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Article(id=1308817816967545222, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-1016, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1756137600000, receivedDateStr=2025-08-26, revisedDate=1763654400000, revisedDateStr=2025-11-21, acceptedDate=null, acceptedDateStr=null, onlineDate=1789976084224, onlineDateStr=2026-09-21, pubDate=1770825600000, pubDateStr=2026-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789976084224, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789976084224, creator=13701087609, updateTime=1789976084224, updator=13701087609, issue=Issue{id=1308817633789698171, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='2', pageStart='321', pageEnd='676', issueExtLink='null', onlineDate='null', pubDate='1770825600000', pubDateStr='2026-02-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789976040551, creator='13701087609', updateTime=1789984264575, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308852127921963901, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308852127921963902, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308817633789698171, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=553, endPage=559, ext={EN=ArticleExt(id=1308817817194037639, articleId=1308817816967545222, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Determination of the related substances degradated by tryptophan in pediatric compound amino acid injection by HPLC and 2D-LC-Q-TOF/MS, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

The study aimed to establish a HPLC method and a two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (2D-LC-Q-TOF/MS) method for the determination of the related substances degradated by tryptophan in pediatric compound amino acid injection and the exploration of the degradation pathway of tryptophan. The HPLC method was carried out on a Waters Atlantis T3 C18 (250 mm × 4.6 mm, 5 μm) column by gradient elution using phosphate buffer solution-acetonitrile (990∶12) and phosphate buffer solution-acetonitrile (65∶35) as the mobile phases to separate tryptophan and the related substances degradated by tryptophan. The selected components were then trapped in switch valve tube lines respectively and delivered to the second-dimensional desalting and deacidification gradient elution which was performed with an Agilent ZORBAX Eclipse Plus C18 (50 mm × 3.0 mm, 1.8 μm) column using acetonitrile-water (95∶5) as the mobile phases. The positive ion mode of the electrospray ionization source was adopted, the parent ions were detected using MS scan mode and the fragment ions were detected using targeted MS/MS mode. The structure of the unknown impurities was figured out by mass spectrometry elucidation. The results showed that tryptophan and its related substances in pediatric compound amino acid injection can be adequately separated under the established analytical conditions. A new impurity produced by the interaction between tryptophan and antioxidant excipients such as sodium bisulfite or sodium metabisulfite was discovered for the first time. The method can provide reference for the quality control of this injection.

, authors=Ge JIANG, Zhi-yuan GUO, Feng LIU, Hua XIE, Heng-yi ZHU*, authorsList=Ge JIANG, Zhi-yuan GUO, Feng LIU, Hua XIE, Heng-yi ZHU, authorCompany=null, correspAuthors=Heng-yi ZHU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 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, fund=null), CN=ArticleExt(id=1308817818443940243, articleId=1308817816967545222, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=HPLC法和二维液相色谱-质谱联用法研究小儿复方氨基酸注射液中色氨酸有关物质, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

建立HPLC法和二维液相色谱-质谱联用法研究小儿复方氨基酸注射液中色氨酸降解产生的有关物质, 探讨色氨酸的降解途径。HPLC法采用Waters Atlantis T3 C18色谱柱(250 mm × 4.6 mm, 5 μm), 以磷酸盐缓冲液-乙腈(990∶12) 和磷酸盐缓冲液-乙腈(65∶35) 为流动相进行梯度洗脱, 实现样品中色氨酸及其各降解杂质的分离, 通过多次简单中心切割工作模式将目标杂质捕集送入下一级与质谱串联的色谱系统, 从而达到在线快速脱盐和脱酸的目的, 二维采用超高效液相色谱-四级杆飞行时间质谱(UPLC-QTOF), Agilent ZORBAX Eclipse Plus C18色谱柱(50 mm × 3.0 mm, 1.8 μm), 以乙腈-水(95∶5) 为流动相进行等度洗脱。在电喷雾离子源正离子扫描(ESI+) 模式下, 通过一级全扫描锁定母离子后, 进行目标触发式二级质谱扫描, 获取碎片离子信息, 对未知降解杂质进行定性研究, 初步确定杂质结构。结果显示, 建立的分析条件可以有效分离检测小儿复方氨基酸注射液中色氨酸降解产生的有关物质, 并首次发现色氨酸与抗氧剂辅料亚硫酸氢钠或焦亚硫酸钠发生相互作用产生的一个新杂质, 为该品种的质量控制提供参考依据。

, authors=江舸, 郭志渊, 刘峰, 谢华, 朱恒怡*, authorsList=江舸, 郭志渊, 刘峰, 谢华, 朱恒怡, authorCompany=null, correspAuthors=朱恒怡, authorNote=

作者贡献:

江舸负责实验操作、有关物质检查方法建立、未知杂质结构鉴定、样品测定及论文撰写; 郭志渊、刘峰和谢华负责实验指导; 朱恒怡设计实验、提供文章思路、处理实验数据、负责文章修改及定稿。

