基于LC-MS/MS方法的喹诺酮类药物的杂质谱研究
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摘要
本论文系统地开展了基于LC-MS/MS方法的喹诺酮类药物杂质谱研究。首先在正离子模式下,对喹诺酮类化合物的质谱裂解行为与结构特征之间的相关性进行了系统研究,发现并总结出喹诺酮类化合物的质谱裂解规律。在此基础上,将高效的数据采集方法与快速自动的数据挖掘方法相结合,建立了整合性的药物中微量杂质的LC-MS/MS定性分析方法,用于快速、可靠地发现与识别杂质。采用该方法对喹诺酮类药物原料药及强制破坏试验样品进行分析,明确了药物中杂质的种类、数量和来源。基于药物杂质的定性分析方法,建立了喹诺酮类药物杂质的LC-MS/MS定量分析方法,并通过对市售药品中杂质的分析,掌握了杂质在制剂中的存在状况。对于原料药和制剂中存在的工艺杂质和可能呈增长趋势的降解产物,通过化学合成方法获取杂质纯品,开展了杂质的质量研究和细胞毒性评价。
本论文的研究内容主要包括以下三个部分：
1.喹诺酮类化合物的质谱裂解规律研究
在正离子检测模式下,采用(+) ESI-MSn与(+) ESI-HRMS/MS相结合的手段,系统地研究了不同结构类型喹诺酮类化合物[M+H]+离子的质谱裂解行为,考察了各化合物结构与质谱裂解行为的相关性。研究发现,喹诺酮类化合物的4-喹诺酮母核结构比较稳定,质谱裂解特征的多样性主要取决于化合物取代基种类和取代位置。例如,N-1位烷基取代基的主要裂解反应是丢失烷基自由基或烯烃分子；C-3位取代基主要通过脱羧或脱水反应,C-6或C-8的卤素原子通过卤化氢中性丢失产生相应的一系列特征离子。当C-7被哌嗪环或其衍生物取代时,通过取代基裂解产生43Da、57Da等奇数质量的中性丢失或直接产生m/z70等子离子,这些特征离子可以用于药物或杂质的分析鉴定。本研究结果为喹诺酮类药物中杂质的筛查及结构鉴定等提供了重要的分析依据。
2.基于LC-MS/MS技术的喹诺酮类药物中微量杂质的整合性定性分析方法研究
本研究以上述喹诺酮类化合物的质谱裂解规律为主要依据,以左氧氟沙星为模型药物,采用LC-DAD-MS/MS技术,并将高效的数据采集方法与快速自动的数据挖掘方法有效地整合起来,建立了快速、可靠和自动的发现与鉴定药物杂质的定性分析新方法。采用该方法可通过一次进样同时获取包含UV光谱、色谱、MS和MS/MS谱的综合性数据；运用多重质量亏损过滤(Multiple mass defect filters, MMDFs)与背景扣除(Background subtraction, BS)相结合的数据挖掘方法,可以实现在药物主成分、背景离子或未知信号干扰下快速、自动挖掘可能的杂质信息。进一步利用保留时间、UV吸收特征、HRMS和MS/MS谱分析相结合的手段,通过与喹诺酮类药物的特征质谱裂解行为系统比较,完成了相关杂质的结构鉴定。研究结果表明,建立的整合性杂质定性分析方法具有快速、灵敏度高、专属性好以及高效地采集数据和挖掘杂质信息的优势,适用于药物中微量或未知杂质的分析和检测。
采用该分析方法,对不同批次原料药和强制破坏试验不同时间的样品进行了分析,掌握了喹诺酮类药物中杂质的来源、种类和数量。根据药物中杂质随强制破坏时间动态变化的趋势对药物的降解途径进行了研究,阐明了原料药和制剂生产、储存及流通等环节中影响药物稳定性的化学和环境因素。此外,为了验证上述杂质定性分析方法的适用性,采用本方法对临床使用广泛的代表性喹诺酮药物的原料药和强制破坏试验样品进行分析,结果表明本研究建立的整合性杂质定性分析方法具有很好的适用性和推广应用的潜力。
3.喹诺酮类药物杂质的定量分析方法及杂质的细胞毒性评价
在上述研究基础上,通过系统优化质谱参数和方法学验证与考察,建立了基于LC-MS/MS的稳定、可靠的杂质定量分析方法。采用该方法对市售喹诺酮类药物制剂中的杂质进行定量分析,结果发现该类药物制剂中的杂质主要是由药物本身降解产生,而且不同厂家相同制剂中的杂质控制水平存在明显差异。对于发现的部分工艺杂质和随时间呈增长趋势的降解产物,采用化学合成方法制备了5个杂质,并通过杂质的结构确证及纯度检查对其进行了质量评价。杂质的结构确认进一步证明了上述杂质分析方法及其结果的可靠性和准确性。此外,利用L929小鼠成纤维细胞对杂质进行了细胞毒性评价,结果表明上述杂质没有明显的细胞毒性。
The impurity profiles of quinolones were systematically investigated using liquid chromatography coupled with tandem mass spectrometry. In order to investigate the relationship between the structural characteristics and the mass spectrometric behavior of quinolones, a number of quinolones with several structural skeletons were studied in detail by electrospray ionization tandem mass spectrometry in positive ion mode. An integrated approach on basis of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the rapid, automatic and efficient detection and identification of impurities from quinolone antibiotics using the data acquisition method and automatic impurity screening method. Some process-related impurities and degradation products were found by analyzing the different batches of drug substances and degradation samples under various stress tests using the integrated approach, and the degradation pathway was also elucidated by analyzing the trends of degradation products with time. A validated quantitative method for the impurities in the quinolone formulations was established, it was estimated to be sensitive, stable and accurate for the detection and monitoring of trace impurities. The impurities in different formulations from different pharmaceutical plants were determined using this approach, and the degradation products were the major impurities in the formulations which were generated by the degradation of drug ingredient. Some process-related impurities and degradation products in the drug substances and formulations were synthesized, their quality and cytotoxity were evaluated.
