液相色谱质谱联用技术在小型家用电器安全和药物代谢方面的应用
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摘要
液相色谱-质谱联用(LC-MS)技术因其具有高分离能力、高灵敏度、较广的应用范围和较强的专属性等特点,已成为当代一种重要的分离分析技术,它在各个领域的应用不断扩展。本文应用LC-MS技术在挪威PoHS指令新增的小型家用电器中有毒有害物质的检测和药物代谢方面做了以下研究：
1.PoHS指令新增的小型家用电器中有毒有害物质的检测方法研究
(1)建立了加热回流萃取-超高效液相色谱-串联四极杆质谱检测小型家用电器中六溴环十二烷(HBCD)的方法。实验优化了萃取溶剂、对比了前处理方法、优化了加热回流萃取时间,最终选择较优方法—加热回流萃取法,其提取回收率大于68%。实验以甲苯：甲醇=10：1作为萃取剂,加热回流4小时。萃取出的溶液经N2吹干,初始流动相复溶,涡旋、离心、过膜,经ACQUITYTM UPLC BEH C18色谱柱分离,质谱的多反应监测模式(MRM)进行检测,HBCD的三种同分异构体在3min内完全分开,该物质的检出限为0.1μg·mL-1,定量限为0.5μg·mL-1,标准曲线的范围为1.6-32.4μg·mL-1,线性相关系数均大于0.996,萃取回收率为68%-75.2%。通过外标法定量,并应用于实际样品的检测。
(2)建立了加速溶剂萃取-超高效液相色谱-串联四极杆质谱(ASE-UPLC-MS/MS)检测小型家用电器中双酚A(BPA)、四溴双酚A(TBBPA).全氟辛酸(PFOA)的方法。实验利用正交实验设计法确定了ASE的较优化条件：萃取剂为甲苯：甲醇=10：1,温度100℃,压力1500psi,加热时间5min,静态萃取时间20min,循环3次,N2吹扫时间100s,冲洗体积20%。萃取出的溶液经N2吹干,初始流动相复溶,涡旋、离心、过膜,经ACQUITYTM UPLC BEH C18色谱柱分离,三种物质在3min内完全分开,BPA、TBBA、PFOA的检出限分别为0.1、10、1ng·mL-1,定量限分别为0.5、50、5ng·mL-1,标准曲线的范围分别为1-100ng·mL-1、0.1-10μgmL-1、10-1000ng·mL-1,线性相关系数均大于0.996,通过外标法定量,BPA、TBBPA和PFOA的回收率分别为84%-92%、76%-82%和72%-74%,相对标准偏差均小于5%。实验方法和结果均用岛津的离子阱-飞行时间高分辨质谱(LC-IT-TOF)仪器进行了验证,通过验证实验进一步证实了该方法具有可行性。并用该法对实际11种样品进行了检测。
2.人体血清中丁丙诺啡、诺丁丙诺啡、纳洛酮三种药物的检测方法建立及药片中丁丙诺啡和纳洛酮药物的含量测定
实验建立了同时检测丁丙诺啡(BP)、诺丁丙诺啡(NBP)、纳洛酮(NLX)的UPLC-MS/MS方法,并对其方法学进行了全面考察。利用固相萃取的方法对血清中BP、NBP、NLX三种物质进行分离富集,用内标法定量。实验采用Oasis MCX(?)固相萃取柱分离富集,0.1%的盐酸水溶液淋洗除去杂质,再用1mL5%的氨化甲醇洗脱目标化合物,将洗脱下来的溶液经N2吹干,用1mL初始流动相复溶,涡旋、离心、过膜,经ACQUITYTM UPLC BEH C18色谱柱分离,用电喷雾质谱的MRM模式进行检测,三种物质在4.5min之内达到完全分离。BP, NBP, NLX的标准曲线范围分别为0.1-25、0.25-25、0.05-25ng·mL-1,而且线性相关系数R均大于0.9948,回收率在97.6%-109.2%之间,BP,NBP,NLX的检出限分别为：0.02,0.10.01ng·mL-1,定量限分别为0.05,0.2,0.025ng·mL-1且RSD≤25%,实验按照国家食品药品监督管理局(SFDA)的规定对该方法学进行了严格的确证,包括方法的特异性、基质效应、标准曲线、检出限和定量限、准确度和精密度、日间和日内的RSD、储备液的稳定性、血清的稳定性等方面确证。同时实验还建立了BP、NLX的UPLC-UV的检测方法,并检测了实际药片中这两种物质的含量,判断盐酸丁丙诺啡舌下含片是否合格。
As its high separation ability, high sensitivity, wide application scope and specificity, liquid chromatography-mass spectrometry technology (LC-MS) had become more and more important for all kinds of analysis fields. The paper was doing the two following research using LC-MS:
1. Determination of toxic and harmful substances in small electrical appliances products of PoHS instructions
(1) The experiment established detection of hexabromocyclododecane (HBCD) in small household electrical appliances products by heating reflux extraction-ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Comparing the ultrasonic extraction, accelerated solvent extraction, soxhlet extraction and heating reflux extraction, the optimum pretreated method for extracting three isomerides of HBCD in small household electrical appliances products was heating reflux extraction. The experiment used toluene:methanol = 10:1 as extracting solvent and heating backflow 4 hours. The extract solution was dried by N2, dissolved by the initial mobile phase, vortexed, centrifuged and filmed. After the separation by BEH C18 column, the three isomerides of HBCD were detected by mass spectrometry in the negative electrospray ionization with multiple reaction monitoring (MRM) mode. The three compounds were separated effectively in 3 min. The linear ranges of the compounds were 1.6-32.4μg·mL-1 for HBCDs with correlation coefficient greater than 0.996. The limit of detection(LOD) and the limit of quantitation(LOQ) for HBCD were 0.1 and 0.5μg·mL-1, and the recoveries was 68%-75.2%. This method was successfully used in determination the real samples.
