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Article(id=1201158423221067896, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201158414379479837, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0603, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1683648000000, receivedDateStr=2023-05-10, revisedDate=1693324800000, revisedDateStr=2023-08-30, acceptedDate=null, acceptedDateStr=null, onlineDate=1764308084539, onlineDateStr=2025-11-28, pubDate=1707667200000, pubDateStr=2024-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764308084539, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764308084539, creator=13701087609, updateTime=1764308084539, updator=13701087609, issue=Issue{id=1201158414379479837, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='2', pageStart='269', pageEnd='492', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764308082432, creator=13701087609, updateTime=1764308181123, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201158828365669286, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201158414379479837, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201158828365669287, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201158414379479837, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=424, endPage=431, ext={EN=ArticleExt(id=1201158424571633892, articleId=1201158423221067896, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Detection of 14 sulfonate esters impurities of active pharmaceutical ingredients based on GC-MS/MS and LC-MS/MS, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Two methods including gas chromatography tandem mass spectrometry (GC-MS/MS) and high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) were established to detect common alkyl sulfonates and aryl sulfonates genotoxic impurities. Four alkyl sulfonates and methyl benzenesulfonate were determined by GC-MS/MS using butyl methanesulfonate as the internal standard, the chromatographic column was HP-5MS UI (30 mm × 0.25 mm, 0.25 µm), the carrier gas was helium, the flow rate was 1.0 mL·min-1 in a constant flow mode, the sample inlet temperature was set to 250 ℃, the split ratio was 10∶1, and the initial temperature of the heating program was 80 ℃, maintained for 1 minute, and then increased to 240 ℃ at a heating rate of 30 ℃·min-1 for 2 minutes. The mass spectrometry detector was an electron bombardment ion source (EI source), the data collection condition was multi reaction monitoring mode (MRM), and method validation using the raw material of clinical drug citalopram hydrobromide as a sample. The results showed that the linear range of four alkyl sulfonates and methyl benzenesulfonate were good at 3-50 ng·mL-1 and 9-150 ng·mL-1, with a correlation coefficient of r > 0.999, The spiked recovery was 80%-120%. The detection limits were 1 and 3 ng·mL-1; Ten aryl sulfonates determined by LC-MS/MS, the chromatographic column was CSH Fluoro phenyl (100 mm × 2.1 mm, 1.7 µm), the mobile phase was methanol (B)-5 mmol·L-1 ammonium formate (D), with