1. The fragmentation behavior of quinolones using electrospray ionization tandem mass spectrometry
The relationship between the structural characteristics and the fragmentation behavior of quinolones were investigated in positive ion mode using QTRAP and Q-TOF mass spectrometers. It was found that the quinolone moiety was stable in collision induced dissociation (CID) mode, and the fragment ions were generated by the fragmentation of the substituents. The product ions were generated by the fragmentation of the substituent at N-1through the loss of alkyl radical or the neutral loss of alkene. The product ions were formed by the loss of H2O or CO2due to the fragmentation of carboxyl group at C-3and were always observed in the MS/MS spectra. Dehydrohalogenation can take place when the halogen atom is at C-6or C-8.7-piperazinyl-quinolones could generate characteristic ions by the neutral loss of43Da,57Da and so on, or the fragment ions at m/z70, et al, which can be used for the sensitive class-specific screening of7-piperazinyl-quinolones. The present study supplemented the gas-phase ion chemistry of quinolones and should be valuable in the structural identification of impurities.
2. Integrated LC-MS/MS approach for the identification and characterization of the trace impurity of quinolones
Based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), an approach integrating efficient data acquisition method and automatic impurity screening method using MMDFs and BS was developed. This approach was used to acquire the structural and semi-quantitative information related to UV and MS data in a single sample run, and even to discover the impurity signals submerged by background and drug ions. Structural characterization was performed through accurate mass measurement and comparison of fragmentation behaviors of impurities with the parent drug. This approach was illustrated by the comprehensive impurity analysis of levofloxacin, and was demonstrated to be rapid, sensitive and automatic for the detection, characterization and monitoring of impurities, especially those unknown or at trace levels.
Process-related impurities and degradation products were screened from the test samples including different batches of quinolone drug substances and degradation samples using the integrated approach. And the degradation pathway was postulated by analyzing the trends of degradation products with time under various chemistry or environmental factors. The approach was estimated to have the widespread application by determining other quinolone antibiotics drug substances and degradation samples to find the impurities.
