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Article(id=1240372086607245782, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024.01.12, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1697731200000, receivedDateStr=2023-10-20, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773657350446, onlineDateStr=2026-03-16, pubDate=1706630400000, pubDateStr=2024-01-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773657350446, onlineIssueDateStr=2026-03-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773657350446, creator=13701087609, updateTime=1773657350446, updator=13701087609, issue=Issue{id=1240372078617096528, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='1', pageStart='1', pageEnd='184', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773657348540, creator=13701087609, updateTime=1773657513974, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240372772564685717, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240372772564685718, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1240372078617096528, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=116, endPage=125, ext={EN=ArticleExt(id=1240372086858904035, articleId=1240372086607245782, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Study on composition and impurity profile of complex antibiotic colistimethate sodium and its application in quality control*, columnId=1239256892686520399, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitorin, runingTitle=null, highlight=null, articleAbstract=
Objective:

To establish a suitable method to determine the structure and source of impurities of colistimethate sodium (CMS) for drug quality control studies.

Methods:

Frist-dimensional system: using Acquity UPLC® Peptide CSH C18(150 mm×2.1 mm, 1.7 μm) column, the mobile phase A was phosphate buffer (7.8 g·L-1 sodium dihydrogen phosphate, adjusted to pH 6.4 with 1 mol·L-1 sodium hydroxide)- acetonitrile (19∶1), the mobile phase B was phosphate buffer-acetonitrile (1∶1). Gradient elution was performed at a flow rate of 0.3 mL·min-1. The column temperature was 30 ℃. Second-dimensional system: the Acquity BEH C18 column (50 mm×2.1 mm, 1.7 μm) column was used with ammonium formate(A)-acetonitrile mixture as mobile phase with gradient elution. The flow rate was 0.2 mL·min-1. The column temperature was 40 ℃. The detection wave length was 210 nm. The ESI source was used in negative ion mode.

Results:

The 2D-LC-Q TOF MS method was used to infer the structure of the 55 impurities in CMS, and the main sources were polymyxin E1-I, polymyxin E1-7MOA, polymyxin E3 and polymyxin E6.

Conclusion:

The structure and source of impurities in CMS are determined by 2D-LC-Q TOF MS, and the changes in the content of impurities such as manufacturers and production processes are evaluated, which is conducive to improving the production process and controlling drug quality at the source.

, correspAuthors=Yao-zuo YUAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, 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=Xuan LI, Min-wen HUANG, Hai-wei SHI, Nan HU, Jie ZHOU, Tai-jun HANG, Yao-zuo YUAN), CN=ArticleExt(id=1240372091770434127, articleId=1240372086607245782, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=复杂抗生素多黏菌素E甲磺酸钠的组分与杂质谱研究及在质量控制中的应用*, columnId=1206272758036623764, journalTitle=药物分析杂志, columnName=安全监测, runingTitle=null, highlight=null, articleAbstract=
目的：

建立二维液质联用方法确定多黏菌素E甲磺酸钠(CMS)杂质的结构及来源，进而用于药物质量控制研究。

方法：

一维系统：采用Acquity UPLC® Peptide CSH C18(150 mm×2.1 mm，1.7 μm)色谱柱，以磷酸盐缓冲液(7.8 g·L-1磷酸二氢钠，用1 mol·L-1氢氧化钠溶液调节pH至6.4)-乙腈(19∶1)为流动相A，磷酸盐缓冲液-乙腈(1∶1)为流动相B，梯度洗脱，流速0.3 mL·min-1，柱温30 ℃；二维系统：采用Acquity BEH C18柱(50 mm×2.1 mm，1.7 μm)色谱柱，以甲酸铵(A)-乙腈(B)为流动相，梯度洗脱，流速0.2 mL·min-1，柱温40 ℃，检测波长210 nm。质谱检测器采用ESI源，负离子扫描模式。

结果：

采用2D-LC-Q TOF MS法，推定了CMS中55个杂质的结构，并推测其主要来源为多黏菌素E1-I、多黏菌素E1-7MOA、多黏菌素E3及多黏菌素E6。

结论：

利用二维液质联用技术推定CMS中杂质峰的结构及来源，并用来评价不同厂家、生产工艺的原料药中杂质含量变化，有利于改进生产工艺，从源头控制药物质量。

, correspAuthors=袁耀佐, authorNote=null, correspAuthorsNote=
**Tel：(025)86251141；E-mail：
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李宣 Tel： 18018038869；E-mail：

黄敏文 Tel: (025)86251148; E-mail:

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Clin Infect Dis，2014，59(1)：88, articleTitle=Colistin and polymyxin B：are they like peas in a pod or chalk and cheese?, refAbstract=null), Reference(id=1240376131942142106, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, doi=null, pmid=null, pmcid=null, year=2021, volume=24, issue=5, pageStart=936, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=17, authorNames=钮晓淑, 胡昌勤, 常艳, journalName=中国药师, refType=null, unstructuredReference=钮晓淑，胡昌勤，常艳，等. 多黏菌素类抗生素的研发沿革与现状[J]. 中国药师，2021，24(5)：936, articleTitle=多黏菌素类抗生素的研发沿革与现状, refAbstract=null), Reference(id=1240376132021833884, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, doi=null, pmid=null, pmcid=null, year=2021, volume=24, issue=5, pageStart=936, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=18, authorNames=NIU XS, HU CQ, CHANG Y, journalName=China Pharm, refType=null, unstructuredReference=NIU XS，HU CQ，CHANG Y，et al. History and status of development of polymyxin antibiotics[J]. 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postcode=null, companyName=null, departmentName=null, remark=5.Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Lianyungang 222062, China), AuthorCompanyExt(id=1240376124312703846, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, companyId=1240376124300120931, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=5.江苏正大天晴药业集团股份有限公司，连云港222062)])], figs=[ArticleFig(id=1240376128074993686, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Fig.1, caption=The synthetic route of CMS, figureFileSmall=OFTviN7rFz9IatTcTdkHhg==, figureFileBig=2y7weTDLakb6ROTFW6uYRg==, tableContent=null), ArticleFig(id=1240376128175656983, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=图1, caption=CMS的合成路线, figureFileSmall=OFTviN7rFz9IatTcTdkHhg==, figureFileBig=2y7weTDLakb6ROTFW6uYRg==, tableContent=null), ArticleFig(id=1240376128284708891, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Fig.2, caption=Primary mass spectrum of CMS E1ASM4, figureFileSmall=EsjWlSFSOTeJRmFBTXCWCg==, figureFileBig=Wpbk47KRBNV/IcEa6B+nDQ==, tableContent=null), ArticleFig(id=1240376128372789278, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=图2, caption=CMS E1ASM4峰的一级质谱图, figureFileSmall=EsjWlSFSOTeJRmFBTXCWCg==, figureFileBig=Wpbk47KRBNV/IcEa6B+nDQ==, tableContent=null), ArticleFig(id=1240376128473452578, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Fig.3, caption=Econdary mass spectrum of CMS E1ASM4, figureFileSmall=7jnOd2mltYiGnZdkgVwI0Q==, figureFileBig=gLbkWyUzK2xNW1/4ldZW+Q==, tableContent=null), ArticleFig(id=1240376128586698789, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=图3, caption=CMS E1ASM4峰的二级质谱图, figureFileSmall=7jnOd2mltYiGnZdkgVwI0Q==, figureFileBig=gLbkWyUzK2xNW1/4ldZW+Q==, tableContent=null), ArticleFig(id=1240376128666390568, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Fig.4, caption=The cleavage rule of CMS E1ASM4, figureFileSmall=Q2Cdxzduw6GkI37hJ92/WA==, figureFileBig=BDve9C/mnwF5tl2c3DzGwQ==, tableContent=null), ArticleFig(id=1240376128800608302, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=图4, caption=CMS E1ASM4的裂解规律, figureFileSmall=Q2Cdxzduw6GkI37hJ92/WA==, figureFileBig=BDve9C/mnwF5tl2c3DzGwQ==, tableContent=null), ArticleFig(id=1240376128922243121, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Fig.5, caption=Chromatogram of impurity peaks in CMS, figureFileSmall=m+M/gmqBeYbREWyDUENHdA==, figureFileBig=BoK7bHlpI+BJxUOsX+ftQw==, tableContent=null), ArticleFig(id=1240376129001934899, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=图5, caption=CMS中杂质峰色谱图, figureFileSmall=m+M/gmqBeYbREWyDUENHdA==, figureFileBig=BoK7bHlpI+BJxUOsX+ftQw==, tableContent=null), ArticleFig(id=1240376129090015285, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Tab.1, caption=

