坦的三条竞争性的质谱碎裂途径,并应用液质联用技术、电喷雾串联质谱法及核磁共振技术,通过依普罗沙坦及其杂质的质谱碎裂谱图的对照比较,分析鉴定了依普罗沙坦中微量杂质的化学结构。
第三部分应用核磁共振技术,通过对左氧氟羧酸及其杂质的核磁共振谱图的比较,对其微小的差别进行分析,推断出了左氧氟羧酸中微量杂质的化学结构。同时应用液质联用技术、电喷雾串联质谱法对左氧氟羧酸及其杂质正离子模式下的两条竞争性质谱碎裂途径进行了分析总结。
此外,论文还简要介绍了液质联用技术在药物分析中的研究进展。
It is important to undertake qualitative analysis and quantitative analysis of drug impurities.High-performance liquid chromatography,when combined with electrospray ion trap mass spectrometry,possesses high separation efficiency and great qualitative capability.As it holds the advantages of high sensitivity,relatively short analysis time,low sample amount,and the ability to obtain structural information,HPLC/ESI-MS~n has been widely used as a powerful tool in various online drugs analysis.In this dissertation,the liquid chromatograpy/electospray tandem mass spectrometry(HPLC/ESI-MS) method was developed to identify the degradation products of crude drugs:Imipenem and Meropenem,also used to identify the impurities of Eprosartan and Levofloxacin carboxylic acid.The details are listed in the following:
PartⅠA method based on HPLC/ESI-MS~n and nuclear magnetic resonance (NMR) has been established to analyze the degradation products of Imipenem and Meropenem in an acid solution,as well as the generation procedures involved.Offline Fourier transform ion cyclotron resonance mass spectrometry(FTICR-MS) was also performed to assign the accurate elemental compositions.The proposed structures by were confirmed by NMR technology.After conducting the tracing detection experiments,the structures of intermediate products in the acid degradation procedure were then identified.
PartⅡThree competitive fragmentation methods of Eprosartan in the positive mode were summarized by electrospray mass spectrum multistage fragmentation experiments(ESI-MS~n).In this phase,HPLC/ESI-MS~n and NMR technologies were employed to identify the chemical structure of a microimpurity by comparing the spectral data of Eprosartan and its impurity.
PartⅢThe chemical structure of the microimpurity in Levofloxacin carboxylic acid was identified by analyzing minor differences between Levofloxacin and the impurity in the NMR spectrometry.Furthermore,two competitive mass fragmentation methods in the positive mode were summed up by multistage mass fragmentation experiments.
In addition,the recent progress of the LC/MS~n technique in pharmaceutical analysis was reviewed in brief.
第一部分应用液质联用技术、电喷雾串联质谱法及核磁共振技术分析了亚胺培南和美罗培南在酸性条件下的降解产物的产生过程及化学结构,通过傅里叶变换离子回旋共振质谱(FTICR-MS)离线确定了这些化合物的准确元素组成。并用核磁共振数据进行了确证。同时对其降解的中间产物进行了跟踪检测和分析鉴定。
第二部分应用电喷雾串联质谱探讨并归纳了正离子模式下依普罗沙坦的三条竞争性的质谱碎裂途径,并应用液质联用技术、电喷雾串联质谱法及核磁共振技术,通过依普罗沙坦及其杂质的质谱碎裂谱图的对照比较,分析鉴定了依普罗沙坦中微量杂质的化学结构。
第三部分应用核磁共振技术,通过对左氧氟羧酸及其杂质的核磁共振谱图的比较,对其微小的差别进行分析,推断出了左氧氟羧酸中微量杂质的化学结构。同时应用液质联用技术、电喷雾串联质谱法对左氧氟羧酸及其杂质正离子模式下的两条竞争性质谱碎裂途径进行了分析总结。
此外,论文还简要介绍了液质联用技术在药物分析中的研究进展。
It is important to undertake qualitative analysis and quantitative analysis of drug impurities.High-performance liquid chromatography,when combined with electrospray ion trap mass spectrometry,possesses high separation efficiency and great qualitative capability.As it holds the advantages of high sensitivity,relatively short analysis time,low sample amount,and the ability to obtain structural information,HPLC/ESI-MS~n has been widely used as a powerful tool in various online drugs analysis.In this dissertation,the liquid chromatograpy/electospray tandem mass spectrometry(HPLC/ESI-MS) method was developed to identify the degradation products of crude drugs:Imipenem and Meropenem,also used to identify the impurities of Eprosartan and Levofloxacin carboxylic acid.The details are listed in the following:
PartⅠA method based on HPLC/ESI-MS~n and nuclear magnetic resonance (NMR) has been established to analyze the degradation products of Imipenem and Meropenem in an acid solution,as well as the generation procedures involved.Offline Fourier transform ion cyclotron resonance mass spectrometry(FTICR-MS) was also performed to assign the accurate elemental compositions.The proposed structures by were confirmed by NMR technology.After conducting the tracing detection experiments,the structures of intermediate products in the acid degradation procedure were then identified.
PartⅡThree competitive fragmentation methods of Eprosartan in the positive mode were summarized by electrospray mass spectrum multistage fragmentation experiments(ESI-MS~n).In this phase,HPLC/ESI-MS~n and NMR technologies were employed to identify the chemical structure of a microimpurity by comparing the spectral data of Eprosartan and its impurity.
PartⅢThe chemical structure of the microimpurity in Levofloxacin carboxylic acid was identified by analyzing minor differences between Levofloxacin and the impurity in the NMR spectrometry.Furthermore,two competitive mass fragmentation methods in the positive mode were summed up by multistage mass fragmentation experiments.
In addition,the recent progress of the LC/MS~n technique in pharmaceutical analysis was reviewed in brief.
引文
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