, correspAuthorsNote=
朱恒怡, Tel: 86-28-64020254, E-mail:
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Determination of antioxidant sodium bisulfite in pediatric compound amino acid injection by ion chromatography [J]. Tianjin Pharm (天津药学), 2020, 32: 22-24., articleTitle=null, refAbstract=null), Reference(id=1308817949138444774, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=2, rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Lou YM, Lin M, Cheng XL. Preliminary research of an HPLC method for the related substances in compound amino acid injection (18AA) [J]. Drug Stand China (中国药品标准), 2019, 20: 37-41., articleTitle=null, refAbstract=null), Reference(id=1308817949243302375, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=3, rfOrder=2, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhu HY, Jiang G, Guo ZY, et al. Determination of related substances produced by glutamate degradation in pediatric compound amino acid injection by HPLC [J]. West China J Pharm Sci (华西药学杂志), 2021, 36: 579-582., articleTitle=null, refAbstract=null), Reference(id=1308817949318799848, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=4, rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Jiang G, Zhu HY, Guo ZY, et al. Determination of related substances of methionine in pediatric compound amino acid injection [J]. West China J Pharm Sci (华西药学杂志), 2022, 37: 440-443., articleTitle=null, refAbstract=null), Reference(id=1308817949381714409, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=5, rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Shao YH, Fan JW, Ding M. The relation between stability of tryptophan and residual oxygen in compound amino acid injection [J]. Qilu Pharm Aff (齐鲁药事), 2010, 29: 497-499., articleTitle=null, refAbstract=null), Reference(id=1308817949453017578, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=6, rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=European Pharmacopoeia Committee. European Pharmacopoeia (欧洲药典) [S]. 10.0 Ed. France: European Directorate for the Quality of Medicine & Healthcare, 2020: 4115-4117., articleTitle=null, refAbstract=null), Reference(id=1308817949520126443, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=7, rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Jin W, Jiang WM, Liu Q, et al. Study on the structure of an unknown impurity in carboplatin injection and the relationship with the excipient [J]. Acta Pharm Sin (药学学报), 2018, 53: 604-608., articleTitle=null, refAbstract=null), Reference(id=1308817949654344172, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=8, rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu JM, Lu YT, Song M, et al. Structural identification of the related substances in phloroglucinol injection by two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry [J]. Acta Pharm Sin (药学学报), 2024, 59: 202-213., articleTitle=null, refAbstract=null), Reference(id=1308817949738230253, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=9, rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Xing JD. Study on the Synthesis of Indole (吲哚合成工艺的研究) [D]. Tianjin: Tianjin University, 2006., articleTitle=null, refAbstract=null), Reference(id=1308817949822116334, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=10, rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Ahmad T, Khan S, Ullah N. Recent advances in the catalytic asymmetric friedel-crafts reactions of indoles [J]. ACS Omega, 2022, 7: 35446-35485., articleTitle=null, refAbstract=null), Reference(id=1308817950036025839, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=11, rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Deka B, Deb ML, Baruah PK. Recent advances on the C2-functionalization of indole via umpolung [J]. Top Curr Chem, 2022, 378: 22., articleTitle=null, refAbstract=null), Reference(id=1308817951248179696, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=12, rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Dalpozzo R. Strategies for the asymmetric functionalization of indoles: an update [J]. Chem Soc Rev, 2015, 44: 742-778., articleTitle=null, refAbstract=null), Reference(id=1308817951315288561, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=13, rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Shah TA, De PB, Pradhan S, et al. Transition-metal-catalyzed site-selective C7-functionalization of indoles: advancement and future prospects [J]. Chem Commun, 2019, 55: 572-587., articleTitle=null, refAbstract=null), Reference(id=1308817951382397426, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308817816967545222, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=14, rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=Guo L, Zhou CM, Li H, et al. Determination of related substances of tryptophan in compound amino acid injection (18AA-Ⅱ) [J]. 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AnalyteLOD/ µg·mL-1LOQ/ µg·mL-1Linear equationLinear range/µg·mL-1R2
EP impurity B0.0200.0320.032 2-26.8 µg·mL-1y = 29 139.56 x - 1 355.421.000 0
EP impurity D0.0080.0210.021 2-26.5 µg·mL-1y = 151 738.21 x - 1 842.561.000 0
EP impurity C0.0080.0200.020 4-25.5 µg·mL-1y = 109 512.83 x - 7 894.480.999 8
EP impurity G0.1030.2070.207 0-25.9 µg·mL-1y = 31 024.59 x - 3 678.320.999 7
Impurity S0.0080.0200.020 4-25.5 µg·mL-1y = 137 590.50 x + 1 903.101.000 0
Tryptophan0.0080.0200.021 0-26.3 µg·mL-1y = 162 323.83 x - 2 378.171.000 0
USP impurity B0.0080.0200.019 8-24.8 µg·mL-1y = 134 882.99 x - 942.201.000 0
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Linear equation, limit of quantification (LOQ) and limit of detection (LOD)