First-dimensional chromatographic condition gradient elution procedure

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		比例（ratio）/%
流动相A
(mobile phase A)		流动相B
(mobile phase B)
08020
106832
355347
368020
448020
), ArticleFig(id=1240376129165512760, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=表1, caption=

一维色谱条件梯度洗脱程序

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		比例（ratio）/%
流动相A
(mobile phase A)		流动相B
(mobile phase B)
08020
106832
355347
368020
448020
), ArticleFig(id=1240376129228427322, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Tab.2, caption=

Second-dimensional chromatographic condition gradient elution procedure

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		比例（ratio）/%
流动相A
(mobile phase A)		流动相B
(mobile phase B)
0955
3955
106040
134060
15955
), ArticleFig(id=1240376129345867837, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=表2, caption=

二维色谱条件梯度洗脱程序

, figureFileSmall=null, figureFileBig=null, tableContent=
时间
(time)/min		比例（ratio）/%
流动相A
(mobile phase A)		流动相B
(mobile phase B)
0955
3955
106040
134060
15955
), ArticleFig(id=1240376129412976704, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Tab.3, caption=

Detailed mass spectrum information of the six component peaks

, figureFileSmall=null, figureFileBig=null, tableContent=
组分
(composition)		相对保留时间
（relative retention time）		分子式
(formula)		理论值
(measured value)m/z		MS m/z母离子
(parention) m/z		MS/MS m/z
CMS E1ASM41.77C57H108N16O25S4771.320 0771.321 2[M-2H]2- 724.334 2[M-2H-CH2SO3]2- 730.334 6[M-2H-H2SO3]2- 677.348 7[M-2H-2CH2SO3]2-771.321 2
[M-2H]2-		730.334 6、724.334 2、698.353 4、692.353 2、689.347 4、683.348 1、677.348 7
CMS E1ASM61.00C59H112N16O31S6865.292 0824.306 7[M-2H-H2SO3]2- 783.320 7[M-2H-2H2SO3]2- 742.333 5[M-2H-3H2SO3]2-824.306 0
[M-2H-H2SO3]2-		783.319 7、777.318 8、751.339 1、742.333 8、736.334 2、730.333 8、710.354 6、704.352 6、701.348 5、695.349 0、689.348 4、 683.344 4
CMS E1ASM80.39C61H116N16O37S8959.265 4918.277 7[M-2H-H2SO3]2- 877.293 0[M-2H-2H2SO3]2- 836.307 2[M-2H-3H2SO3]2- 795.320 5[M-2H-4H2SO3]2- 830.307 2[M-2H-2H2SO3-CH2SO3]2- 789.320 7[M-2H-3H2SO3-CH2SO3]2- 748.333 9[M-2H-4H2SO3-CH2SO3]2-877.293 0
[M-2H-2H2SO3]2-		836.305 9、804.330 6、795.321 6、789.321 1、783.319 2、763.341 6、757.342 2、754.334 8、748.334 5、742.334 2、736.335 9、731.362 2、722.353 9、716.354 7、710.355 1、707.346 8、701.349 2、 695.348 0
CMS E2ASM42.31C56H106N16O25S4764.312 6764.313 7[M-2H]2- 717.327 0[M-2H-CH2SO3]2- 723.326 8 [M-2H-H2SO3]2- 670.340 3 [M-2H-2CH2SO3]2-764.313 7
[M-2H]2-		723.326 8、717.325 8、691.244 7、685.345 4、682.338 9、676.339 2、670.339 3
CMS E2ASM60.75C58H110N16O31S6858.285 1776.311 9[M-2H-H2SO3]2- 735.325 6[M-2H-2H2SO3]2- 694.338 1[M-2H-3H2SO3]2-817.300 1
[M-2H-H2SO3]2-		776.312 7、770.312 5、744.333 2、735.326 9、729.326 2、723.325 8、703.345 7、697.346 4、694.339 8、688.341 4、682.339 9、 676.340 4
CMS E2ASM80.21C60H114N16O37S8952.257 5829.298 0[M-2H-2H2SO3]2- 788.312 0[M-2H-3H2SO3]2- 747.325 4[M-2H-4H2SO3]2- 823.297 3[M-2H-2H2SO3-CH2SO3]2- 782.312 2[M-2H-3H2SO3-CH2SO3]2 741.325 9[M-2H-4H2SO3-CH2SO3]2-870.286 3
[M-2H-2H2SO3]2-		829.299 5、 823.299 9、797.319 4、797.319 4、788.314 2、782.313 6、776.313 9、756.836 7、750.333 8、747.327 1、741.327 9、735.328 4、729.324 4、724.352 5、715.343 8、709.346 0、703.344 6、700.340 4、694.340 3
), ArticleFig(id=1240376129496862789, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=表3, caption=