a flow rate of 0.2 mL·min-1, and gradient elution was performed. The gradient program (T/% B) was set as 0/20, 25/90, 35/90, 42/20. The mass spectrometer detector was electro spray ionization with positive ionization mode (ESI+), the data collection was in dynamic multi reaction monitoring mode (dMRM), and the method was validated using the raw material of the clinical drug citalopram hydrobromide as a sample. The results showed that the linear range of aryl sulfonates were good at 9-2 000 ng·mL-1, 3-100 ng·mL-1 and 0.9-30 ng·mL-1, respectively. The correlation coefficient r > 0.999, the spiked recovery was 80%-120%. The detection limits were 30, 1 and 0.3 ng·mL-1. Two detection methods did not detect potential sulfonate genotoxicity impurities in the above APIs. The established analytical methods are reliable and effective, which can provide reference for drug quality control and detection.

, correspAuthors=Lan LIN, Guo-wei WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Die LIU, Xiao-xiao PENG, Jing-mei FANG, Fan YANG, Fang HE, Min CHEN, Lan LIN, Guo-wei WANG), CN=ArticleExt(id=1201158425389523239, articleId=1201158423221067896, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于GC-MS/MS和LC-MS/MS检测原料药中的14种磺酸酯类基因毒性杂质, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究建立了气相色谱串联质谱法(GC-MS/MS) 和高效液相色谱串联质谱法(LC-MS/MS) 对常见烷基磺酸酯类和芳基磺酸酯类基因毒性杂质进行检测。4种烷基磺酸酯和苯磺酸甲酯以甲磺酸丁酯做内标通过GC-MS/MS法测定, 色谱柱为HP-5MS UI (30 mm × 0.25 mm, 0.25 µm), 载气为氦气, 流速为1.0 mL·min-1, 进样口温度设为250 ℃, 分流比为10∶1, 升温程序的初始温度为80 ℃, 保持1 min, 然后以30 ℃·min-1的升温速率上升到240 ℃保持2 min。质谱检测器为电子轰击离子源(EI源), 数据采集条件为多反应监测模式(MRM), 以临床药物氯沙坦钾和甲磺酸加贝酯的原料药为样品进行验证。结果显示, 线性范围在3~50 ng·mL-1和9~150 ng·mL-1, 相关系数r > 0.999, 加标回收率在80%~120%之间, 检测限分别是1和3 ng·mL-1; 10种芳基磺酸酯通过LC-MS/MS法测定, 色谱柱为CSH Fluoro-phenyl (100 mm × 2.1 mm, 1.7 µm), 流动相为甲醇(B)-5 mmol·L-1甲酸铵(D), 流速为0.2 mL·min-1, 进行梯度洗脱, 梯度程序(T/% B) 设置为0/20、25/90、35/90、42/20。质谱检测器为电喷雾电离, 电离模式为正模式(ESI+), 数据采集为动态多反应监测模式(dMRM), 以临床药物氢溴酸西酞普兰的原料药为样品进行方法验证。结果显示, 线性范围分别在9~2 000 ng·mL-1、3~100 ng·mL-1和0.9~30 ng·mL-1, 相关系数r > 0.999, 加标回收率在80%~120%之间, 检测限分别是30、1和0.3 ng·mL-1。两种检测方法在上述原料药中均未检出潜在的磺酸酯类基因毒性杂质, 建立的分析方法可靠有效, 可为药物质量控制和检测提供参考依据。

, correspAuthors=林岚, 王国伟, authorNote=null, correspAuthorsNote=
*林岚
王国伟, E-mail:
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AnalyteFragmentor/VIon pair (m/z)Collision voltage/eV
MMS/79-657
80-659
EMS/97-7910
109-793
IMS/123-592
123-795
PMS/97-798
109-793
BMS/97-797
109-793
MBS/77-5117
141-779
MBS40190-7744
190-5177
EBS40204-7744
204-5179
PBS30218-5190
218-7747
IBS70218-5179
218-7742
BBS50232-7747
232-15914
MTS60204-6557
204-9137
ETS60218-6561
218-9138
PTS60232-9138
232-17311
ITS50232-9137
232-17311
BTS70246-9137
246-17311
), ArticleFig(id=1201158430611432092, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201158423221067896, language=CN, label=Table 1, caption=

