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Article(id=1200147770922333119, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147768326062257, articleNumber=1001-2494(2024)09-0834-06, orderNo=null, doi=10.11669/cpj.2024.09.009, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1692547200000, receivedDateStr=2023-08-21, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1764067126254, onlineDateStr=2025-11-25, pubDate=1715097600000, pubDateStr=2024-05-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764067126254, onlineIssueDateStr=2025-11-25, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764067126254, creator=13701087609, updateTime=1764067126254, updator=13701087609, issue=Issue{id=1200147768326062257, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='9', pageStart='757', pageEnd='856', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764067125636, creator=13701087609, updateTime=1764067301065, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200148504178950495, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147768326062257, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200148504178950496, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147768326062257, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=834, endPage=839, ext={EN=ArticleExt(id=1200147771287237580, articleId=1200147770922333119, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Determination of Main Carbohydrate Residues in Dextran 40 by HPLC-RID Method, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To establish a high performance liquid chromatography-refractive index detector method for the determination of main potential carbohydrate residues fructose and sucrose concentration in dextran 40 raw materials from different of production processes, analyze the differences in carbohydrate residues in dextran 40 produced by different manufactures, and provide a reference for the quality evaluation of related drugs and the formulation or edit of national drug standards. METHODS Isocratic elution was performed on a ZORBAX-NH2 column. Mobile phase consisted of 75% acetonitrile and 25% water at a flow rate of 1.0 mL·min-1. RID was used as detector. The detector temperature and column temperature was maintained at 40 ℃ and the injection volume was 50 μL. RESULTS Sucrose was not detected in all batches of dextran 40. Fructose residue could only be detected in dextran 40 which using alcohol precipitation production process, and the content was 0.005%-0.14%. No fructose residue was detected in the dextran 40 of manufacturer B using membrane filtration method. CONCLUSION The HPLC-RID method is established to determine the content of fructose and sucrose in dextran 40. The method has strong specificity, high sensitivity, good stability and simple operation. The amount of fructose residual in dextran 40 produced by different processes varies greatly. The fructose residual in the raw material of dextran 40 obtained by membrane filtration is significantly lower than that by alcohol precipitation, it is necessary to control the fructose residue in the quality standard.

, correspAuthors=Qiaoqiao HUANG, Jinqi ZHENG, 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=Shenggu XIE, Zhuyu JIN, Xiao SUN, Qiaoqiao HUANG, Jinqi ZHENG), CN=ArticleExt(id=1200147772386145274, articleId=1200147770922333119, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=HPLC-RID法测定不同来源右旋糖酐40中主要糖类残留物含量, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 建立高效液相色谱-示差折光(HPLC-RID)法,测定不同生产工艺的右旋糖酐40原料药中主要的可能发酵残留物(果糖、蔗糖)的含量,并结合不同的生产工艺,对右旋糖酐40中糖类残留物的差异原因进行分析,为相关药品的质量评价及国家药品标准的制修订提供参考依据。方法 采用ZORBAX-NH2色谱柱,以乙腈-水(75∶25)为流动相,流速1.0 mL·min-1,RID为检测器,温度设置为40 ℃,柱温40 ℃,进样体积50 μL。结果 所有批次右旋糖酐40原料药均未检出蔗糖,采用醇沉法生产工艺的右旋糖酐40中果糖残留量为0.005%~0.14%;采用膜过滤法生产工艺的右旋糖酐40未检出果糖残留。结论 本研究建立的HPLC-RID法能有效测定右旋糖酐40中果糖和蔗糖残留量,方法专属性强、灵敏度高、稳定性好,简单易操作。不同工艺生产的右旋糖酐40中果糖残留量差异较大,采用膜过滤法制得的右旋糖酐40中果糖残留量显著低于醇沉法,因此有必要在质量标准中对果糖残留量予以控制。

, correspAuthors=黄巧巧, 郑金琪, authorNote=null, correspAuthorsNote=
*黄巧巧,女,副主任药师 研究方向:药品质量控制、医疗器械技术审评 Tel: (0571) 86459413;
郑金琪,男,主任药师 研究方向:药品质量控制 Tel:(0571) 86459413
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谢升谷,男,副主任药师 研究方向:药品质量控制