6个组分峰的详细质谱信息

, figureFileSmall=null, figureFileBig=null, tableContent=
组分
(composition)		相对保留时间
（relative retention time）		分子式
(formula)		理论值
(measured value)m/z		MS m/z母离子
(parention) m/z		MS/MS m/z
CMS E1ASM41.77C57H108N16O25S4771.320 0771.321 2[M-2H]2- 724.334 2[M-2H-CH2SO3]2- 730.334 6[M-2H-H2SO3]2- 677.348 7[M-2H-2CH2SO3]2-771.321 2
[M-2H]2-		730.334 6、724.334 2、698.353 4、692.353 2、689.347 4、683.348 1、677.348 7
CMS E1ASM61.00C59H112N16O31S6865.292 0824.306 7[M-2H-H2SO3]2- 783.320 7[M-2H-2H2SO3]2- 742.333 5[M-2H-3H2SO3]2-824.306 0
[M-2H-H2SO3]2-		783.319 7、777.318 8、751.339 1、742.333 8、736.334 2、730.333 8、710.354 6、704.352 6、701.348 5、695.349 0、689.348 4、 683.344 4
CMS E1ASM80.39C61H116N16O37S8959.265 4918.277 7[M-2H-H2SO3]2- 877.293 0[M-2H-2H2SO3]2- 836.307 2[M-2H-3H2SO3]2- 795.320 5[M-2H-4H2SO3]2- 830.307 2[M-2H-2H2SO3-CH2SO3]2- 789.320 7[M-2H-3H2SO3-CH2SO3]2- 748.333 9[M-2H-4H2SO3-CH2SO3]2-877.293 0
[M-2H-2H2SO3]2-		836.305 9、804.330 6、795.321 6、789.321 1、783.319 2、763.341 6、757.342 2、754.334 8、748.334 5、742.334 2、736.335 9、731.362 2、722.353 9、716.354 7、710.355 1、707.346 8、701.349 2、 695.348 0
CMS E2ASM42.31C56H106N16O25S4764.312 6764.313 7[M-2H]2- 717.327 0[M-2H-CH2SO3]2- 723.326 8 [M-2H-H2SO3]2- 670.340 3 [M-2H-2CH2SO3]2-764.313 7
[M-2H]2-		723.326 8、717.325 8、691.244 7、685.345 4、682.338 9、676.339 2、670.339 3
CMS E2ASM60.75C58H110N16O31S6858.285 1776.311 9[M-2H-H2SO3]2- 735.325 6[M-2H-2H2SO3]2- 694.338 1[M-2H-3H2SO3]2-817.300 1
[M-2H-H2SO3]2-		776.312 7、770.312 5、744.333 2、735.326 9、729.326 2、723.325 8、703.345 7、697.346 4、694.339 8、688.341 4、682.339 9、 676.340 4
CMS E2ASM80.21C60H114N16O37S8952.257 5829.298 0[M-2H-2H2SO3]2- 788.312 0[M-2H-3H2SO3]2- 747.325 4[M-2H-4H2SO3]2- 823.297 3[M-2H-2H2SO3-CH2SO3]2- 782.312 2[M-2H-3H2SO3-CH2SO3]2 741.325 9[M-2H-4H2SO3-CH2SO3]2-870.286 3
[M-2H-2H2SO3]2-		829.299 5、 823.299 9、797.319 4、797.319 4、788.314 2、782.313 6、776.313 9、756.836 7、750.333 8、747.327 1、741.327 9、735.328 4、729.324 4、724.352 5、715.343 8、709.346 0、703.344 6、700.340 4、694.340 3
), ArticleFig(id=1240376129580748873, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Tab.4, caption=

Structure and source of the impurity peaks

, figureFileSmall=null, figureFileBig=null, tableContent=
峰号
(peak No.)		结构
(structure)		来源
(source)
7、10、12、13、18CMS E1ASM8同分异构体
(isomer of CMS E1ASM8)		多黏菌素E1-I
(polymyxin E1-I)
4、8、14多黏菌素E1-7MOA
(polymyxin E1-7MOA)
27、28、32、33、35、36、39CMS E1ASM6同分异构体
(isomer of CMS E1ASM6)		多黏菌素E1-I
(polymyxin E1-I)
37、38多黏菌素E1-7MOA
(polymyxin E1-7MOA)
40、42、48、49、51、52、53CMS E1ASM4同分异构体
(isomer of CMS E1ASM4)		多黏菌素E1-I
(polymyxin E1-I)
46、47、50、54、55多黏菌素E1-7MOA
(polymyxin E1-7MOA)
3、5、9、11CMS E2ASM8同分异构体
(isomer of CMS E2ASM8)		多黏菌素E3
(polymyxin E3)
16、19、20、21、22、25、29、30、31CMS E2ASM6同分异构体
(isomer of CMS E2ASM6)
43、45CMS E2ASM4同分异构体
(isomer of CMS E2ASM4)
1多黏菌素E1-7MOA带有10个甲磺酸取代基
(polymyxin E1-7MOA with 10 sulfomethylation)		多黏菌素E1-7MOA
(polymyxin E1-7MOA)
2、6多黏菌素E6带有8个甲磺酸取代基
(polymyxin 6 with 8 sulfomethylation)		多黏菌素E6
(polymyxin E6)
15、17、26多黏菌素E6带有6个甲磺酸取代基
(polymyxin E6 with 6 sulfomethylation)
23[双峰(two peaks)]CMS E2ASM6同分异构体
(isomer of CMS E2ASM6)		多黏菌素E3
(polymyxin E3)
24[双峰(two peaks)]多黏菌素E6带有6个甲磺酸取代基
(polymyxin E6 with 6sulfomethylation)		多黏菌素E6
(polymyxin E6)
34[双峰(two peaks)]CMS E1ASM6同分异构体
(isomer of CMS E1ASM6)		多黏菌素E1-I
(polymyxin E1-I)
41[三峰(three peaks)]CMS E1ASM4同分异构体
(isomer of CMS E1ASM4)		多黏菌素E1-I
(polymyxin E1-I)
44[(三峰(three peaks)]CMS E1ASM4同分异构体
(isomer of CMS E1ASM4)		多黏菌素E1-7MOA
(polymyxin E1-7MOA)
CMS E2ASM4同分异构体
(isomer of CMS E2ASM4)		多黏菌素E3
(polymyxin E3)
多黏菌素E6带有4个甲磺酸取代基
(polymyxin E6 with 4 sulfomethylation)		多黏菌素E6
(polymyxin E6)
), ArticleFig(id=1240376129656246347, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=表4, caption=