Ion pairs and voltages screening of MMS-BTS. MMS: Methyl methanesulfonate; EMS: Ethyl methanesulfonate; IMS: Isopropyl methanesulfonate; PMS: Propyl methanesulfonate; BMS: Butyl methanesulfonate; MBS: Methyl benzenesulfonate; EBS: Ethyl benzenesulfonate; PBS: Propyl benzenesulfonate; IBS: Isopropyl benzenesulfonate; BBS: Butyl benzenesulfonate; MTS: Methyl p-toluenesulfonate; ETS: Ethyl p-toluenesulfonate; PTS: Propyl p-toluenesulfonate; ITS: Isopropyl p-toluenesulfonate; BTS: Butyl p-toluenesulfonate

, figureFileSmall=null, figureFileBig=null, tableContent=
AnalyteFragmentor/VIon pair (m/z)Collision voltage/eV
MMS/79-657
80-659
EMS/97-7910
109-793
IMS/123-592
123-795
PMS/97-798
109-793
BMS/97-797
109-793
MBS/77-5117
141-779
MBS40190-7744
190-5177
EBS40204-7744
204-5179
PBS30218-5190
218-7747
IBS70218-5179
218-7742
BBS50232-7747
232-15914
MTS60204-6557
204-9137
ETS60218-6561
218-9138
PTS60232-9138
232-17311
ITS50232-9137
232-17311
BTS70246-9137
246-17311
), ArticleFig(id=1201158430733066917, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201158423221067896, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
AnalytePrecision (RSD, %)LOD /ng·mL-1LOQ /ng·mL-1Linear range /ng·mL-1Regression equation with correlation coefficient (r)
MMS7.861.033.103-50y = 0.242 1x - 0.087 7 (r = 0.999)
EMS5.011.033.103-50y = 0.182 1x - 0.032 4 (r = 0.999)
PMS3.141.033.083-50y = 0.137 1x - 0.022 5 (r = 0.999)
IMS4.593.069.199-150y = 0.026 7x - 0.020 2 (r = 0.999)
MBS6.821.093.283-50y = 0.057 8x - 0.048 5 (r = 0.999)
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Precision, LOD, LOQ, linear range, and regression equations for the 5 sulfonate analytes

, figureFileSmall=null, figureFileBig=null, tableContent=
AnalytePrecision (RSD, %)LOD /ng·mL-1LOQ /ng·mL-1Linear range /ng·mL-1Regression equation with correlation coefficient (r)
MMS7.861.033.103-50y = 0.242 1x - 0.087 7 (r = 0.999)
EMS5.011.033.103-50y = 0.182 1x - 0.032 4 (r = 0.999)
PMS3.141.033.083-50y = 0.137 1x - 0.022 5 (r = 0.999)
IMS4.593.069.199-150y = 0.026 7x - 0.020 2 (r = 0.999)
MBS6.821.093.283-50y = 0.057 8x - 0.048 5 (r = 0.999)
), ArticleFig(id=1201158430972142254, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201158423221067896, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
AnalytePrecision (RSD, %)LOD /ng·mL-1LOQ /ng·mL-1Linear range /ng·mL-1Regression equation with correlation coefficient (r)
MBS0.1130.3390.9890-2 000y = 3.366x - 105.360 (r = 0.999)
EBS0.241.344.013-100y = 29.237x - 25.514 (r = 0.999)
PBS0.201.133.403-100y = 46.394x - 90.970 (r = 0.999)
IBS0.101.093.273-100y = 107.37x - 88.119 (r = 0.999)
BBS0.151.133.383-100y = 54.872x - 21.052 (r = 0.999)
MTS0.331.454.343-100y = 22.556x - 23.463 (r = 0.999)
ETS0.071.223.663-100y = 136.62x - 8.197 9 (r = 0.999)
PTS0.110.330.980.9-30y = 270.14x - 99.150 (r = 0.999)
ITS0.060.310.930.9-30y = 450.30x - 76.816 (r = 0.999)
BTS0.080.310.940.9-30y = 419.49x - 29.137 (r = 0.999)
), ArticleFig(id=1201158431102165682, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201158423221067896, language=CN, label=Table 3, caption=

LOQ, LOD peak area and signal-to-noise ratio of phenyl sulfonates

, figureFileSmall=null, figureFileBig=null, tableContent=