3. A LC-MS/MS quantitative method for the impurities in quinolone antibiotics and the evaluation of cytotoxcity of impurities
A validated quantitative LC-MS/MS method for the impurities in the formulations of quinolones was developed. The performance characteristics of the method in terms of robustness and information content clearly showed that this approach was adequate for the reliable detection, identification, and quantitative determination of trace levels of impurities in quinolones. Degradation products were the major impurities in formulations and there was remarkable difference in the impurity contents among the different pharmaceutical plants. The pure impurities were synthesized to obtain more enough to perform the quality evaluation and the evaluation of cytotoxicity. The cytotoxicity test was performed using L929mouse fibroblasts.
本论文的研究内容主要包括以下三个部分：
1.喹诺酮类化合物的质谱裂解规律研究
在正离子检测模式下,采用(+) ESI-MSn与(+) ESI-HRMS/MS相结合的手段,系统地研究了不同结构类型喹诺酮类化合物[M+H]+离子的质谱裂解行为,考察了各化合物结构与质谱裂解行为的相关性。研究发现,喹诺酮类化合物的4-喹诺酮母核结构比较稳定,质谱裂解特征的多样性主要取决于化合物取代基种类和取代位置。例如,N-1位烷基取代基的主要裂解反应是丢失烷基自由基或烯烃分子；C-3位取代基主要通过脱羧或脱水反应,C-6或C-8的卤素原子通过卤化氢中性丢失产生相应的一系列特征离子。当C-7被哌嗪环或其衍生物取代时,通过取代基裂解产生43Da、57Da等奇数质量的中性丢失或直接产生m/z70等子离子,这些特征离子可以用于药物或杂质的分析鉴定。本研究结果为喹诺酮类药物中杂质的筛查及结构鉴定等提供了重要的分析依据。
2.基于LC-MS/MS技术的喹诺酮类药物中微量杂质的整合性定性分析方法研究
本研究以上述喹诺酮类化合物的质谱裂解规律为主要依据,以左氧氟沙星为模型药物,采用LC-DAD-MS/MS技术,并将高效的数据采集方法与快速自动的数据挖掘方法有效地整合起来,建立了快速、可靠和自动的发现与鉴定药物杂质的定性分析新方法。采用该方法可通过一次进样同时获取包含UV光谱、色谱、MS和MS/MS谱的综合性数据；运用多重质量亏损过滤(Multiple mass defect filters, MMDFs)与背景扣除(Background subtraction, BS)相结合的数据挖掘方法,可以实现在药物主成分、背景离子或未知信号干扰下快速、自动挖掘可能的杂质信息。进一步利用保留时间、UV吸收特征、HRMS和MS/MS谱分析相结合的手段,通过与喹诺酮类药物的特征质谱裂解行为系统比较,完成了相关杂质的结构鉴定。研究结果表明,建立的整合性杂质定性分析方法具有快速、灵敏度高、专属性好以及高效地采集数据和挖掘杂质信息的优势,适用于药物中微量或未知杂质的分析和检测。
采用该分析方法,对不同批次原料药和强制破坏试验不同时间的样品进行了分析,掌握了喹诺酮类药物中杂质的来源、种类和数量。根据药物中杂质随强制破坏时间动态变化的趋势对药物的降解途径进行了研究,阐明了原料药和制剂生产、储存及流通等环节中影响药物稳定性的化学和环境因素。此外,为了验证上述杂质定性分析方法的适用性,采用本方法对临床使用广泛的代表性喹诺酮药物的原料药和强制破坏试验样品进行分析,结果表明本研究建立的整合性杂质定性分析方法具有很好的适用性和推广应用的潜力。
3.喹诺酮类药物杂质的定量分析方法及杂质的细胞毒性评价
在上述研究基础上,通过系统优化质谱参数和方法学验证与考察,建立了基于LC-MS/MS的稳定、可靠的杂质定量分析方法。采用该方法对市售喹诺酮类药物制剂中的杂质进行定量分析,结果发现该类药物制剂中的杂质主要是由药物本身降解产生,而且不同厂家相同制剂中的杂质控制水平存在明显差异。对于发现的部分工艺杂质和随时间呈增长趋势的降解产物,采用化学合成方法制备了5个杂质,并通过杂质的结构确证及纯度检查对其进行了质量评价。杂质的结构确认进一步证明了上述杂质分析方法及其结果的可靠性和准确性。此外,利用L929小鼠成纤维细胞对杂质进行了细胞毒性评价,结果表明上述杂质没有明显的细胞毒性。
The impurity profiles of quinolones were systematically investigated using liquid chromatography coupled with tandem mass spectrometry. In order to investigate the relationship between the structural characteristics and the mass spectrometric behavior of quinolones, a number of quinolones with several structural skeletons were studied in detail by electrospray ionization tandem mass spectrometry in positive ion mode. An integrated approach on basis of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the rapid, automatic and efficient detection and identification of impurities from quinolone antibiotics using the data acquisition method and automatic impurity screening method. Some process-related impurities and degradation products were found by analyzing the different batches of drug substances and degradation samples under various stress tests using the integrated approach, and the degradation pathway was also elucidated by analyzing the trends of degradation products with time. A validated quantitative method for the impurities in the quinolone formulations was established, it was estimated to be sensitive, stable and accurate for the detection and monitoring of trace impurities. The impurities in different formulations from different pharmaceutical plants were determined using this approach, and the degradation products were the major impurities in the formulations which were generated by the degradation of drug ingredient. Some process-related impurities and degradation products in the drug substances and formulations were synthesized, their quality and cytotoxity were evaluated.