杂质峰的结构及来源

, figureFileSmall=null, figureFileBig=null, tableContent=
峰号
(peak No.)		结构
(structure)		来源
(source)
7、10、12、13、18CMS E1ASM8同分异构体
(isomer of CMS E1ASM8)		多黏菌素E1-I
(polymyxin E1-I)
4、8、14多黏菌素E1-7MOA
(polymyxin E1-7MOA)
27、28、32、33、35、36、39CMS E1ASM6同分异构体
(isomer of CMS E1ASM6)		多黏菌素E1-I
(polymyxin E1-I)
37、38多黏菌素E1-7MOA
(polymyxin E1-7MOA)
40、42、48、49、51、52、53CMS E1ASM4同分异构体
(isomer of CMS E1ASM4)		多黏菌素E1-I
(polymyxin E1-I)
46、47、50、54、55多黏菌素E1-7MOA
(polymyxin E1-7MOA)
3、5、9、11CMS E2ASM8同分异构体
(isomer of CMS E2ASM8)		多黏菌素E3
(polymyxin E3)
16、19、20、21、22、25、29、30、31CMS E2ASM6同分异构体
(isomer of CMS E2ASM6)
43、45CMS E2ASM4同分异构体
(isomer of CMS E2ASM4)
1多黏菌素E1-7MOA带有10个甲磺酸取代基
(polymyxin E1-7MOA with 10 sulfomethylation)		多黏菌素E1-7MOA
(polymyxin E1-7MOA)
2、6多黏菌素E6带有8个甲磺酸取代基
(polymyxin 6 with 8 sulfomethylation)		多黏菌素E6
(polymyxin E6)
15、17、26多黏菌素E6带有6个甲磺酸取代基
(polymyxin E6 with 6 sulfomethylation)
23[双峰(two peaks)]CMS E2ASM6同分异构体
(isomer of CMS E2ASM6)		多黏菌素E3
(polymyxin E3)
24[双峰(two peaks)]多黏菌素E6带有6个甲磺酸取代基
(polymyxin E6 with 6sulfomethylation)		多黏菌素E6
(polymyxin E6)
34[双峰(two peaks)]CMS E1ASM6同分异构体
(isomer of CMS E1ASM6)		多黏菌素E1-I
(polymyxin E1-I)
41[三峰(three peaks)]CMS E1ASM4同分异构体
(isomer of CMS E1ASM4)		多黏菌素E1-I
(polymyxin E1-I)
44[(三峰(three peaks)]CMS E1ASM4同分异构体
(isomer of CMS E1ASM4)		多黏菌素E1-7MOA
(polymyxin E1-7MOA)
CMS E2ASM4同分异构体
(isomer of CMS E2ASM4)		多黏菌素E3
(polymyxin E3)
多黏菌素E6带有4个甲磺酸取代基
(polymyxin E6 with 4 sulfomethylation)		多黏菌素E6
(polymyxin E6)
), ArticleFig(id=1240376129719160910, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Tab.5, caption=

Comparison of impurities in raw materials of two different enterprises

, figureFileSmall=null, figureFileBig=null, tableContent=
检测项目
(test item)		A企业
(enterprise A)		B企业
(enterprise B)
相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%		相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%
含量>0.5%的杂质峰(impurity peak with a content >0.5%)0.35E1-I80.850.35E1-I80.56
0.76E360.570.95E1-I60.92
0.95E1-I60.921.26E1-I60.57
0.99E1-I60.63/
1.26E1-I60.59
最大杂质峰含量(maximum impurity peak content)/%0.920.92
杂质总含量(total impurity peak content)/%3.562.05
), ArticleFig(id=1240376129794658387, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=表5, caption=

2个不同企业原料药杂质对比

, figureFileSmall=null, figureFileBig=null, tableContent=
检测项目
(test item)		A企业
(enterprise A)		B企业
(enterprise B)
相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%		相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%
含量>0.5%的杂质峰(impurity peak with a content >0.5%)0.35E1-I80.850.35E1-I80.56
0.76E360.570.95E1-I60.92
0.95E1-I60.921.26E1-I60.57
0.99E1-I60.63/
1.26E1-I60.59
最大杂质峰含量(maximum impurity peak content)/%0.920.92
杂质总含量(total impurity peak content)/%3.562.05
), ArticleFig(id=1240376129903710293, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=EN, label=Tab.6, caption=

Comparison of impurities in different production processes of the same enterprise

, figureFileSmall=null, figureFileBig=null, tableContent=
检测项目
(test item)		冻干制剂
(freeze-drying preparation)		无菌灌装制剂
(aseptic filling preparation)
相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%		相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%
含量>0.5%的杂质峰(impurity peak with a content >0.5%)0.36E1-I80.590.36E1-I80.55
0.95E1-I61.060.95E1-I60.77
1.26E1-I60.671.26E1-I60.56
最大杂质峰含量(maximum impurity peak content)/%1.060.77
杂质总含量(total impurity peak content)/%2.321.88
), ArticleFig(id=1240376129970819160, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1240372086607245782, language=CN, label=表6, caption=

同一企业不同生产工艺制剂杂质对比

, figureFileSmall=null, figureFileBig=null, tableContent=
检测项目
(test item)		冻干制剂
(freeze-drying preparation)		无菌灌装制剂
(aseptic filling preparation)
相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%		相对保留时间
(relative retention time)		来源
(source)		取代基数量
(substituent number)		含量
(content)/%
含量>0.5%的杂质峰(impurity peak with a content >0.5%)0.36E1-I80.590.36E1-I80.55
0.95E1-I61.060.95E1-I60.77
1.26E1-I60.671.26E1-I60.56
最大杂质峰含量(maximum impurity peak content)/%1.060.77
杂质总含量(total impurity peak content)/%2.321.88
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复杂抗生素多黏菌素E甲磺酸钠的组分与杂质谱研究及在质量控制中的应用*
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李宣 1, 2, 3 , 黄敏文 1, 2 , 施海蔚 1, 2 , 胡楠 4 , 周杰 5 , 杭太俊 3 , 袁耀佐 1, 2, **
药物分析杂志 | 安全监测 2024,44(1): 116-125
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药物分析杂志 | 安全监测 2024, 44(1): 116-125
复杂抗生素多黏菌素E甲磺酸钠的组分与杂质谱研究及在质量控制中的应用*
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李宣1, 2, 3 , 黄敏文1, 2 , 施海蔚1, 2, 胡楠4, 周杰5, 杭太俊3, 袁耀佐1, 2, **
作者信息
  • 1.江苏省食品药品监督检验研究院，南京210008
  • 2.国家药品监督管理局化学药物杂质谱研究重点实验室，南京210008
  • 3.中国药科大学分析教研室，南京210009
  • 4.安捷伦科技中国有限公司，北京100102
  • 5.江苏正大天晴药业集团股份有限公司，连云港222062