AnalytePrecision (RSD, %)LOD /ng·mL-1LOQ /ng·mL-1Linear range /ng·mL-1Regression equation with correlation coefficient (r)
MBS0.1130.3390.9890-2 000y = 3.366x - 105.360 (r = 0.999)
EBS0.241.344.013-100y = 29.237x - 25.514 (r = 0.999)
PBS0.201.133.403-100y = 46.394x - 90.970 (r = 0.999)
IBS0.101.093.273-100y = 107.37x - 88.119 (r = 0.999)
BBS0.151.133.383-100y = 54.872x - 21.052 (r = 0.999)
MTS0.331.454.343-100y = 22.556x - 23.463 (r = 0.999)
ETS0.071.223.663-100y = 136.62x - 8.197 9 (r = 0.999)
PTS0.110.330.980.9-30y = 270.14x - 99.150 (r = 0.999)
ITS0.060.310.930.9-30y = 450.30x - 76.816 (r = 0.999)
BTS0.080.310.940.9-30y = 419.49x - 29.137 (r = 0.999)
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基于GC-MS/MS和LC-MS/MS检测原料药中的14种磺酸酯类基因毒性杂质
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刘蝶 1 , 彭霄逍 2 , 方静美 2 , 杨帆 2 , 何方 2 , 陈敏 1 , 林岚 2, * , 王国伟 1, *
药学学报 | 研究论文 2024,59(2): 424-431
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药学学报 | 研究论文 2024, 59(2): 424-431
基于GC-MS/MS和LC-MS/MS检测原料药中的14种磺酸酯类基因毒性杂质
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刘蝶1, 彭霄逍2, 方静美2, 杨帆2, 何方2, 陈敏1, 林岚2, *, 王国伟1, *
作者信息
  • 1.西南大学药学院, 重庆 400715
  • 2.博腾制药科技股份有限公司, 重庆 400722

通讯作者:

*林岚
王国伟, E-mail:
Detection of 14 sulfonate esters impurities of active pharmaceutical ingredients based on GC-MS/MS and LC-MS/MS
Die LIU1, Xiao-xiao PENG2, Jing-mei FANG2, Fan YANG2, Fang HE2, Min CHEN1, Lan LIN2, *, Guo-wei WANG1, *
Affiliations
  • 1. Southwest University College of Pharmaceutical Sciences, Chongqing 400715, China
  • 2. Porton Fine Chemicals Ltd., Chongqing 400722, China
出版时间: 2024-02-12 doi: 10.16438/j.0513-4870.2023-0603
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摘要
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本研究建立了气相色谱串联质谱法(GC-MS/MS) 和高效液相色谱串联质谱法(LC-MS/MS) 对常见烷基磺酸酯类和芳基磺酸酯类基因毒性杂质进行检测。4种烷基磺酸酯和苯磺酸甲酯以甲磺酸丁酯做内标通过GC-MS/MS法测定, 色谱柱为HP-5MS UI (30 mm × 0.25 mm, 0.25 µm), 载气为氦气, 流速为1.0 mL·min-1, 进样口温度设为250 ℃, 分流比为10∶1, 升温程序的初始温度为80 ℃, 保持1 min, 然后以30 ℃·min-1的升温速率上升到240 ℃保持2 min。质谱检测器为电子轰击离子源(EI源), 数据采集条件为多反应监测模式(MRM), 以临床药物氯沙坦钾和甲磺酸加贝酯的原料药为样品进行验证。结果显示, 线性范围在3~50 ng·mL-1和9~150 ng·mL-1, 相关系数r > 0.999, 加标回收率在80%~120%之间, 检测限分别是1和3 ng·mL-1; 10种芳基磺酸酯通过LC-MS/MS法测定, 色谱柱为CSH Fluoro-phenyl (100 mm × 2.1 mm, 1.7 µm), 流动相为甲醇(B)-5 mmol·L-1甲酸铵(D), 流速为0.2 mL·min-1, 进行梯度洗脱, 梯度程序(T/% B) 设置为0/20、25/90、35/90、42/20。质谱检测器为电喷雾电离, 电离模式为正模式(ESI+), 数据采集为动态多反应监测模式(dMRM), 以临床药物氢溴酸西酞普兰的原料药为样品进行方法验证。结果显示, 线性范围分别在9~2 000 ng·mL-1、3~100 ng·mL-1和0.9~30 ng·mL-1, 相关系数r > 0.999, 加标回收率在80%~120%之间, 检测限分别是30、1和0.3 ng·mL-1。两种检测方法在上述原料药中均未检出潜在的磺酸酯类基因毒性杂质, 建立的分析方法可靠有效, 可为药物质量控制和检测提供参考依据。

基因毒性杂质  /  磺酸酯  /  气相色谱串联质谱  /  液相色谱串联质谱  /  分析方法开发