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AnalyteLOD/ µg·mL-1LOQ/ µg·mL-1Linear equationLinear range/µg·mL-1R2
EP impurity B0.0200.0320.032 2-26.8 µg·mL-1y = 29 139.56 x - 1 355.421.000 0
EP impurity D0.0080.0210.021 2-26.5 µg·mL-1y = 151 738.21 x - 1 842.561.000 0
EP impurity C0.0080.0200.020 4-25.5 µg·mL-1y = 109 512.83 x - 7 894.480.999 8
EP impurity G0.1030.2070.207 0-25.9 µg·mL-1y = 31 024.59 x - 3 678.320.999 7
Impurity S0.0080.0200.020 4-25.5 µg·mL-1y = 137 590.50 x + 1 903.101.000 0
Tryptophan0.0080.0200.021 0-26.3 µg·mL-1y = 162 323.83 x - 2 378.171.000 0
USP impurity B0.0080.0200.019 8-24.8 µg·mL-1y = 134 882.99 x - 942.201.000 0
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HPLC法和二维液相色谱-质谱联用法研究小儿复方氨基酸注射液中色氨酸有关物质
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江舸 , 郭志渊 , 刘峰 , 谢华 , 朱恒怡 *
药学学报 | 研究论文 2026,61(2): 553-559
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药学学报 |研究论文 2026 , 61 (2) : 553 -559
HPLC法和二维液相色谱-质谱联用法研究小儿复方氨基酸注射液中色氨酸有关物质
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江舸, 郭志渊, 刘峰, 谢华, 朱恒怡*
作者信息
  • 四川省药品检验研究院, 四川 成都 611731
通讯作者:
朱恒怡, Tel: 86-28-64020254, E-mail:
作者简介:

作者贡献:

江舸负责实验操作、有关物质检查方法建立、未知杂质结构鉴定、样品测定及论文撰写; 郭志渊、刘峰和谢华负责实验指导; 朱恒怡设计实验、提供文章思路、处理实验数据、负责文章修改及定稿。

Determination of the related substances degradated by tryptophan in pediatric compound amino acid injection by HPLC and 2D-LC-Q-TOF/MS
Ge JIANG, Zhi-yuan GUO, Feng LIU, Hua XIE, Heng-yi ZHU*
Affiliations
  • Sichuan Institute for Drug Control, Chengdu 611731, China
出版时间: 2026-02-12 doi: 10.16438/j.0513-4870.2025-1016
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摘要
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建立HPLC法和二维液相色谱-质谱联用法研究小儿复方氨基酸注射液中色氨酸降解产生的有关物质, 探讨色氨酸的降解途径。HPLC法采用Waters Atlantis T3 C18色谱柱(250 mm × 4.6 mm, 5 μm), 以磷酸盐缓冲液-乙腈(990∶12) 和磷酸盐缓冲液-乙腈(65∶35) 为流动相进行梯度洗脱, 实现样品中色氨酸及其各降解杂质的分离, 通过多次简单中心切割工作模式将目标杂质捕集送入下一级与质谱串联的色谱系统, 从而达到在线快速脱盐和脱酸的目的, 二维采用超高效液相色谱-四级杆飞行时间质谱(UPLC-QTOF), Agilent ZORBAX Eclipse Plus C18色谱柱(50 mm × 3.0 mm, 1.8 μm), 以乙腈-水(95∶5) 为流动相进行等度洗脱。在电喷雾离子源正离子扫描(ESI+) 模式下, 通过一级全扫描锁定母离子后, 进行目标触发式二级质谱扫描, 获取碎片离子信息, 对未知降解杂质进行定性研究, 初步确定杂质结构。结果显示, 建立的分析条件可以有效分离检测小儿复方氨基酸注射液中色氨酸降解产生的有关物质, 并首次发现色氨酸与抗氧剂辅料亚硫酸氢钠或焦亚硫酸钠发生相互作用产生的一个新杂质, 为该品种的质量控制提供参考依据。

小儿复方氨基酸注射液  /  色氨酸  /  有关物质  /  质量控制  /  高效液相色谱法  /  二维液相色谱-质谱联用

The study aimed to establish a HPLC method and a two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (2D-LC-Q-TOF/MS) method for the determination of the related substances degradated by tryptophan in pediatric compound amino acid injection and the exploration of the degradation pathway of tryptophan. The HPLC method was carried out on a Waters Atlantis T3 C18 (250 mm × 4.6 mm, 5 μm) column by gradient elution using phosphate buffer solution-acetonitrile (990∶12) and phosphate buffer solution-acetonitrile (65∶35) as the mobile phases to separate tryptophan and the related substances degradated by tryptophan. The selected components were then trapped in switch valve tube lines respectively and delivered to the second-dimensional desalting and deacidification gradient elution which was performed with an Agilent ZORBAX Eclipse Plus C18 (50 mm × 3.0 mm, 1.8 μm) column using acetonitrile-water (95∶5) as the mobile phases. The positive ion mode of the electrospray ionization source was adopted, the parent ions were detected using MS scan mode and the fragment ions were detected using targeted MS/MS mode. The structure of the unknown impurities was figured out by mass spectrometry elucidation. The results showed that tryptophan and its related substances in pediatric compound amino acid injection can be adequately separated under the established analytical conditions. A new impurity produced by the interaction between tryptophan and antioxidant excipients such as sodium bisulfite or sodium metabisulfite was discovered for the first time. The method can provide reference for the quality control of this injection.