    • 李宣 Tel： 18018038869；E-mail：

    黄敏文 Tel: (025)86251148; E-mail:

通讯作者:

**Tel：(025)86251141；E-mail：
Study on composition and impurity profile of complex antibiotic colistimethate sodium and its application in quality control*
Xuan LI1, 2, 3 , Min-wen HUANG1, 2 , Hai-wei SHI1, 2, Nan HU4, Jie ZHOU5, Tai-jun HANG3, Yao-zuo YUAN1, 2, **
Affiliations
  • 1.Jiangsu Institute for Food and Drug Control, Nanjing 210008, China
  • 2.NMPA Key Laboratory for Impurity Profile of Chemical Drugs, Nanjing 210008, China
  • 3.Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
  • 4.Agilent Technologies Inc, Beijing 100102, China
  • 5.Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Lianyungang 222062, China
出版时间: 2024-01-31 doi: 10.16155/j.0254-1793.2024.01.12
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摘要
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目的：

建立二维液质联用方法确定多黏菌素E甲磺酸钠(CMS)杂质的结构及来源，进而用于药物质量控制研究。

方法：

一维系统：采用Acquity UPLC® Peptide CSH C18(150 mm×2.1 mm，1.7 μm)色谱柱，以磷酸盐缓冲液(7.8 g·L-1磷酸二氢钠，用1 mol·L-1氢氧化钠溶液调节pH至6.4)-乙腈(19∶1)为流动相A，磷酸盐缓冲液-乙腈(1∶1)为流动相B，梯度洗脱，流速0.3 mL·min-1，柱温30 ℃；二维系统：采用Acquity BEH C18柱(50 mm×2.1 mm，1.7 μm)色谱柱，以甲酸铵(A)-乙腈(B)为流动相，梯度洗脱，流速0.2 mL·min-1，柱温40 ℃，检测波长210 nm。质谱检测器采用ESI源，负离子扫描模式。

结果：

采用2D-LC-Q TOF MS法，推定了CMS中55个杂质的结构，并推测其主要来源为多黏菌素E1-I、多黏菌素E1-7MOA、多黏菌素E3及多黏菌素E6。

结论：

利用二维液质联用技术推定CMS中杂质峰的结构及来源，并用来评价不同厂家、生产工艺的原料药中杂质含量变化，有利于改进生产工艺，从源头控制药物质量。

多黏菌素类抗生素  /  多黏菌素E甲磺酸钠  /  组分及杂质  /  二维液质联用技术  /  结构推定  /  质量控制
Objective:

To establish a suitable method to determine the structure and source of impurities of colistimethate sodium (CMS) for drug quality control studies.

Methods:

Frist-dimensional system: using Acquity UPLC® Peptide CSH C18(150 mm×2.1 mm, 1.7 μm) column, the mobile phase A was phosphate buffer (7.8 g·L-1 sodium dihydrogen phosphate, adjusted to pH 6.4 with 1 mol·L-1 sodium hydroxide)- acetonitrile (19∶1), the mobile phase B was phosphate buffer-acetonitrile (1∶1). Gradient elution was performed at a flow rate of 0.3 mL·min-1. The column temperature was 30 ℃. Second-dimensional system: the Acquity BEH C18 column (50 mm×2.1 mm, 1.7 μm) column was used with ammonium formate(A)-acetonitrile mixture as mobile phase with gradient elution. The flow rate was 0.2 mL·min-1. The column temperature was 40 ℃. The detection wave length was 210 nm. The ESI source was used in negative ion mode.

Results:

The 2D-LC-Q TOF MS method was used to infer the structure of the 55 impurities in CMS, and the main sources were polymyxin E1-I, polymyxin E1-7MOA, polymyxin E3 and polymyxin E6.

Conclusion:

The structure and source of impurities in CMS are determined by 2D-LC-Q TOF MS, and the changes in the content of impurities such as manufacturers and production processes are evaluated, which is conducive to improving the production process and controlling drug quality at the source.