Two methods including gas chromatography tandem mass spectrometry (GC-MS/MS) and high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) were established to detect common alkyl sulfonates and aryl sulfonates genotoxic impurities. Four alkyl sulfonates and methyl benzenesulfonate were determined by GC-MS/MS using butyl methanesulfonate as the internal standard, the chromatographic column was HP-5MS UI (30 mm × 0.25 mm, 0.25 µm), the carrier gas was helium, the flow rate was 1.0 mL·min-1 in a constant flow mode, the sample inlet temperature was set to 250 ℃, the split ratio was 10∶1, and the initial temperature of the heating program was 80 ℃, maintained for 1 minute, and then increased to 240 ℃ at a heating rate of 30 ℃·min-1 for 2 minutes. The mass spectrometry detector was an electron bombardment ion source (EI source), the data collection condition was multi reaction monitoring mode (MRM), and method validation using the raw material of clinical drug citalopram hydrobromide as a sample. The results showed that the linear range of four alkyl sulfonates and methyl benzenesulfonate were good at 3-50 ng·mL-1 and 9-150 ng·mL-1, with a correlation coefficient of r > 0.999, The spiked recovery was 80%-120%. The detection limits were 1 and 3 ng·mL-1; Ten aryl sulfonates determined by LC-MS/MS, the chromatographic column was CSH Fluoro phenyl (100 mm × 2.1 mm, 1.7 µm), the mobile phase was methanol (B)-5 mmol·L-1 ammonium formate (D), with a flow rate of 0.2 mL·min-1, and gradient elution was performed. The gradient program (T/% B) was set as 0/20, 25/90, 35/90, 42/20. The mass spectrometer detector was electro spray ionization with positive ionization mode (ESI+), the data collection was in dynamic multi reaction monitoring mode (dMRM), and the method was validated using the raw material of the clinical drug citalopram hydrobromide as a sample. The results showed that the linear range of aryl sulfonates were good at 9-2 000 ng·mL-1, 3-100 ng·mL-1 and 0.9-30 ng·mL-1, respectively. The correlation coefficient r > 0.999, the spiked recovery was 80%-120%. The detection limits were 30, 1 and 0.3 ng·mL-1. Two detection methods did not detect potential sulfonate genotoxicity impurities in the above APIs. The established analytical methods are reliable and effective, which can provide reference for drug quality control and detection.

genotoxic impurity  /  sulfonic ester  /  gas chromatograohy mass spectrometry  /  liquid chromatograph mass spectrometry  /  analytical method development
刘蝶, 彭霄逍, 方静美, 杨帆, 何方, 陈敏, 林岚, 王国伟. 基于GC-MS/MS和LC-MS/MS检测原料药中的14种磺酸酯类基因毒性杂质. 药学学报, 2024 , 59 (2) : 424 -431 . DOI: 10.16438/j.0513-4870.2023-0603
Die LIU, Xiao-xiao PENG, Jing-mei FANG, Fan YANG, Fang HE, Min CHEN, Lan LIN, Guo-wei WANG. Detection of 14 sulfonate esters impurities of active pharmaceutical ingredients based on GC-MS/MS and LC-MS/MS[J]. Acta Pharmaceutica Sinica, 2024 , 59 (2) : 424 -431 . DOI: 10.16438/j.0513-4870.2023-0603
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基因毒性杂质能够直接或间接地与生物大分子发生烷基化反应, 对这些大分子的结构进行修饰和干扰导致基因序列突变, 使其具有致基因突变的风险。而磺酸酯类基因毒性杂质根据其结构的不同分为烷基磺酸酯类和芳基磺酸酯类, 烷基磺酸酯类包括甲磺酸甲酯、乙酯、丙酯、异丙酯和正丁酯; 芳基磺酸酯类包括苯磺酸和对甲苯磺酸甲酯、乙酯、丙酯、异丙酯和正丁酯。目前烷基磺酸酯类中甲磺酸的甲酯、乙酯及异丙酯已经被证明具有基因毒性, 而其他具有磺酸基的化合物也可能存在潜在的基因毒性, 对人体健康造成危害。由于药物和磺酸形成盐后具有稳定性增强、溶解度和溶解速率增加、吸湿性降低和结晶形式更稳定的特点, 使其在药物合成中具有独特优势, 然而生产过程中低级醇与磺酸反应会生成具有遗传毒性的磺酸酯类杂质, 该类杂质对人体的致癌性伤害引起了各国的重视, 为控制其风险, 各国开始发展相应的法规来对药物生产中可能形成的致毒性杂质进行管控[1-3]。早在2000年, 欧洲药品质量管理局(EDQM) 就要求需要关注药物的成盐过程中可能形成遗传毒性杂质磺酸盐的潜在风险, 并且对烷基磺酸酯类不仅要进行限度检查, 还要提供相关的研究信息[4]。