pediatric compound amino acid injection  /  tryptophan  /  related substance  /  quality control  /  HPLC  /  2D-LC-Q-TOF/MS
江舸, 郭志渊, 刘峰, 谢华, 朱恒怡. HPLC法和二维液相色谱-质谱联用法研究小儿复方氨基酸注射液中色氨酸有关物质. 药学学报, 2026 , 61 (2) : 553 -559 . DOI: 10.16438/j.0513-4870.2025-1016
Ge JIANG, Zhi-yuan GUO, Feng LIU, Hua XIE, Heng-yi ZHU. Determination of the related substances degradated by tryptophan in pediatric compound amino acid injection by HPLC and 2D-LC-Q-TOF/MS[J]. Acta Pharmaceutica Sinica, 2026 , 61 (2) : 553 -559 . DOI: 10.16438/j.0513-4870.2025-1016
正文
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小儿复方氨基酸注射液(18AA-Ⅰ、18AA-Ⅱ、19AA-Ⅰ) 是一种由多种氨基酸根据营养或治疗需要以适当比例配制而成, 与复方氨基酸注射液的区别在于降低了苯丙氨酸、甲硫氨酸、甘氨酸的用量, 增加半胱氨酸和组氨酸的用量, 以适应婴幼儿代谢的特点并满足小儿营养需要[1]。由于其中存在多种易氧化氨基酸[2], 处方中均加入了抗氧剂焦亚硫酸钠或亚硫酸氢钠作为制剂辅料。
小儿复方氨基酸注射液中各氨基酸成分大多只有末端吸收且极性较大, 采用HPLC法进行杂质谱研究, 由于成分多、分离困难、末端吸收干扰多, 因此需针对其中不稳定氨基酸单独建立适当的方法进行分析。已有文献报道在制剂生产过程中谷氨酸会高温降解为焦谷氨酸[3], 在制剂生产和储存过程中甲硫氨酸会氧化产生甲硫氨酸亚砜[4]。色氨酸化学结构中因存在吲哚环而易被氧化降解, 导致输液颜色变深, 含量下降[5], 因此有必要对色氨酸的有关物质进行研究控制, 保障儿童用药安全。
本研究试验期间查询欧洲药典(EP10.0)、英国药典(BP2020) 和美国药典(USP43) 均收载了色氨酸原料的有关物质检查方法, 经过比较, 本文参照EP10.0色氨酸原料有关物质检查方法[6], 进行色谱条件优化, 并对收集到的7家企业生产的135批小儿复方氨基酸注射液中色氨酸有关物质进行研究。二维液相色谱-高分辨质谱联用技术因不受流动相类型限制, 且具备强大的定性能力, 已被广泛应用于药物有关物质的鉴定研究[7, 8], 本研究即采用该技术手段进行分析, 发现了小儿复方氨基酸注射液中色氨酸的一个新杂质, 为该品种的质量控制提供参考依据。
材料与方法
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仪器  Waters e2695-2487-2998高效液相色谱系统、Empower工作站(美国Waters公司); Agilent 2D-LCMS-6540 Q-TOF二维超高效液相色谱-四级杆飞行时间质谱联用仪、Agilent MassHunter工作站(美国Agilent公司); XSE205DU电子天平(美国Mettler Toledo公司); Mill-Q Advantage A10超纯水仪(Merck Millipore公司)。
药品与试剂  小儿复方氨基酸注射液(18AA-Ⅰ) 由国内J、T、L、C厂家提供; 小儿复方氨基酸注射液(18AA-Ⅱ) 由国内S厂家提供; 小儿复方氨基酸注射液(19AA-Ⅰ) 由国内H、Q厂家提供。二氧吲哚丙氨酸(EP杂质B, 批号: 1-WAI-183-3) 和2-羟基-L-色氨酸盐酸盐(EP杂质G, 批号: 2-KMW-109-6), TRC公司; 5-羟基-L-色氨酸(EP杂质D, 批号: BCBS6333V) 和犬尿氨酸(EP杂质C, 批号: BCBW1487), Sigma-Aldrich公司; 杂质S由H厂家提供; 色氨酸(批号: 140686-201904), 中国食品药品检定研究院; N-乙酰色氨酸(USP杂质B, 批号: F427576), 上海一飞生物科技有限公司。小儿复方氨基酸注射液(18AA-Ⅰ、18AA-Ⅱ、19AA-Ⅰ) 处方中的20种氨基酸原料药及辅料焦亚硫酸钠和亚硫酸氢钠由国内H、J厂家提供。磷酸(HPLC级) 和乙腈(HPLC级), Fisher公司; 二水磷酸二氢钠(AR级), 成都市科隆化学品有限公司; 水为超纯水, 其余试剂为分析纯。
色谱条件