polymyxin antibiotics  /  colistimethate sodium  /  compositions and impurities  /  2D-LC-Q TOF MS  /  structural deduction  /  quality control
李宣, 黄敏文, 施海蔚, 胡楠, 周杰, 杭太俊, 袁耀佐. 复杂抗生素多黏菌素E甲磺酸钠的组分与杂质谱研究及在质量控制中的应用*. 药物分析杂志, 2024 , 44 (1) : 116 -125 . DOI: 10.16155/j.0254-1793.2024.01.12
Xuan LI, Min-wen HUANG, Hai-wei SHI, Nan HU, Jie ZHOU, Tai-jun HANG, Yao-zuo YUAN. Study on composition and impurity profile of complex antibiotic colistimethate sodium and its application in quality control*[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (1) : 116 -125 . DOI: 10.16155/j.0254-1793.2024.01.12
正文
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多重耐药性革兰阴性菌对抗生素的耐药性日益增加，在世界范围内构成了重大的健康问题，加之缺乏有效的新型药物，促使人们重新考虑诸如多黏菌素类的旧药物，多黏菌素类药物成为最后有希望的治疗方法[1-2]，同时WHO也将多黏菌素类抗生素列为最高优先至关重要的抗微生物药物。多黏菌素E甲磺酸钠(colistimethate sodium，CMS)与其他类抗生素或抗菌药不会产生交叉耐药性，是当前治疗多重耐药铜绿假单胞菌及其他革兰阴性菌引起感染的首选药物。
CMS是由多黏菌素E(colistin，polymyxin E)上5个游离的伯氨基与甲醛、亚硫酸钠反应生成。多黏菌素E本身为一种混合物，其组分较复杂，主要有多黏菌素E1、多黏菌素E2、多黏菌素E3、多黏菌素E6、多黏菌素E1-7MOA、多黏菌素E1-I等多种组分，而CMS则是这些组分中的胺基发生不同程度的甲磺酸化后形成的混合物[3]，每个单独的多黏菌素E组分将产生一组CMS子组分，见图1。
药物质量控制和安全性研究的重点是药物杂质，药物杂质的含量直接影响药物的纯度，药物的纯度则是药物质量的一项关键因素。近年来，在药物质量研究过程中，对杂质的研究越来越重视，这一研究贯穿于药物研发的整个过程[4]。杂质水平在一定程度上反映了药物的质量，只有在全面杂质分析的基础上，药物质量控制才能得到有效控制。对多肽类药物进行系统的杂质研究，确定杂质产生的原因，有助于从源头控制产品质量，加强过程控制，降低产品质量风险。CMS等多黏菌素类药物组分众多且复杂，不同组分间在生物活性和毒性方面均可能存在差异[5]，为了有效控制药物质量，保证药物全性，需要对其杂质进行深入的研究。
EP 10.3[6]、USP 43[7]和JP 18[8]均收载了CMS，但上述药典标准在项目控制及检测方法上存在较大差异，尤其在控制药物的有效性和安全性的组分及杂质检查方面，目前仅有EP将组分及杂质设定为检查项目，并对杂质含量进行了控制。根据EMA相关报告[9]，起始物料多黏菌素E中含量最高的多黏菌素E1和多黏菌素E2甲磺酸化后所得的一系列产物归属于组分，将其他含量低，鉴定困难的甲磺酸化产物归属于杂质，并采用UPLC-UV法测定CMS组分及杂质的含量。
由于CMS结构复杂，研究难度较大，目前对CMS中杂质研究的报道极少，且均是在挥发性流动相条件下直接进入质谱[10-13]，难以达到理想的分离效果，无法得到完整的CMS杂质结构信息。为了弥补在CMS杂质研究方面的空白，本文在EP 10.3的色谱条件基础上，建立了二维液质联用技术，成功地实现了对CMS杂质的结构推定及来源归属。并在此基础上对比了不同厂家、不同生产工艺的原料药的杂质情况，进而了解生产工艺等变化对杂质的影响，有利于从源头控制药物质量。
1 仪器与试药
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1.1 仪器
Agilent 1290 Infinity ⅡLC-6545 Q-TOF/MS液相色谱-质谱联用仪(Agilent公司)，Mass Hunter工作站定性分析软件；Waters ACQUITY UPLC H-Class超高效液相色谱仪(Waters公司)；Milli-Q超纯水机(Millipore公司)；XS205万分之一电子天平(Mettler Toledo公司)。
1.2 试药与试剂
无水磷酸氢二钠(Aladdin公司，色谱纯)，50%氢氧化钠溶液(ThermoFisher Scientific公司，色谱纯)，乙腈(Merck公司，质谱纯)，甲酸铵(上海麦克林生化科技有限公司，质谱纯)，甲醇(Merck公司，色谱纯)，多黏菌素E1甲磺酸钠(CMS E1)供峰鉴别用对照品(EP，批号2.0)，多黏菌素E2甲磺酸钠(CMS E2)供峰鉴别用对照品(EP，批号2.0)，CMS供峰鉴别用对照品(EP，批号1.0)，多黏菌素E1-I甲磺酸钠(CMS E1-I)对照品(江苏正大天晴有限公司)，娃哈哈纯净水(杭州娃哈哈集团有限公司)。CMS原料药(A企业：来自Xellia公司的进口原研原料药，批号为A1680958；B企业：来自江苏正大天晴有限公司的国产仿制原料药，批号为11121011)；CMS制剂(来自江苏正大天晴有限公司，批号210927148、190405115)。
2 方法与结果
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2.1 色谱条件
2.1.1 UPLC一维色谱条件
采用Acquity UPLC®Peptide CSH C18(150 mm×2.1 mm，1.7 μm)色谱柱，以磷酸盐缓冲液(7.8 g·L-1磷酸二氢钠，用1 mol·L-1氢氧化钠溶液调节pH至6.4)-乙腈(19∶1)为流动相A，磷酸盐缓冲液-乙腈(1∶1)为流动相B，梯度洗脱(见表1)，流速0.3 mL·min-1，柱温30 ℃，检测波长210 nm，进样量2 μL。
2.1.2 UPLC二维色谱条件
采用Acquity BEH C18柱(50 mm×2.1 mm，1.7 μm)色谱柱，以1.26 g·L-1甲酸铵(A)-乙腈(B)为流动相，流速0.2 mL·min-1，柱温40 ℃，检测波长210 nm，样品切换到二维色谱中开始梯度洗脱(表2)。
2.2 质谱条件
高分辨QTOFMS测定，ESI离子源，负离子检测模式，干燥气温度为200 ℃，干燥气流速为5 L·min-1，鞘气温度为300 ℃，鞘气流速为11 L·min-1，毛细管电压为3 500 V，喷嘴电压为1 500 V，碎裂电压为100 V，雾化器压力为241 kPa，扫描范围为m/z 100~1 700。
2.3 对照品溶液的配制
取CMS供峰鉴别用对照品、CMS E1供峰鉴别用对照品、CMS E2供峰鉴别用对照品、CMS E1-I对照品适量，分别加水0.25 mL溶解，用甲醇分别稀释制成2、1、0.3以及2 mg·mL-1的溶液，即得。
2.4 质谱信息采集及裂解规律分析