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谢升谷,男,副主任药师 研究方向:药品质量控制

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谢升谷,男,副主任药师 研究方向:药品质量控制

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J Chem Technol Biotechnol, 2005, 80(8):845-860., articleTitle=Leuconostoc dextransucrase and dextran: production, properties and applications, refAbstract=null), Reference(id=1200147778908287221, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, doi=null, pmid=null, pmcid=null, year=2013, volume=10, issue=9, pageStart=40, pageEnd=null, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=CHEN X M, JIN G D, DU W W, journalName=J North Pharm(北方药学), refType=null, unstructuredReference=CHEN X M, JIN G D, DU W W. Adverse reaction report of low molecular dextran injection[J]. 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Guangxi Med J(广西医学), 2004, 26(9):1367-1368., articleTitle=Analysis of adverse reactions of low molecular dextran in 15 cases, refAbstract=null), Reference(id=1200147779172528382, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, doi=null, pmid=null, pmcid=null, year=2023, volume=38, issue=2, pageStart=710, pageEnd=718, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=XOU Y X, WANG Q X, QI D M, journalName=China J Tradit Chin Med Pharm(中华中医药杂志), refType=null, unstructuredReference=XOU Y X, WANG Q X, QI D M, et al. Research progress on qualitative and quantitative methods of carbohydrate extracts from traditional Chinese medicine[J]. 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A-system suitability solution; B-reference solution; C-test solution; D-blank solution.

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A-系统适用性溶液;B-对照品溶液;C-供试品溶液;D-空白溶液。

, figureFileSmall=G8/8ML8sz0mThWlynupPeQ==, figureFileBig=sEo2PvbKzNS0mUlMCFqsZg==, tableContent=null), ArticleFig(id=1200147776165212320, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, language=EN, label=Fig.2, caption=Production process diagram of dextran 40 alcohol precipitation method and membrane filter method, figureFileSmall=vttl0fRihJwd2waoNyJ1Og==, figureFileBig=j4aRhq8S052MHlZ9msAMpw==, tableContent=null), ArticleFig(id=1200147776249098406, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, language=CN, label=图2, caption=右旋糖酐40醇沉法和膜过滤法生产工艺图, figureFileSmall=vttl0fRihJwd2waoNyJ1Og==, figureFileBig=j4aRhq8S052MHlZ9msAMpw==, tableContent=null), ArticleFig(id=1200147776337178792, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, language=EN, label=Tab.1, caption=

Experimental results of recovery of fructose and sucrose

, figureFileSmall=null, figureFileBig=null, tableContent=
Substance Concentration
level/%		 m(Added)
/mg		 m(Found)
/mg		 Recovery
/%		 Average
recovery/%		 RSD
/%
Fructose 150 1.51 1.53 101.8 100.0 1.6
1.51 1.54
1.51 1.54
100 1.01 1.01 100.3
1.01 1.01
1.01 1.02
50 0.50 0.49 98.0
0.50 0.49
0.50 0.49
10 0.10 0.10 100.0
0.10 0.10
0.10 0.10
Sucrose 150 1.51 1.51 100.4 100.0 0.5
1.51 1.53
1.51 1.51
100 1.00 1.01 100.3
1.00 1.02
1.00 0.98
50 0.50 0.49 99.3
0.50 0.51
0.50 0.49
10 0.10 0.10 100.0
0.10 0.10
0.10 0.10
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果糖、蔗糖的回收率试验结果

, figureFileSmall=null, figureFileBig=null, tableContent=
Substance Concentration
level/%		 m(Added)
/mg		 m(Found)
/mg		 Recovery
/%		 Average
recovery/%		 RSD
/%
Fructose 150 1.51 1.53 101.8 100.0 1.6
1.51 1.54
1.51 1.54
100 1.01 1.01 100.3
1.01 1.01
1.01 1.02
50 0.50 0.49 98.0
0.50 0.49
0.50 0.49
10 0.10 0.10 100.0
0.10 0.10
0.10 0.10
Sucrose 150 1.51 1.51 100.4 100.0 0.5
1.51 1.53
1.51 1.51
100 1.00 1.01 100.3
1.00 1.02
1.00 0.98
50 0.50 0.49 99.3
0.50 0.51
0.50 0.49
10 0.10 0.10 100.0
0.10 0.10
0.10 0.10
), ArticleFig(id=1200147776500756657, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, language=EN, label=Tab.2, caption=