色氨酸有关物质检查条件(HPLC法色谱条件) 采用Waters Atlantis T3 C18 (250 mm × 4.6 mm, 5 µm) 为色谱柱; 以乙腈-磷酸盐缓冲液(取3.9 g·L-1二水磷酸二氢钠溶液1 L与2.9 g·L-1磷酸溶液700 mL混匀), 12∶990, 为流动相A, 以乙腈-磷酸盐缓冲液(35∶65) 为流动相B, 线性梯度洗脱(A∶B, 流速): 0 min (100∶0, 0.8 mL·min-1) → 28 min (100∶0, 0.8 mL·min-1) → 35 min (95∶5, 0.8 mL·min-1) → 38 min (95∶5, 1.2 mL·min-1) → 50 min (95∶5, 1.2 mL·min-1) → 70 min (0∶100, 1.2 mL·min-1) → 75 min (0∶100, 1.2 mL·min-1) → 76 min (100∶0, 0.8 mL·min-1) → 85 min (100∶0, 0.8 mL·min-1); 柱温45 ℃, 自动进样器温度15 ℃, 检测波长220 nm, 进样量20 μL。
未知杂质定性分析条件(二维液相色谱条件) 采用Agilent ZORBAX Eclipse Plus C18 (50 mm × 3.0 mm, 1.8 µm) 为色谱柱; 以乙腈-水(95∶5) 为流动相进行等度洗脱; 流速0.4 mL·min-1, 柱温45 ℃, 检测波长220 nm。
质谱条件  离子源为ESI源, 正离子模式; 毛细管电压4 kV; 锥孔电压65 V; 毛细管出口电压110 V; 干燥气温度325 ℃; 干燥气流量8.0 L·min-1; 雾化器压力40 psig; 鞘气温度350 ℃; 鞘气流量11 L·min-1; 二级质谱扫描采用Targeted MS/MS模式: MS扫描范围m/z 60~800, MS/MS扫描范围m/z 30~400; 碰撞气氦气, 碰撞能量10、20、30 V (自动切换)。
溶液制备
对照品溶液  分别取EP杂质B、D、C、G、S、色氨酸和USP杂质B对照品适量, 精密称定, 加甲醇适量使溶解并用水稀释制成每1 mL中约含上述各物质250 µg的溶液, 作为色氨酸和上述各杂质对照品储备液。分别精密量取各对照品储备液适量, 加水制成每1 mL中约含上述各物质5 μg的溶液, 作为对照品溶液。
供试品溶液  取本品作为供试品溶液。
强制降解实验溶液制备
色氨酸储备溶液  精密称取色氨酸原料药140 mg, 置10 mL量瓶中, 加水使溶解并稀释至刻度, 摇匀, 即得。
强酸破坏溶液  取色氨酸储备溶液1 mL, 置具塞试管中, 加1 mol·L-1盐酸溶液1 mL混匀, 室温下放置7天后, 加1 mol·L-1氢氧化钠溶液1 mL中和, 用水转移至10 mL量瓶中并稀释至刻度, 摇匀, 即得。
强碱破坏溶液  取色氨酸储备溶液1 mL, 置具塞试管中, 加1 mol·L-1氢氧化钠溶液1 mL混匀, 室温下放置7天后, 加1 mol·L-1盐酸溶液1 mL中和, 用水转移至10 mL量瓶中并稀释至刻度, 摇匀, 即得。
氧化破坏溶液  取色氨酸储备溶液1 mL, 置具塞试管中, 加3%过氧化氢溶液1 mL混匀, 密封, 置80 ℃水浴放置2 h, 取出放冷, 用水转移至10 mL量瓶中并稀释至刻度, 摇匀, 即得。
强光破坏溶液  取色氨酸储备溶液1 mL, 置10 mL透明量瓶中, 在光照强度为4 500 ± 500 lx光源下、紫外灯254和366 nm下交替放置8天, 加水使溶解并稀释至刻度, 摇匀, 即得。
高温破坏溶液  取色氨酸储备溶液1 mL, 置顶空瓶中, 轧盖密封, 置高压蒸汽灭菌锅(121 ℃) 放置99 min, 取出放冷, 用水转移至10 mL量瓶中并稀释至刻度, 摇匀, 即得。
方法学考察
专属性  取空白溶剂(水)、空白阴性原辅料(处方中除色氨酸外的其他氨基酸及辅料) 溶液、对照品溶液、供试品溶液、各强制降解实验溶液, 照一维液相色谱条件实验, 记录色谱图, 考察分析方法的专属性。
线性范围  精密量取各对照品储备液适量, 加水定量稀释制成每1 mL中含色氨酸和各杂质对照品分别约为0.02、0.03、0.2、0.5、1、2、5、8、10、16.7、25 µg的系列对照品溶液, 照HPLC法色谱条件实验, 以峰面积(A) 为纵坐标, 浓度(C) 为横坐标, 进行线性回归。
检测限和定量限  精密量取各对照品储备液适量, 加水逐级稀释后照HPLC法色谱条件进样分析, 当稀释至信噪比约为3时计算其检测限, 信噪比约为10时计算其定量限。
精密度  精密量取对照品溶液20 μL, 注入液相色谱仪, 连续进样6次, 记录色谱图, 计算对照品溶液中色氨酸和各杂质色谱峰峰面积的RSD。