(2) The experiment established simultaneously detection of bisphenol A(BPA), tetrabromobisphenol A(TBBPA), and perfluorooctanoic acid (PFOA) in small household electrical appliances products by accelerated solvent extraction (ASE)-UPLC-MS/MS. We designed L9(34) orthogonal table for ASE, and selected the optimum extraction conditions:extracting solvent was toluene:methanol = 10:1; the pressure was 1500psi; the temperature was 100℃; heating time was 5min; static extraction time was 20min; circular 3 times; and N2 purged time was 100s; the volume for washing was 20%. The extract solution was dried by N2, dissolved by the initial mobile phase, vortexed, centrifuged and filmed. After the separation by BEH C18 column, three compounds were detected by mass spectrometry in the negative electrospray ionization with MRM mode. The three compounds were separated effectively in 3 min. The linear ranges of the compounds were 1-100ng·mL-1,0.1-10μg·mL-1,10-1000ng-mL"1 for BPA, TBBPA, PFOA with correlation coefficient greater than 0.996. The LODs for the three compounds were 0.1,10, 1ng-mL-1 and the LOQs were 0.5,50,5ng·mL-1 individually. Through the external standard method to quantitative, the recoveries for BPA, TBBPA, PFOA were 84%-92%,76%-82%,72%-74% respectively with RSD lower than 5%. The method and the result were confirmed by liquid chromatography - ion trap - time of flight mass spectrometry (LC-IT-TOF). The results were good and the method was successfully used in determination the real samples.
2. Established detection of naloxone, buprenorphine and nor-buprenorphine in human serum and determination naloxone and buprenorphine in tablet
A simultaneous method was successfully established and validated for the separation and determination of buprenorphine (BP), its primary metabolite, nor-buprenorphine (NBP) and a proposed co-formulate, naloxone (NLX) in human serum. The method used buprenorphine-d4 (BP-D4), nor-buprenorphine-d3 (NBP-D3), naltrexone (NTX) as internal standards (ISs). 100μL of plasma sample fortified with the ISs was cleaned up by solid-phase extraction (SPE), and was then separated on a Waters AcquityTM BEH C18 column with gradient elution using methanol and water (containing 0.2% formic) at a flow rate of 0.25mL·min-1. The mass spectrometer was used for detection and was operated in the positive electrospray ionization with MRM mode. The three compounds were effectively separated in 4.5 min. The linear ranges of the compounds were 0.1-25,0.25-25 and 0.05-25ng·mL-1 for BP, NBP and NLX, respectively, with R≥0.9948. The method had high sensitivity (the LODs were 0.02,0.1 and 0.01ng·mL-1 and the LOQs were 0.05, 0.2 and 0.025ng·mL-1 for BP, NBP and NLX, respectively) and high recoveries (≥97.6%). The result was shown to be linear and satisfactorily met current acceptance criteria for validation of bioanalytical method:intra and inter assay precisions within the required limits of≤25% RSD. The LOQs fulfilled the LOQ requirements:precision≤25% RSD, and was fully validated according to the State Food and Drug Administration (SFDA) regulations. The results demonstrated that UPLC-MS/MS with SPE was a powerful detection tool and contributed to pharmaceutical analysis in biological matrices. The experiment had also established UPLC-TUV to detect BP, NLX in tablet. All the results were satisfied.