1. The fragmentation behavior of quinolones using electrospray ionization tandem mass spectrometry
The relationship between the structural characteristics and the fragmentation behavior of quinolones were investigated in positive ion mode using QTRAP and Q-TOF mass spectrometers. It was found that the quinolone moiety was stable in collision induced dissociation (CID) mode, and the fragment ions were generated by the fragmentation of the substituents. The product ions were generated by the fragmentation of the substituent at N-1through the loss of alkyl radical or the neutral loss of alkene. The product ions were formed by the loss of H2O or CO2due to the fragmentation of carboxyl group at C-3and were always observed in the MS/MS spectra. Dehydrohalogenation can take place when the halogen atom is at C-6or C-8.7-piperazinyl-quinolones could generate characteristic ions by the neutral loss of43Da,57Da and so on, or the fragment ions at m/z70, et al, which can be used for the sensitive class-specific screening of7-piperazinyl-quinolones. The present study supplemented the gas-phase ion chemistry of quinolones and should be valuable in the structural identification of impurities.
2. Integrated LC-MS/MS approach for the identification and characterization of the trace impurity of quinolones
Based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), an approach integrating efficient data acquisition method and automatic impurity screening method using MMDFs and BS was developed. This approach was used to acquire the structural and semi-quantitative information related to UV and MS data in a single sample run, and even to discover the impurity signals submerged by background and drug ions. Structural characterization was performed through accurate mass measurement and comparison of fragmentation behaviors of impurities with the parent drug. This approach was illustrated by the comprehensive impurity analysis of levofloxacin, and was demonstrated to be rapid, sensitive and automatic for the detection, characterization and monitoring of impurities, especially those unknown or at trace levels.
Process-related impurities and degradation products were screened from the test samples including different batches of quinolone drug substances and degradation samples using the integrated approach. And the degradation pathway was postulated by analyzing the trends of degradation products with time under various chemistry or environmental factors. The approach was estimated to have the widespread application by determining other quinolone antibiotics drug substances and degradation samples to find the impurities.
3. A LC-MS/MS quantitative method for the impurities in quinolone antibiotics and the evaluation of cytotoxcity of impurities
A validated quantitative LC-MS/MS method for the impurities in the formulations of quinolones was developed. The performance characteristics of the method in terms of robustness and information content clearly showed that this approach was adequate for the reliable detection, identification, and quantitative determination of trace levels of impurities in quinolones. Degradation products were the major impurities in formulations and there was remarkable difference in the impurity contents among the different pharmaceutical plants. The pure impurities were synthesized to obtain more enough to perform the quality evaluation and the evaluation of cytotoxicity. The cytotoxicity test was performed using L929mouse fibroblasts.
引文
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