重复性  平行制备供试品溶液6份, 精密量取20 μL, 注入液相色谱仪, 记录色谱图, 计算供试品溶液中各杂质色谱峰峰面积的RSD。
准确度  精密量取各对照品储备液5 mL, 置50 mL量瓶中, 加水稀释至刻度, 摇匀, 精密量取1.0、2.0和3.0 mL, 置已称量空白阴性原辅料(以最大处方量称取除色氨酸外的所有原辅料, 并按处方比例、以处方量的1/100进行称量) 的10 mL量瓶中, 加水使溶解并稀释至刻度, 摇匀, 各平行做3份, 照HPLC法色谱条件进样分析, 以标准曲线法测定并计算回收率。
稳定性  取对照品溶液各20 μL, 于0、3、6、12、18、24 h分别进样分析, 记录色谱图, 计算对照品溶液中色氨酸和各杂质色谱峰峰面积的RSD。取供试品溶液各20 μL, 于0、1、3、5、6、9 h分别进样分析, 记录色谱图, 计算供试品溶液中各杂质色谱峰峰面积的RSD。
耐用性  取对照品溶液和供试品溶液, 在HPLC法色谱条件基础上, 分别微调下列各色谱参数: 同品牌同类型不同序列号色谱柱、不同流速(±0.1 mL·min-1)、不同柱温(±2 ℃), 分别进样分析, 考察各杂质检出情况。
样品测定  按照建立的色氨酸有关物质检查方法对收集到的来自国内7个厂家共135批样品进行了检测分析, 采用杂质对照品外标法计算已知杂质量, 采用不加校正因子的主成分外标法计算未知杂质量。
结果
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1　方法学验证
1.1　专属性
专属性结果表明, 溶剂及空白阴性原辅料不影响色氨酸有关物质的测定, 且色氨酸各已知杂质色谱峰与周围化合物色谱峰均能达到基线分离, 其中EP杂质B色谱峰1受到空白阴性原辅料峰的干扰, 因此EP杂质B色谱峰以峰2计, 色谱图见图1。
强制降解实验结果表明, 色氨酸原料在各降解条件下产生的主要降解产物为EP杂质B、EP杂质D、EP杂质C、EP杂质G; 色氨酸在氧化和光照条件下稳定性较差, 在高温条件下略不稳定, 在强酸、强碱条件下较稳定。降解产生的各杂质之间、杂质与主成分之间、杂质与阴性原辅料之间均能达到基线分离。强制降解实验前后供试品溶液中主峰面积和各杂质峰峰面积总和在95%~103%之间, 物料基本守恒。
1.2　未知杂质结构确证
供试品溶液中均检出了杂质S, 且该杂质的质量相对较高, 但在色氨酸原料强制降解供试品溶液中均未检出杂质S, 照二维液相色谱条件和质谱条件实验, 对杂质S进行定性分析。测得其[M+H]+的准确离子质量m/z 285.053 5, [2M+H]+的准确离子质量m/z 569.097 8, 见图2。经软件检索, 该质量数匹配度最高的分子式为C11H12N2O5S, 得分为95.55。以m/z 285.053 5作为母离子, 做子离子扫描, 得到主要特征碎片离子m/z 205.096 5、188.070 2、146.060 0、118.064 8, 见图3。推断杂质S为色氨酸和抗氧剂(亚硫酸氢钠或焦亚硫酸钠)反应产生的新杂质(2-亚硫酸氢色氨酸), 推测其质谱裂解规律见图4。
按处方比例配制色氨酸原料与辅料(亚硫酸氢钠或焦亚硫酸钠) 的样品溶液, 分别在高温、强光条件下开展强制降解实验。结果显示, 两种条件下均产生大量杂质S, 且强光条件下杂质S的生成量远高于高温条件, 进一步证实杂质S是色氨酸与亚硫酸氢钠或焦亚硫酸钠反应生成的降解杂质。H厂家根据这一反应制备纯化出了杂质S对照品, 并进行了结构确证, 1H NMR (400 MHz, CD3OD) δ 3.545~3.601 (dd, 1H), 3.677~3.727 (dd, 1H), 4.220~4.250 (m, 1H), 7.055~7.092 (m, 1H), 7.181~7.219 (m, 1H), 7.396~7.416 (d, 1H), 7.594~7.614 (d, 1H)。该对照品用于本研究的开展, 其保留时间和质谱信息均与样品中杂质S的结果一致。
1.3　线性范围、检测限和定量限
色氨酸和各已知杂质的线性范围、线性回归方程、相关系数、检测限和定量限见表1。结果表明, 色氨酸和各已知杂质在线性浓度范围内线性关系良好, 方法的灵敏度能够满足色氨酸有关物质的检测要求。
1.4　精密度
精密量取对照品溶液20 μL, 连续进样6次, 记录色谱图, EP杂质B、EP杂质D、EP杂质C、EP杂质G、杂质S、色氨酸和USP杂质B色谱峰面积RSD (n = 6) 分别为0.21%、0.12%、0.23%、0.67%、0.14%、0.20%、0.28%, 保留时间RSD (n = 6) 分别为0.11%、0.17%、0.14%、0.19%、0.04%、0.11%、0.01%, 表明仪器精密度良好。
1.5　重复性