EP规定了6个组分峰，其中CMS E1ASM8、CMS E1ASM6、CMS E1ASM4的结构分别为多黏菌素E1经磺甲基化后带有8个、6个、4个取代基，CMS E2ASM8、CMS E2ASM6、CMS E2ASM4的结构分别为多黏菌素E2经磺甲基化后带有8个、6个、4个取代基。取CMS E1对照品溶液、CMS E2对照品溶液分别注入一维液相色谱仪，确定6个组分峰的出峰位置，在一维液相色谱方法中设置阀切换时间，将组分收集于定量环中，再通过阀切换将组分从定量环反冲至二维色谱柱上分离并脱盐，经由二维系统的挥发性流动相继续将其带入质谱检测器中。通过6个特定组分的质谱信息确定其裂解规律。
质谱数据显示，6个特定组分发生了源内裂解，中性丢失不同数量的CH2SO3、H2SO3，产生了一系列质荷比相差41或47的高丰度的双电荷的分子离子峰。因此在母离子选择时，CMS E1ASM8、CMS E2ASM8选取了丰度相对较强且源内裂解程度较轻的[M-2H-2H2SO3]2-分子离子峰，CMS E1ASM6、CMS E2ASM6选择了[M-2H-H2SO3]2-分子离子峰。通过Agilent Mass Hunter Workstation Software软件，在Target MS/MS模式下采集6个组分的二级碎片离子质谱图。
CMS E1ASM4的质谱数据显示(图2)，准分子离子峰m/z 771.321 2([M-2H]2-)丰度最强，与结构式C57H108N16O25S4相应，结构为多黏菌素E1带有4个甲磺酸取代基。MS/MS主要特征碎片离子(图3)为m/z 730.334 6、m/z 724.334 2，分别是母离子中性丢失个H2SO3、CH2SO3后的碎片。m/z 689.347 4、m/z 698.353 4分别是母离子先中性丢失1个H2SO3后，再进一步分别丢失H2SO3、SO2后的碎片，m/z 677.348 7、m/z 683.348 1、m/z 692.353 2分别是母离子在失去1个CH2SO3的基础上，再分别失去1个CH2SO3、H2SO3、SO2后的碎片。CMS E2ASM4的准分子离子峰为m/z 764.313 7([M-2H]2-)，与分子式C56H106N16O25S4相应，其结构为多黏菌素E2带有4个甲磺酸取代基。MS/MS的裂解规律如图4，CMS E1ASM4的裂解途径主要为中性丢失CH2SO3、H2SO3、SO2。
采集CMS E1ASM6的质谱数据，一级质谱图中m/z 865.292 0、m/z 824.306 7、m/z 783.320 7、m/z 742.333 5等一系列碎片离子峰表明CMS E1ASM6结构式的碳数相较于多黏菌素E1多6，进一步证实了CMS E1ASM6的结构为多黏菌素E1带有6个取代基，而m/z 824.306 7是CMS E1ASM6发生源内断裂中性丢失1个H2SO3造成。CMS E1ASM6的准分子离子峰[M-2H]2-为m/z 865.292 0，但是该峰丰度较低，因此选取m/z 824.306 7([M-2H-H2SO3]2-)为母离子，通过碰撞诱导解离得到一系列碎片离子，其中m/z 783.319 7、m/z 742.333 8、m/z 701.348 5是不断中性丢失H2SO3产生的碎片离子；m/z 777.318 8、m/z 730.333 8是不断丢失CH2SO3产生的碎片离子；m/z 736.334 2、m/z 695.349 0、m/z 689.348 4、m/z 683.344 4是既丢失CH2SO3又丢失H2SO3产生的碎片离子；m/z 751.339 1、m/z 710.354 6、m/z 704.352 6是丢失不同数量CH2SO3、H2SO3、SO2产生的碎片离子。CMS E2ASM6的准分子离子峰[M-2H]2-为m/z 858.285 1，但是该化合物易发生源内裂解，因此选取m/z 817.300 1为母离子，通过碰撞诱导解离得到一系列碎片离子。MS/MS主要特征碎片离子如表3，与CMS E1ASM6一致，CMS E2ASM6的裂解途径主要为中性丢失CH2SO3、H2SO3、SO2。
采集CMS E1ASM8的质谱数据，一级质谱图中m/z 918.277 7、m/z 877.293 0、m/z 836.307 2、m/z 795.320 5等一系列碎片离子峰表明CMS E1ASM8结构式的碳数相较于多黏菌素E1多8，进一步证实了CMS E1ASM8的结构应该是多黏菌素E1带有8个取代基。CMS E1ASM8的准分子离子峰[M-2H]2-为m/z 959.265 4，但是该化合物发生源内裂解产生一系列丢失H2SO3或者CH2SO3的峰，因此选取m/z 877.293 0([M-2H-2H2SO3]2-)为母离子，通过碰撞诱导解离得到一系列碎片离子，其中m/z 836.305 9、m/z 795.321 6、m/z 754.334 8是不断中性丢失H2SO3产生的碎片离子；m/z 783.319 2、m/z 736.335 9是不断丢失CH2SO3产生的碎片离子；m/z 789.321 1、m/z 748.334 5、m/z 707.346 8、m/z 742.334 2、m/z 701.349 2、m/z 695.348 0是既丢失CH2SO3又丢失H2SO3产生的碎片离子；m/z 804.330 6、m/z 757.342 2、m/z 763.341 6、m/z 731.362 2、m/z 722.353 9、m/z 710.355 1、m/z 716.354 7是丢失了CH2SO3、H2SO3、SO2产生的碎片离子。CMS E2ASM8的准分子离子峰[M-2H]2-为m/z 959.265 4，但是该化合物易发生源内裂解，因此选取m/z 870.286 3为母离子，通过碰撞诱导解离得到一系列碎片离子。MS/MS主要特征碎片离子如表3，CMS E2ASM8的裂解途径与CMS E1ASM8一致，主要为中性丢失CH2SO3、H2SO3、SO2。
质谱信息的采集及解析进一步确认了CMS E1ASM8、CMS E1ASM6、CMS E1ASM4的结构分别是多黏菌素E1带有8个、6个、4个甲磺酸取代基，CMS E2ASM8、CMS E2ASM6、CMS E2ASM4的结构分别是多黏菌素E2带有8个、6个、4个甲磺酸取代基，也证实了CMS的结构不再是之前报道的单-磺甲基化取代，而是双-磺甲基的取代。
2.5 CMS杂质结构推定及来源分析
利用二维质谱联用技术采集CMS对照品溶液的质谱数据，推定了一维色谱图中杂质峰对应的化合物结构式。由于其他来源的CMS混合物的子成分含量较低，鉴定较为困难，因此将多黏菌素E中除多黏菌素E1和多黏菌素E2之外的磺甲基化产物均归类为杂质。根据质谱数据的分析以及各对照品溶液色谱图对比，定义为杂质的色谱峰有55个(图5)，推测杂质峰的主要来源是多黏菌素E1-I、多黏菌素E1-7MOA、多黏菌素E3和多黏菌素E6(表4)。
有8个化合物为CMS E1ASM8同分异构体，其中7、10、12、13、18号峰在CMS E1-I对照品溶液色谱图中有相对应保留时间的峰，可以确定它们来源于多黏菌素E1-I(多黏菌素E1的同分异构体)；4、8、14号峰在CMS E1对照品溶液色谱图、CMS E1-I对照品溶液色谱图中均没有相对应保留时间的峰，推测它们来源于多黏菌素E1-7MOA(在多黏菌素E中含量较高的多黏菌素E1同分异构体)。有9个化合物为CMS E1ASM6同分异构体，其中27、28、32、33、35、36、39号峰来源于多黏菌素E1-I，37、38号峰来源于多黏菌素E1-7MOA。有12个化合物为CMS E1ASM4同分异构体，其中40、42、48、49、51、52、53号峰来源于多黏菌素E1-I，46、47、50、54、55来源于多黏菌素E1-7MOA。