在2007年6月生产甲磺酸奈非那韦的罗氏公司收到6名患者反映服药后出现基因序列异常的情况, 随后欧洲药品管理局暂停其销售该药, 该公司也召回产品并寻找原因, 发现生产过程用于清洗甲磺酸存储罐的乙醇与甲磺酸发生反应生成了甲磺酸乙酯导致其含量超标[5]。这是触发欧洲药监部门和制药企业高度关注磺酸酯类基因毒性杂质的标志性事件。在2006年欧洲药品质量管理局又最先颁布《基因毒性杂质限度指南》[6, 7], 本指南提供了解决限制新活性物质中遗传毒性杂质问题的框架和具体方法, 介绍了测定、检验和控制药物中特定潜在基因毒性杂质的基本原理。指南引入了毒理学关注阈值(threshold of toxicological concern, TTC), 即每人每天摄入一定量的诱变杂质, 其致癌风险被认为是可以忽略的限度。要求所有的基因毒性杂质都遵循毒理学每日最高允许摄入量TTC限度为1.5 μg·d-1, 以确定是否对人体健康有害, 且在该接触水平下, 其终身患癌风险为十万分之一[8]。基因毒性杂质的最大限度是以TTC与药物最大日服用剂量的比值计算。2008年12月, 美国食品和药物管理局发布了一份关于遗传毒性杂质指南的草案, 该草案在核心原则上与EMA关于遗传毒性限值的指南类似。由于欧洲和美国颁布的法规两地对于基因毒性杂质的限度要求存在差异, 直到2010年, 人类药品注册技术国际协调会议ICH专家组开始制定ICH M7遗传毒性杂质指南, 该指南经过修改后于2014年7月15日正式发布, 指南M7 (R1) 的第四版经过多次修订后于2017年发布, 确认并改进了每种方法的分阶段TTC, 以及五分类策略[9]。各监管机构采用的阶段化TTC要求略微有些差距, EMA和FDA规定较细致, ICH兼顾多方要求实行了放宽如12个月的服药周期。EMA和FDA均规定每日不超过5 µg, 而ICH放宽至20 µg, 服药周期12月以上EMA和FDA规定每日不超过1.5 µg, 而ICH规定服药周期10年以上才规定每日摄入杂质不超过1.5 µg。我国对遗传毒性杂质的规定是在2020年《中华人民共和国药典》 (第四批) 四部通则的修订增加了《遗传毒性杂质控制指导原则审核草案》, 并参考ICH的规定发布了遗传毒性杂质相关限值要求[10]。
根据遗传毒性杂质的物理和化学性质、杂质的限度要求以及仪器设备的条件, 开发和选择基因毒性杂质分析方法[11, 12]。建立痕量基因毒性杂质分析方法的关键是要对待测物和复杂样品的物理化学性质有全面了解[13-16]。检测器的选择取决于杂质的特征基团, 分离分析方法和样品预处理方法取决于遗传毒性杂质的挥发性、极性和化学稳定性, 分析方法的灵敏度取决于杂质要求限度, 判断待测杂质是否被干扰取决于其性质和结构与其他杂质的相似度。磺酸酯类遗传毒性杂质的测定主要包括气相色谱法和液相色谱法。气相色谱法是检测烷基磺酸酯类遗传毒性杂质最常用的分析方法, 进样方式包括直接进样和顶空进样。液相色谱法是比较常用的分析方法, 在磺酸酯的测定中应用广泛[17, 18]。一般由于基因毒性杂质要求的检测限度很低, 气相和液相色谱使用会结合不同的检测器如氢火焰离子化检测器(FID)、紫外检测器(DAD) 和质谱检测器(MS)[19-21]。对于一般的氢火焰离子化检测仪和紫外检测器, 灵敏度低无法满足检测要求。通常会结合质谱来提高灵敏度, 质谱的原理是将待测物的分子电离成不同质荷比的带电粒子, 在电磁场的作用下, 根据质荷比在空间或时间上分离这些带电粒子, 并测量离子峰强度, 最终获得化合物的分子式、分子量和其他结构信息, 结合气相或液相对待测物实现快速分离, 准确定量[22]。目前关于磺酸酯类杂质检测方法, EP9.0附录2.5.37提供了甲磺酸中甲磺酸甲酯、乙酯和异丙酯的GC-MS/MS检测方法[23]。Ahirrao等[24]采用GC-MS/MS的动态SRM模式, 以二氯甲烷为萃取剂检测甲磺酸甲酯(MMS)、甲磺酸乙酯(EMS) 和甲磺酸丙酯(PMS) 的含量, 检测限为3~20 ng·mL-1。Wollein等[25]采用GC-MS/MS的MRM模式, 检测原料药中甲磺酸甲酯、乙酯、丙酯、苯磺酸甲酯和乙酯的含量, 检测限达3~5 ng·mL-1。Liu等[26]借鉴该方法, 通过衍生顶空气相色谱质谱法测定甲苯磺酸烷基酯类杂质, 检测限达到0.6~1.1 ng·mL-1, 灵敏度较高。Jin等[27]采用LC-APCI-MS/MS法同时测定了15种磺酸酯类基因毒性杂质, 其中对烷基磺酸酯的响应较低, 检测限高达10 ng·mL-1, 对芳基磺酸酯的检测限为0.5~2.0 ng·mL-1。Guo等[28]采用了LC-MS/MS方法定量12种磺酸酯类杂质, SRM模式监测可以达到较低的检测限, 该方法的检测限为2~4 ng·mL-1。由此可知, 目前采用GC-MS和LC-MS, 再结合衍生法, 检测限最低可达到1 ng·mL-1。而本方法不采用衍生法, 对14种磺酸酯类基因毒性杂质进行方法开发和优化, 以达到较低检测限。
材料与方法
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实验仪器  7890B-7000D气相色谱-质谱联用仪、1290infinity+TQ+G6470B液相色谱-质谱联用仪均购于美国安捷伦科技有限公司; XS205DU电子天平(梅特勒托利多集团); KQ-300超声仪(昆山市超声仪器有限公司); Milli-Q超纯水制备系统(美国Millipore公司)。
供试品与试剂  氯沙坦钾(批号: EC160007, 上海萨恩化学技术有限公司); 甲磺酸甲酯(批号: 23MLD-LY)、甲磺酸乙酯(批号: H6VUB-WY)、甲磺酸丙酯(批号: LZVUA-KC)、甲磺酸异丙酯(IMS, 批号: NQFBH-SN) 均购于日本梯希爱化成工业发展有限公司; 甲磺酸正丁酯(BMS, 批号: C13255393, 上海麦克林生化科技有限公司); 苯磺酸甲酯(MBS, 批号: BMZ269)、苯磺酸乙酯(EBS, 批号: CMY561)、苯磺酸丙酯(PBS, 批号: BGZ456)、苯磺酸正丁酯(BBS, 批号: BRX613)、对甲苯磺酸甲酯(MTS, 批号: CLW520)、对甲苯磺酸乙酯(ETS, 批号: BQZ052)、对甲苯磺酸丙酯(PTS, 批号: BLP198)、对甲苯磺酸异丙酯(ITS, 批号: CQC787)、对甲苯磺酸正丁酯(BTS, 批号: CNY676) 和甲磺酸加贝酯(批号: BTW047) 均购于上海毕得医药科技有限公司; 苯磺酸异丙酯(IBS, 批号: DKW828) 和氢溴酸西酞普兰(批号: P1632318) 均购于上海阿达玛斯试剂有限公司; 色谱纯乙腈、色谱纯甲醇均购于美国西格玛奥德里奇贸易有限公司; 色谱纯乙酸乙酯(美国霍尼韦尔有限公司); 质谱级甲酸铵、质谱级氨水均购于美国阿拉丁试剂有限公司; 质谱级甲酸(美国赛默飞世尔科技有限公司)。
GC-MS/MS条件