1.PoHS指令新增的小型家用电器中有毒有害物质的检测方法研究
(1)建立了加热回流萃取-超高效液相色谱-串联四极杆质谱检测小型家用电器中六溴环十二烷(HBCD)的方法。实验优化了萃取溶剂、对比了前处理方法、优化了加热回流萃取时间,最终选择较优方法—加热回流萃取法,其提取回收率大于68%。实验以甲苯：甲醇=10：1作为萃取剂,加热回流4小时。萃取出的溶液经N2吹干,初始流动相复溶,涡旋、离心、过膜,经ACQUITYTM UPLC BEH C18色谱柱分离,质谱的多反应监测模式(MRM)进行检测,HBCD的三种同分异构体在3min内完全分开,该物质的检出限为0.1μg·mL-1,定量限为0.5μg·mL-1,标准曲线的范围为1.6-32.4μg·mL-1,线性相关系数均大于0.996,萃取回收率为68%-75.2%。通过外标法定量,并应用于实际样品的检测。
(2)建立了加速溶剂萃取-超高效液相色谱-串联四极杆质谱(ASE-UPLC-MS/MS)检测小型家用电器中双酚A(BPA)、四溴双酚A(TBBPA).全氟辛酸(PFOA)的方法。实验利用正交实验设计法确定了ASE的较优化条件：萃取剂为甲苯：甲醇=10：1,温度100℃,压力1500psi,加热时间5min,静态萃取时间20min,循环3次,N2吹扫时间100s,冲洗体积20%。萃取出的溶液经N2吹干,初始流动相复溶,涡旋、离心、过膜,经ACQUITYTM UPLC BEH C18色谱柱分离,三种物质在3min内完全分开,BPA、TBBA、PFOA的检出限分别为0.1、10、1ng·mL-1,定量限分别为0.5、50、5ng·mL-1,标准曲线的范围分别为1-100ng·mL-1、0.1-10μgmL-1、10-1000ng·mL-1,线性相关系数均大于0.996,通过外标法定量,BPA、TBBPA和PFOA的回收率分别为84%-92%、76%-82%和72%-74%,相对标准偏差均小于5%。实验方法和结果均用岛津的离子阱-飞行时间高分辨质谱(LC-IT-TOF)仪器进行了验证,通过验证实验进一步证实了该方法具有可行性。并用该法对实际11种样品进行了检测。
2.人体血清中丁丙诺啡、诺丁丙诺啡、纳洛酮三种药物的检测方法建立及药片中丁丙诺啡和纳洛酮药物的含量测定
实验建立了同时检测丁丙诺啡(BP)、诺丁丙诺啡(NBP)、纳洛酮(NLX)的UPLC-MS/MS方法,并对其方法学进行了全面考察。利用固相萃取的方法对血清中BP、NBP、NLX三种物质进行分离富集,用内标法定量。实验采用Oasis MCX(?)固相萃取柱分离富集,0.1%的盐酸水溶液淋洗除去杂质,再用1mL5%的氨化甲醇洗脱目标化合物,将洗脱下来的溶液经N2吹干,用1mL初始流动相复溶,涡旋、离心、过膜,经ACQUITYTM UPLC BEH C18色谱柱分离,用电喷雾质谱的MRM模式进行检测,三种物质在4.5min之内达到完全分离。BP, NBP, NLX的标准曲线范围分别为0.1-25、0.25-25、0.05-25ng·mL-1,而且线性相关系数R均大于0.9948,回收率在97.6%-109.2%之间,BP,NBP,NLX的检出限分别为：0.02,0.10.01ng·mL-1,定量限分别为0.05,0.2,0.025ng·mL-1且RSD≤25%,实验按照国家食品药品监督管理局(SFDA)的规定对该方法学进行了严格的确证,包括方法的特异性、基质效应、标准曲线、检出限和定量限、准确度和精密度、日间和日内的RSD、储备液的稳定性、血清的稳定性等方面确证。同时实验还建立了BP、NLX的UPLC-UV的检测方法,并检测了实际药片中这两种物质的含量,判断盐酸丁丙诺啡舌下含片是否合格。
As its high separation ability, high sensitivity, wide application scope and specificity, liquid chromatography-mass spectrometry technology (LC-MS) had become more and more important for all kinds of analysis fields. The paper was doing the two following research using LC-MS:
1. Determination of toxic and harmful substances in small electrical appliances products of PoHS instructions
(1) The experiment established detection of hexabromocyclododecane (HBCD) in small household electrical appliances products by heating reflux extraction-ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Comparing the ultrasonic extraction, accelerated solvent extraction, soxhlet extraction and heating reflux extraction, the optimum pretreated method for extracting three isomerides of HBCD in small household electrical appliances products was heating reflux extraction. The experiment used toluene:methanol = 10:1 as extracting solvent and heating backflow 4 hours. The extract solution was dried by N2, dissolved by the initial mobile phase, vortexed, centrifuged and filmed. After the separation by BEH C18 column, the three isomerides of HBCD were detected by mass spectrometry in the negative electrospray ionization with multiple reaction monitoring (MRM) mode. The three compounds were separated effectively in 3 min. The linear ranges of the compounds were 1.6-32.4μg·mL-1 for HBCDs with correlation coefficient greater than 0.996. The limit of detection(LOD) and the limit of quantitation(LOQ) for HBCD were 0.1 and 0.5μg·mL-1, and the recoveries was 68%-75.2%. This method was successfully used in determination the real samples.