有4个化合物为CMS E2ASM8同分异构体，3、5、9、11号峰在CMS E2对照品溶液色谱图中没有相对应保留时间的峰，推测它们来源于多黏菌素E3(在多黏菌素E中含量较高的多黏菌素E2同分异构体)。有9个化合物为CMS E2ASM6同分异构体，16、19、20、21、22、25、29、30、31号峰推测其来源于多黏菌素E3。有2个化合物为CMS E2ASM4同分异构体，43、45号峰推测其来源于多黏菌素E3。
1号峰在CMS E1对照品溶液、CMS E2对照品溶液、CMS E1-I对照品溶液色谱图中均没有保留时间一致的峰，推测其来源于多黏菌素E1-7MOA，其结构为多黏菌素E1-7MOA带有10个甲磺酸取代基。
2、6号峰对应化合物与CMS E1ASM8的相对分子质量均相差8，考虑到为双电荷，在结构上即相差16，推测其来源于多黏菌素E6(结构上较多黏菌素E1多1个羟基)；15、17、26、24号峰对应化合物与CMS E1ASM6相对分子质量相差8，推测它们也来源于多黏菌素E6。
色谱图显示23号峰为双峰，但在高浓度(8 mg·mL-1)的CMS样品色谱图中合并成1个峰，质谱信息显示这2个峰对应化合物均为CMS E2ASM6的同分异构体，且在CMS E2对照品溶液中均没有相对应保留时间的峰，推测23号双峰均来源于多黏菌素E3。
质谱信息显示24号峰应为双峰，其中1个峰对应化合物为CMS E2ASM6的同分异构体，且在CMS E2对照品溶液色谱图中有相对应保留时间的峰；另1个峰对应化合物与CMS E1ASM6的相对分子质量相差8，推测24号双峰为分别来源于多黏菌素E2和多黏菌素E6。
质谱信息显示34号峰为双峰，其中1个峰对应化合物为CMS E2ASM6的同分异构体，且在CMS E2对照品溶液色谱图中有相对应保留时间的峰，另1个峰对应化合物为CMS E1ASM6的同分异构体，且在CMS E1-I对照品溶液色谱图中有相对应保留时间的峰，可以确定34号双峰分别来源于多黏菌素E2和多黏菌素E1-I。
质谱信息及各对照品溶液色谱图对比推测41号峰应为三峰，其中2个峰对应化合物均为CMS E1ASM6的同分异构体，且分别在CMS E1对照品溶液、CMS E1-I对照品溶液色谱图中有相对应保留时间的峰；另1个峰对应化合物为CMS E2ASM4的同分异构体，且在CMS E2对照品溶液色谱图中相对应保留时间的峰；可以确定41号三峰分别来源于多黏菌素E2、多黏菌素E1和多黏菌素E1-I。
质谱信息显示44号峰为三峰，其中1个峰对应化合物为CMS E1ASM4的同分异构体，但在CMS E1对照品溶液、CMS E1-I对照品溶液色谱图中均无相对应保留时间的峰；另1个峰对应化合物为CMS E2ASM4的同分异构体，但在CMS E2对照品溶液色谱图中无相对应保留时间的峰；第3个峰与CMS E1ASM4的相对分子质量相差8；推测75号三峰分别来源于多黏菌素E1-7MOA、多黏菌素E3和多黏菌素E6。
2.6 质量控制
为了有效控制CMS药物质量，EP通过峰面积归一化法对CMS的杂质含量进行了控制，规定任意单一杂质含量应≤1.5%，杂质总和应≤5.5%（含量低于0.5%的峰忽略不计）。在此基础上对比不同企业、不同生产工艺的原料药的杂质情况，进而了解生产工艺等变化对杂质的影响，有利于从源头控制药物质量。
2.6.1 2个不同企业的原料药对比分析
考察2个不同企业原料药的杂质峰个数、最大杂质峰含量、杂质总含量，将结果进行对比(表5)。A企业杂质总和高于B企业，而且A企业较B企业的原料药多了2个含量>0.5%杂质峰(通过分析，2个峰分别来源于多黏菌素E3、多黏菌素E1-I)；除此之外，2个企业中相对保留时间一致（分别为0.35、0.95和1.26）的3个杂质峰面积相比较，B企业均略低。
B企业在传统方法的基础上加以改进，将硫酸多粘菌素E加水溶解，向其中加入甲醛溶液，将二者进行反应；再向上述的反应产物中加入亚硫酸氢钠溶液，继续反应，采用超滤膜进行分离纯化。该方法具有低污染，低能耗，工艺简单，重现性好，且所得产品的纯度和活性很高的优点。对比结果也表明2个不同企业原料药存在一定的差异，B企业纯度较高，杂质较少。2个不同企业的原料药发酵菌株、合成工艺、纯化分离方法的不同，造成原料药间的差异。
2.6.2 同一企业不同生产工艺对比分析
CMS制剂生产工艺有2种，冻干及无菌灌装。B企业同时拥有2种生产工艺的制剂(无菌灌装制剂，批号210927148；冻干制剂，批号190405115)，现对不同生产工艺制剂的质量进行对比分析。
结合杂质分析结果，考察不同生产工艺制剂的有机杂质峰个数、最大杂质峰含量、杂质总含量，将结果进行对比(表6)。无菌灌装制剂与冻干制剂的杂质峰数量相同，但相对保留时间一致的3个杂质峰含量相比，无菌灌装制剂杂质明显较低，可见，冻干工艺造成了制剂中有机杂质含量的增加。
3 讨论
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随着分析技术的发展，多黏菌素类抗生素的组分控制和含量测定已受到越来越多的关注[14-15]。硫酸多黏菌素E在临床应用时，其组分多黏菌素E1、多黏菌素E2、多黏菌素E3、多黏菌素E6、多黏菌素E1-7MOA、多黏菌素E1-I等均作为有效组分发挥作用，各组分在甲磺酸化的过程中均会产生不同的杂质。
本文通过建立的二维液质联用技术，结合CMS主要组分的裂解规律，成功地实现了对CMS中55个杂质的结构推定及来源归属，其杂质主要为多黏菌素E1-I、多黏菌素E1-7MOA、多黏菌素E3、多黏菌素E6甲磺酸化后产生的一系列化合物。可见起始物料多黏菌素E的组成和纯度是生产CMS的关键质量属性，在生产原料药时需要厂家严格控制多黏菌素E各组分的含量，才能保证其药物质量。对不同生产工艺的CMS有关物质分析比较结果显示，在制剂生产中，无菌灌装较冻干燥所得的制剂，杂质更少，产品的纯度更高。
基金
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  • *江苏省药品监督管理局药品监管科学科研计划项目(202122)
文献
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2024年第44卷第1期
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doi: 10.16155/j.0254-1793.2024.01.12
  • 接收时间：2023-10-20
  • 首发时间：2026-03-16
  • 出版时间：2024-01-31
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  • 收稿日期：2023-10-20
基金
*江苏省药品监督管理局药品监管科学科研计划项目(202122)
作者信息
    1.江苏省食品药品监督检验研究院，南京210008
    2.国家药品监督管理局化学药物杂质谱研究重点实验室，南京210008
    3.中国药科大学分析教研室，南京210009
    4.安捷伦科技中国有限公司，北京100102
    5.江苏正大天晴药业集团股份有限公司，连云港222062

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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