制备小儿复方氨基酸注射液(19AA-Ⅰ, 批号: K1701031) 供试品溶液6份, 照HPLC法色谱条件实验, 采用杂质对照品外标法计算已知杂质量, 采用不加校正因子的主成分外标法计算未知杂质量, 样品中EP杂质D和USP杂质B均未检出, EP杂质B、EP杂质C、EP杂质G、杂质S、未知最大单个杂质和总杂质的平均含量分别为0.017%、0.124%、0.111%、0.352%、0.036%和0.703%, RSD分别为4.1%、4.8%、2.9%、3.9%、4.3%和3.6% (n = 6)。
1.6　准确度
照HPLC法色谱条件实验, 以标准曲线法测定并计算回收率, EP杂质B、EP杂质D、EP杂质C、EP杂质G、杂质S、色氨酸、USP杂质B的平均回收率分别为101.0%、98.3%、99.6%、93.1%、98.9%、98.0%和97.5%, RSD分别为1.0%、0.5%、0.8%、1.5%、0.4%、0.5%和0.5% (n = 9)。
1.7　稳定性
对照品溶液在自动进样器(设置温度15 ℃) 中, 12 h进样结果显示, EP杂质B、EP杂质D、EP杂质C、EP杂质G、杂质S、色氨酸、USP杂质B峰面积的RSD值分别为1.5%、1.7%、1.3%、1.7%、0.8%、1.5%和1.1%。供试品溶液在自动进样器(设置温度15 ℃) 中, 5 h进样结果显示, 样品中EP杂质D和USP杂质B均未检出, EP杂质B、EP杂质C、EP杂质G、杂质S、未知最大单个杂质峰面积的RSD值分别为0.8%、3.6%、4.8%、0.3%和1.9%。结果表明, 对照品溶液在自动进样器中放置12 h稳定, 供试品溶液在自动进样器中放置5 h稳定。
1.8　耐用性
耐用性试验结果表明, 更换色谱柱及流速和柱温发生微小变化时, 除保留时间稍有变化外, 各杂质出峰顺序不变, 各杂质色谱峰与周围化合物色谱峰均能达到基线分离, 检出杂质个数、杂质量均未发生明显变化, 方法的耐用性良好。
2　样品测定
对收集到的7个厂家共135批样品[其中小儿复方氨基酸注射液(18AA-Ⅰ) 来源于L、J、T、C厂家共计83批, 小儿复方氨基酸注射液(18AA-Ⅱ) 来源于S厂家共计8批, 小儿复方氨基酸注射液(19AA-Ⅰ) 来源于Q、H厂家共计44批] 进行了有关物质检查。参照注册标准YBH01482017有关物质项下色氨酸杂质总量的限度值2.0%, 结合样品测定结果, 确定该品种杂质S不得过1.2%, 其他单个杂质不得过1.0%, 杂质总量不得过2.0%。结果样品中均未检出EP杂质D和USP杂质B, 有6批样品不符合规定, 合格率95.6%, 见图5。
结果显示, 厂家C生产的100 mL玻璃输液瓶包装小儿复方氨基酸注射液(18AA-Ⅰ) 中色氨酸杂质量较高, 且显著高于该厂家20 mL安瓿瓶包装的同类产品。此外, 厂家C的100 mL规格产品与厂家S的产品在不同批次间的色氨酸杂质量均存在较大差异, 提示相关产品的生产工艺关键参数控制存在一定的不稳定性。
讨论
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本研究开发了一种2D-LC-Q-TOF/MS分析方法, 对小儿复方氨基酸注射液(18AA-Ⅰ、18AA-Ⅱ、19AA-Ⅰ) 中色氨酸降解产生的有关物质进行定性分析, 并首次鉴定出色氨酸与抗氧剂辅料亚硫酸氢钠或焦亚硫酸钠发生相互作用产生的一个新杂质, 本研究中命名为杂质S。亚硫酸氢钠或焦亚硫酸钠在光或热的作用下发生反应生成亚硫酸氢自由基, 而色氨酸是一种含有吲哚环结构的氨基酸, 亲电取代先发生在富π电子的吡咯环上, 优先发生的位置在3位, 当吲哚环的3位被占据时, 取代就发生在2位, 当这两个位置都被占据时, 取代才发生在苯环上[9-13]。因此亚硫酸氢自由基进攻色氨酸吲哚环结构的2位, 发生取代反应生成2-亚硫酸氢色氨酸。
亚硫酸氢钠和焦亚硫酸钠作为抗氧剂, 在本产品中应该起到抑制色氨酸氧化降解的作用, 但已有研究表明EP杂质B和EP杂质C的量会随着焦亚硫酸钠含量的增加而明显升高[14], 且在本研究中发现上述抗氧剂会和主成分色氨酸发生反应产生新的杂质, 因此需要考虑上述抗氧剂在本产品中添加的必要性, 进一步优化生产工艺, 提高产品质量。
本研究中发现安瓿包装的样品总体杂质量较低, 批内杂质分布较均匀; 充氮密封性好的输液瓶包装样品比未充氮的输液瓶包装样品中杂质量低, 杂质分布较均匀。厂家C的100 mL规格产品和厂家Q的产品均为玻璃输液瓶包装, 且仅抽真空, 没充氮, 杂质量较高。厂家S的产品杂质量和生产后流通时间长短呈显著正相关, 批内均匀性较差, 推测是瓶内有残余氧, 每瓶残氧量不同, 又无独立外包装, 没有遮光处理, 导致各瓶杂质量差异大; 且玻璃输液瓶内不断会有空气进入进行气体交换, 导致流通时间长的样品杂质量较高。若本产品采用玻璃输液瓶包装, 建议抽真空充氮, 保持瓶内微正压的状态, 并加独立外包装避光, 加强密封性控制, 可以有效抑制杂质的产生, 保证产品质量。