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内标及对照品溶液制备  称取甲磺酸丁酯20 mg至20 mL量瓶中, 用乙腈溶解并稀释至刻度, 摇匀, 然后再精密移取0.5 mL上述溶液至50 mL量瓶加乙腈配制成浓度为10 μg·mL-1后再精密移取上述浓度溶液0.4 mL至200 mL量瓶, 乙腈定容配成浓度20 ng·mL-1的内标溶液。
分别称取20 mg甲磺酸甲酯、甲磺酸乙酯、甲磺酸丙酯、甲磺酸异丙酯、苯磺酸甲酯至20 mL量瓶中, 用内标液溶解定容制备成对照品储备液, 分别取以上各对照品储备液适量逐级稀释其浓度分别为11.7、10.4、10.4、30.2、12.5 ng·mL-1的混合对照品溶液(RS)。
样品制备  称取20 mg样品至10 mL量瓶中, 加2%纯化水溶解后再加内标液稀释定容并摇匀即得。
色谱条件  色谱柱选择HP-5MS UI (30 mm × 0.25 mm, 0.25 µm), 载气为氦气, 流速为1.0 mL·min-1, 进样量1 μL, 进样口温度设为250 ℃, 分流比为10∶1, 升温程序的初始温度为80 ℃, 保持1 min, 然后以30 ℃·min-1的升温速率上升到240 ℃保持2 min。
质谱条件  电离模式为电子轰击电离(EI), 离子源温度为280 ℃, 四极杆1和四极杆2的温度均为190 ℃, 质量扫描范围为m/z 50~500 Da, 离子对及CE电压结果见表 1。
LC-MS/MS条件
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对照品溶液制备  分别称取苯磺酸甲酯、苯磺酸乙酯、苯磺酸丙酯、苯磺酸异丙酯、苯磺酸正丁酯、对甲苯磺酸甲酯、对甲苯磺酸乙酯、对甲苯磺酸丙酯、对甲苯磺酸异丙酯和对甲苯磺酸正丁酯10 mg分别置于20 mL量瓶中, 加入乙腈定容配成0.5 mg·mL-1标准溶液储备液, 分别取以上各对照品储备液适量逐级稀释其浓度分别为309.6、13.4、11.3、10.9、11.3、14.5、12.2、3.3、3.1、3.1 ng·mL-1的混合对照品溶液。
样品制备  称取20 mg样品至10 mL量瓶中, 乙腈稀释定容, 摇匀即得。
色谱条件  色谱柱CSH Fluoro-phenyl (100 mm × 2.1 mm, 1.7 µm), 流速0.2 mL·min-1, 进样量为2 µL, 流动相甲醇作为B相, 5 mmol·L-1甲酸铵作为D相。梯度洗脱, 洗脱程序如下: 0 min, 20% B; 25 min, 90% B; 25~35 min, 90% B; 42 min, 20% B。
质谱条件  离子源为AP-ESI, 雾化器温度为300 ℃, 四极杆1和四极杆2温度均为100 ℃, 干燥器温度为300 ℃, 鞘气温度为250 ℃。正离子模式下, 质量扫描范围为m/z 50~500 Da, 碎裂电压、离子对及CE电压结果见表 1。
结果
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1 GC-MS/MS分析方法验证
方法基本确认后, 根据ICH指导原则[29, 30], 对该方法进行专属性、定量限LOQ、检测限LOD、系统精密度、线性与范围、准确度、溶液稳定性进行验证。其中选择临床药物氯沙坦钾的原料药检测MMS、EMS、PMS、IMS, 选择临床药物甲磺酸加贝酯的原料药检测MBS。
1.1 专属性
取空白溶液, 内标液, 对照品溶液以及加标溶液, 空白和内标液中无干扰峰干扰目标物的测定, 如图 1A, 对照品以及加标溶液各目标物分离均满足要求, 专属性良好。
1.2 系统精密度
将对照品溶液连续进样6针观察系统精密度, 计算相对标准偏差RSD。如表 2, 利用内标进行矫正后, RSD < 10%, 满足要求。
1.3 检测限与定量限
确定检测限与定量限浓度, 如表 2, MMS、EMS、PMS、MBS的检测限和定量限分别为1和3 ng·mL-1。IMS的检测限和定量限分别为3和9 ng·mL-1。
1.4 线性范围
以定量限浓度、对照品浓度的0.5、1、1.5、2、5倍分别进样。如表 2, MMS、EMS、PMS、MBS在3~50 ng·mL-1, 线性良好, IMS在9~150 ng·mL-1线性良好, 相关系数r > 0.999。
1.5 准确度
以临床药物氯沙坦钾原料药(losartan) 做样品, 每日最大用药量为50 mg, 根据ICH M7和欧盟(EMA) 对基因毒性杂质限度指南规定计算该样品限度规定不超过30 ppm。分别配平行组losartan 1和losartan 2约2 mg·mL-1, 进样后并未检测到该类基因毒性杂质, 在样品中分别加入50%、100%、150%的对照品作为加标供试品溶液, 各浓度加标供试品溶液平行配置3份计算回收。MMS、EMS、PMS和IMS回收率在80%~120%, 每组加标回收RSD均小于10%满足要求。MBS受到样品基质干扰, 进样后响应降低, 回收不达标, 另选临床药物样品甲磺酸加贝酯(限度5 ppm) 原料药配制约3 mg·mL-1的加标回收溶液同氯沙坦钾的方法检测回收, 结果也满足要求。
1.6 稳定性
分别配样MMS、EMS、PMS和IMS的对照品溶液与氯沙坦钾加标回收溶液, 在0、2、4、6、8、10、12、24、30 h进样, 计算与首次进样的相对偏差, 检测对照品在溶液以及样品溶液中的稳定性。MBS的稳定性检测与上述几种磺酸酯类杂质相同方法配制对照品溶液与甲磺酸加贝酯加标回收溶液, 间隔不同时间检测与首次进样的相对偏差。MMS、EMS、PMS、IMS、MBS溶液在30 h内较稳定。MMS、EMS、PMS在样品中12 h内保持稳定, IMS在样品中8 h内保持稳定, MBS在样品中30 h内保持稳定。
2 LC-MS/MS分析方法验证
对该方法进行专属性、检测限、定量限、系统精密度、线性与范围、准确度和稳定性进行验证。选择临床药物氢溴酸西酞普兰的原料药对MBS-BTS进行检测。验证结果显示MBS、MTS和BTS在样品中不稳定, 将样品盘控温至4 ℃后, 再次重新验证, 所有验证内容均能达到规定要求。
2.1 专属性
取空白溶液和对照品混合溶液, 进样得到芳基磺酸酯类基因毒性杂质色谱图如图 1B所示, 空白溶剂在对照品出峰位置无干扰及残留, 色谱柱未能分离BBS、PTS, 利用BBS离子对m/z 232~159, 以及PTS离子对m/z 232~173的不同从而达到分离定量, 因此所有目标物均能分离并准确定量, 说明专属性良好。
2.2 系统精密度
将芳基磺酸酯类对照品溶液连续进样6针观察系统精密度, 计算相对标准偏差RSD。如表 3, RSD < 10%, 系统和配样的平行性均满足要求。
2.3 检测限与定量限
配制定量限与检测限浓度进样, 如表 3, MBS的定量限为90 ng·mL-1, 检测限为30 ng·mL-1; EBS、PBS、IBS、BBS、MTS和ETS的定量限为3 ng·mL-1, 检测限为1 ng·mL-1; PTS、ITS和BTS的定量限为0.9 ng·mL-1, 检测限为0.3 ng·mL-1。