(2) The experiment established simultaneously detection of bisphenol A(BPA), tetrabromobisphenol A(TBBPA), and perfluorooctanoic acid (PFOA) in small household electrical appliances products by accelerated solvent extraction (ASE)-UPLC-MS/MS. We designed L9(34) orthogonal table for ASE, and selected the optimum extraction conditions:extracting solvent was toluene:methanol = 10:1; the pressure was 1500psi; the temperature was 100℃; heating time was 5min; static extraction time was 20min; circular 3 times; and N2 purged time was 100s; the volume for washing was 20%. The extract solution was dried by N2, dissolved by the initial mobile phase, vortexed, centrifuged and filmed. After the separation by BEH C18 column, three compounds were detected by mass spectrometry in the negative electrospray ionization with MRM mode. The three compounds were separated effectively in 3 min. The linear ranges of the compounds were 1-100ng·mL-1,0.1-10μg·mL-1,10-1000ng-mL"1 for BPA, TBBPA, PFOA with correlation coefficient greater than 0.996. The LODs for the three compounds were 0.1,10, 1ng-mL-1 and the LOQs were 0.5,50,5ng·mL-1 individually. Through the external standard method to quantitative, the recoveries for BPA, TBBPA, PFOA were 84%-92%,76%-82%,72%-74% respectively with RSD lower than 5%. The method and the result were confirmed by liquid chromatography - ion trap - time of flight mass spectrometry (LC-IT-TOF). The results were good and the method was successfully used in determination the real samples.
2. Established detection of naloxone, buprenorphine and nor-buprenorphine in human serum and determination naloxone and buprenorphine in tablet
A simultaneous method was successfully established and validated for the separation and determination of buprenorphine (BP), its primary metabolite, nor-buprenorphine (NBP) and a proposed co-formulate, naloxone (NLX) in human serum. The method used buprenorphine-d4 (BP-D4), nor-buprenorphine-d3 (NBP-D3), naltrexone (NTX) as internal standards (ISs). 100μL of plasma sample fortified with the ISs was cleaned up by solid-phase extraction (SPE), and was then separated on a Waters AcquityTM BEH C18 column with gradient elution using methanol and water (containing 0.2% formic) at a flow rate of 0.25mL·min-1. The mass spectrometer was used for detection and was operated in the positive electrospray ionization with MRM mode. The three compounds were effectively separated in 4.5 min. The linear ranges of the compounds were 0.1-25,0.25-25 and 0.05-25ng·mL-1 for BP, NBP and NLX, respectively, with R≥0.9948. The method had high sensitivity (the LODs were 0.02,0.1 and 0.01ng·mL-1 and the LOQs were 0.05, 0.2 and 0.025ng·mL-1 for BP, NBP and NLX, respectively) and high recoveries (≥97.6%). The result was shown to be linear and satisfactorily met current acceptance criteria for validation of bioanalytical method:intra and inter assay precisions within the required limits of≤25% RSD. The LOQs fulfilled the LOQ requirements:precision≤25% RSD, and was fully validated according to the State Food and Drug Administration (SFDA) regulations. The results demonstrated that UPLC-MS/MS with SPE was a powerful detection tool and contributed to pharmaceutical analysis in biological matrices. The experiment had also established UPLC-TUV to detect BP, NLX in tablet. All the results were satisfied.
引文
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