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1
Wang P, Huang ZS. Determination of antioxidant sodium bisulfite in pediatric compound amino acid injection by ion chromatography [J]. Tianjin Pharm (天津药学), 2020, 32: 22-24.
2
Lou YM, Lin M, Cheng XL. Preliminary research of an HPLC method for the related substances in compound amino acid injection (18AA) [J]. Drug Stand China (中国药品标准), 2019, 20: 37-41.
3
Zhu HY, Jiang G, Guo ZY, et al. Determination of related substances produced by glutamate degradation in pediatric compound amino acid injection by HPLC [J]. West China J Pharm Sci (华西药学杂志), 2021, 36: 579-582.
4
Jiang G, Zhu HY, Guo ZY, et al. Determination of related substances of methionine in pediatric compound amino acid injection [J]. West China J Pharm Sci (华西药学杂志), 2022, 37: 440-443.
5
Shao YH, Fan JW, Ding M. The relation between stability of tryptophan and residual oxygen in compound amino acid injection [J]. Qilu Pharm Aff (齐鲁药事), 2010, 29: 497-499.
6
European Pharmacopoeia Committee. European Pharmacopoeia (欧洲药典) [S]. 10.0 Ed. France: European Directorate for the Quality of Medicine & Healthcare, 2020: 4115-4117.
7
Jin W, Jiang WM, Liu Q, et al. Study on the structure of an unknown impurity in carboplatin injection and the relationship with the excipient [J]. Acta Pharm Sin (药学学报), 2018, 53: 604-608.
8
Liu JM, Lu YT, Song M, et al. Structural identification of the related substances in phloroglucinol injection by two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry [J]. Acta Pharm Sin (药学学报), 2024, 59: 202-213.
9
Xing JD. Study on the Synthesis of Indole (吲哚合成工艺的研究) [D]. Tianjin: Tianjin University, 2006.
10
Ahmad T, Khan S, Ullah N. Recent advances in the catalytic asymmetric friedel-crafts reactions of indoles [J]. ACS Omega, 2022, 7: 35446-35485.
11
Deka B, Deb ML, Baruah PK. Recent advances on the C2-functionalization of indole via umpolung [J]. Top Curr Chem, 2022, 378: 22.
12
Dalpozzo R. Strategies for the asymmetric functionalization of indoles: an update [J]. Chem Soc Rev, 2015, 44: 742-778.
13
Shah TA, De PB, Pradhan S, et al. Transition-metal-catalyzed site-selective C7-functionalization of indoles: advancement and future prospects [J]. Chem Commun, 2019, 55: 572-587.
14
Guo L, Zhou CM, Li H, et al. Determination of related substances of tryptophan in compound amino acid injection (18AA-Ⅱ) [J]. Chin J Pharm (中国医药工业杂志), 2021, 52: 390-394.
2026年第61卷第2期
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doi: 10.16438/j.0513-4870.2025-1016
  • 接收时间：2025-08-26
  • 首发时间：2026-09-21
  • 出版时间：2026-02-12
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  • 收稿日期：2025-08-26
  • 修回日期：2025-11-21
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    四川省药品检验研究院, 四川 成都 611731

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朱恒怡, Tel: 86-28-64020254, E-mail:
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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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