2.4 线性范围
以定量限浓度、对照品浓度的0.5倍、1倍、1.5倍、2倍、5倍、10倍分别进样。如表 3, MBS在90~2 000 ng·mL-1线性良好, EBS、PBS、IBS、BBS、MTS和ETS在3~100 ng·mL-1线性良好, PTS、ITS和BTS在0.9~30 ng·mL-1线性良好, 相关系数r > 0.999。
2.5 准确度
以临床药物氢溴酸西酞普兰原料药做样品, 每日最大用药量为40 mg, 根据ICH M7和欧盟(EMA) 对基因毒性杂质限度指南规定计算该样品限度规定不超过37.5 ppm。分别配制样品平行组样品1和样品2, 进样后并未检测到该类基因毒性杂质, 在样品中分别加入50%、100%、150%的对照品作为加标供试品溶液, 各浓度加标供试品溶液平行配置3份计算回收。所有对照品回收率在80%~120%, 每组加标回收RSD均小于10%满足要求。
2.6 稳定性
对照品溶液与氢溴酸西酞普兰加标回收溶液, 分别在0、6、14、19、24、32 h进样, 计算与首次进样的相对偏差, 检测对照品在溶液以及样品溶液中的稳定性。MBS、MTS、BTS在控温条件下32 h内保持稳定, 其余7种对照品在室温以及控温下均能在32 h内保持稳定。
讨论
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本研究通过GC-MS/MS法和LC-MS/MS法对常见的磺酸酯类基因毒性杂质进行检测分析, 旨在开发一种不需对磺酸酯类基因毒性杂质结构进行衍生化同时能够达到对该类杂质限度要求的方法, 提高检测效率。
首先在GC-MS上采用直接进样方式对15种常见磺酸酯类杂质进行方法开发, 本研究从样品配制、气相色谱条件、质谱条件及定量方法等进行优化, 样品配制主要是稀释剂的筛选, 气相色谱条件主要是进样口温度、分流模式及色谱柱筛选, 质谱条件主要是离子源温度的筛选。研究对比了极性柱HP-INNOWAX (30 mm × 0.25 mm, 0.25 µm)、中等极性柱VF-624MS (30 mm × 0.25 mm, 1.4 μm)、非极性柱HP-1MS UI (30 mm × 0.25 mm, 0.25 µm) 以及低极性柱HP-5MS UI (30 mm × 0.25 mm, 0.25 µm) 对该类对照品的分离度、峰形及响应, 最终选择了HP-5MS UI色谱柱。方法开发时发现烷基磺酸酯类沸点低, 分子量小, 在GC-MS中出峰靠前, 分析时间短且灵敏度高, 而甲磺酸丁酯以及带苯环的芳基磺酸酯类杂质由于沸点较高, 无法完全气化导致部分残留至衬管[31], 进样过程中该类杂质响应呈现逐渐下降的趋势, 条件筛选后最终确定高沸点的芳基对照品不适合气相直接进样分析, 最终确定以甲磺酸丁酯作内标, 检测5种磺酸酯包括甲磺酸甲酯、乙酯、丙酯、异丙酯和苯磺酸甲酯。MMS、EMS、PMS和MBS的检测限达到1 ng·mL-1, IMS的检测限达到3 ng·mL-1。
其次在LC-MS上对10种常见芳基磺酸酯类进行方法开发, 从样品配制、液相色谱条件及质谱条件等进行优化, 样品配制主要是稀释剂的筛选, 液相色谱条件主要是流动相和色谱柱的筛选, 质谱条件主要是定量扫描模式的筛选。由于芳基磺酸酯具有同分异构体, 因此需首先考虑色谱柱对混合对照品的分离能力, 选择EC C18 (150 mm × 4.6 mm, 3.5 µm)、SB phenyl (150 mm × 4.6 mm, 3.5 µm)、Waters EC C18 (50 mm × 3.0 mm, 2.7 µm)、Waters BEH phenyl (150 mm × 2.1 mm, 1.7 µm)、YMC-Triart-PFP (150 mm × 4.6 mm, 3.0 µm)、ACE C18 PFP (150 mm × 4.6 mm, 3 µm) 以及CSH Fluoro-phenyl (100 mm × 2.1 mm, 1.7 µm) 等色谱柱, 经过筛选最终选择CSH Fluoro-phenyl柱, BBS与PTS出峰虽在同一位置, 但通过PTS的离子对以及BBS的无干扰离子对m/z 232~159能够达到单独提取从而定量。流动相的有机相主要考虑甲醇和乙腈, 对流动相的优化主要考察待测物在水相的情况, 水相中分别为0.1%甲酸、5 mmol·L-1甲酸铵、0.1%氨水以及纯化水, 最终选择甲醇-5 mmol·L-1甲酸铵盐; 定量扫描模式最终选择dMRM模式。结果表明MBS检测限达30 ng·mL-1, EBS、PBS、IBS、BBS、MTS和ETS的检测限达到1 ng·mL-1, PTS、ITS和BTS的检测限达到了0.3 ng·mL-1, 具有较高的灵敏度。
由此可以看出, GC-MS和LC-MS对磺酸酯类基因毒性杂质的检测各具优势, 低沸点的烷基磺酸酯类采用GC-MS检测快速高效, 而高沸点的芳基磺酸酯类则使用LC-MS利用极性进行分离, 在色谱条件下无法分离的同分异构体也可通过质谱条件不同离子对的特异选择性辅以分离并检测。两种分析方法可靠有效, 对磺酸酯类基因毒性杂质检测显示出各自优势, 对于药物质量控制来说该方法无须对该类杂质进行衍生, 操作简便、检测效率高且灵敏度好, 具有较好的实际应用价值。
作者贡献: 本文由刘蝶、彭霄逍、方静美、杨帆负责研究思路设计; 刘蝶负责实验实施、数据处理和论文撰写; 王国伟、何方、林岚、陈敏负责课题监管、文章撰写、文章审阅及技术指导。
利益冲突: 本文的作者和所涉及的内容不存在潜在的利益冲突。
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  • 博腾制药委托科技项目(F2022444)
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2024年第59卷第2期
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doi: 10.16438/j.0513-4870.2023-0603
  • 接收时间：2023-05-10
  • 首发时间：2025-11-28
  • 出版时间：2024-02-12
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  • 收稿日期：2023-05-10
  • 修回日期：2023-08-30
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博腾制药委托科技项目(F2022444)
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    1.西南大学药学院, 重庆 400715
    2.博腾制药科技股份有限公司, 重庆 400722

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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