Robustness test chromatography conditions of HPLC-RID method

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Parameter Condition 1 Condition 2
Column Agilent ZORBAX-NH2(4.6 mm×250 mm,5 μm) Welch Ultimate XB-NH2(4.6 mm×250 mm,5 μm)
RID detector temperature/℃ 38 42
Mobile phase(volume ratio) CH3CN-H2O(76∶24) CH3CN-H2O(74∶26)
Column temperature/℃ 38 42
Flow rate/mL·min-1 0.9 1.1
), ArticleFig(id=1200147776605614260, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, language=CN, label=表2, caption=

HPLC-RID法耐用性试验色谱条件

, figureFileSmall=null, figureFileBig=null, tableContent=
Parameter Condition 1 Condition 2
Column Agilent ZORBAX-NH2(4.6 mm×250 mm,5 μm) Welch Ultimate XB-NH2(4.6 mm×250 mm,5 μm)
RID detector temperature/℃ 38 42
Mobile phase(volume ratio) CH3CN-H2O(76∶24) CH3CN-H2O(74∶26)
Column temperature/℃ 38 42
Flow rate/mL·min-1 0.9 1.1
), ArticleFig(id=1200147776760803514, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147770922333119, language=EN, label=Tab.3, caption=

Summary of determination results for dextran 40 samples

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Manufacturer Production
process		 Lot
number		 Fructose
content/%		 Sucrose
content/%
A Alcohol precipitation method 1 0.11% <LOD
2 0.12% <LOD
3 0.14% <LOD
B Membrane filter method 4 <LOD <LOD
5 <LOD <LOD
6 <LOD <LOD
C Alcohol precipitation method 7 0.006% <LOD
8 0.005% <LOD
9 0.006% <LOD
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右旋糖酐40样品测定结果汇总表

, figureFileSmall=null, figureFileBig=null, tableContent=
Manufacturer Production
process		 Lot
number		 Fructose
content/%		 Sucrose
content/%
A Alcohol precipitation method 1 0.11% <LOD
2 0.12% <LOD
3 0.14% <LOD
B Membrane filter method 4 <LOD <LOD
5 <LOD <LOD
6 <LOD <LOD
C Alcohol precipitation method 7 0.006% <LOD
8 0.005% <LOD
9 0.006% <LOD
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HPLC-RID法测定不同来源右旋糖酐40中主要糖类残留物含量
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谢升谷 1 , 金朱雨 1, 2 , 孙逍 1 , 黄巧巧 3, * , 郑金琪 1, *
中国药学杂志 | 论著 2024,59(9): 834-839
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中国药学杂志 | 论著 2024, 59(9): 834-839
HPLC-RID法测定不同来源右旋糖酐40中主要糖类残留物含量
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谢升谷1, 金朱雨1, 2, 孙逍1, 黄巧巧3, *, 郑金琪1, *
作者信息
  • 1 浙江省食品药品检验研究院, 国家药品监督管理局仿制药评价关键技术重点实验室,浙江省药品接触材料质量控制研究重点实验室, 杭州 310052
  • 2 中国药科大学, 南京 211198
  • 3 浙江省医疗器械审评中心, 杭州 310001

    • 谢升谷,男,副主任药师 研究方向:药品质量控制

通讯作者:

*黄巧巧,女,副主任药师 研究方向:药品质量控制、医疗器械技术审评 Tel: (0571) 86459413;
郑金琪,男,主任药师 研究方向:药品质量控制 Tel:(0571) 86459413
Determination of Main Carbohydrate Residues in Dextran 40 by HPLC-RID Method
Shenggu XIE1, Zhuyu JIN1, 2, Xiao SUN1, Qiaoqiao HUANG3, *, Jinqi ZHENG1, *
Affiliations
  • 1 NMPA Key Laboratory for Core Technology of Generic Drug Evaluation, Zhejiang Institute for Food and Drug Control, Hangzhou 310052, China
  • 2 China Pharmaceutical University, Nanjing 211198, China
  • 3 Zhejiang Medical Device Evaluation Center, Hangzhou 310001, China
出版时间: 2024-05-08 doi: 10.11669/cpj.2024.09.009
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摘要
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目的 建立高效液相色谱-示差折光(HPLC-RID)法,测定不同生产工艺的右旋糖酐40原料药中主要的可能发酵残留物(果糖、蔗糖)的含量,并结合不同的生产工艺,对右旋糖酐40中糖类残留物的差异原因进行分析,为相关药品的质量评价及国家药品标准的制修订提供参考依据。方法 采用ZORBAX-NH2色谱柱,以乙腈-水(75∶25)为流动相,流速1.0 mL·min-1,RID为检测器,温度设置为40 ℃,柱温40 ℃,进样体积50 μL。结果 所有批次右旋糖酐40原料药均未检出蔗糖,采用醇沉法生产工艺的右旋糖酐40中果糖残留量为0.005%~0.14%;采用膜过滤法生产工艺的右旋糖酐40未检出果糖残留。结论 本研究建立的HPLC-RID法能有效测定右旋糖酐40中果糖和蔗糖残留量,方法专属性强、灵敏度高、稳定性好,简单易操作。不同工艺生产的右旋糖酐40中果糖残留量差异较大,采用膜过滤法制得的右旋糖酐40中果糖残留量显著低于醇沉法,因此有必要在质量标准中对果糖残留量予以控制。

右旋糖酐40  /  液相色谱-示差折光检测器  /  生产工艺  /  质量控制  /  果糖残留量

OBJECTIVE To establish a high performance liquid chromatography-refractive index detector method for the determination of main potential carbohydrate residues fructose and sucrose concentration in dextran 40 raw materials from different of production processes, analyze the differences in carbohydrate residues in dextran 40 produced by different manufactures, and provide a reference for the quality evaluation of related drugs and the formulation or edit of national drug standards. METHODS Isocratic elution was performed on a ZORBAX-NH2 column. Mobile phase consisted of 75% acetonitrile and 25% water at a flow rate of 1.0 mL·min-1. RID was used as detector. The detector temperature and column temperature was maintained at 40 ℃ and the injection volume was 50 μL. RESULTS Sucrose was not detected in all batches of dextran 40. Fructose residue could only be detected in dextran 40 which using alcohol precipitation production process, and the content was 0.005%-0.14%. No fructose residue was detected in the dextran 40 of manufacturer B using membrane filtration method. CONCLUSION The HPLC-RID method is established to determine the content of fructose and sucrose in dextran 40. The method has strong specificity, high sensitivity, good stability and simple operation. The amount of fructose residual in dextran 40 produced by different processes varies greatly. The fructose residual in the raw material of dextran 40 obtained by membrane filtration is significantly lower than that by alcohol precipitation, it is necessary to control the fructose residue in the quality standard.

Dextran 40  /  HPLC-RID  /  production process  /  quality control  /  fructose residue
谢升谷, 金朱雨, 孙逍, 黄巧巧, 郑金琪. HPLC-RID法测定不同来源右旋糖酐40中主要糖类残留物含量. 中国药学杂志, 2024 , 59 (9) : 834 -839 . DOI: 10.11669/cpj.2024.09.009
Shenggu XIE, Zhuyu JIN, Xiao SUN, Qiaoqiao HUANG, Jinqi ZHENG. Determination of Main Carbohydrate Residues in Dextran 40 by HPLC-RID Method[J]. Chinese Pharmaceutical Journal, 2024 , 59 (9) : 834 -839 . DOI: 10.11669/cpj.2024.09.009
正文
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右旋糖酐类药物均由蔗糖经肠膜状明串珠菌L.M-1226号菌(Leuconostoc mesenteroides)发酵后生成的高分子葡萄糖聚合物,再进一步精制而得[1-2],根据相对分子质量及其分布的差异可划分为右旋糖酐70、40、20等系列品种[3-4]。蔗糖发酵获得的右旋糖酐粗粉经酸水解、分离纯化并精制后获得右旋糖酐原料药。目前主流的分离纯化工艺有2种,分别为醇沉法和膜过滤法[3-4]。右旋糖酐40属于低相对分子质量右旋糖酐,经静脉注射后可提高血液的胶体渗透压从而扩充血容量、维持血压[5-6]。目前在医药临床领域应用最为广泛的是右旋糖酐40葡萄糖注射液,主要用于增加血浆容量,以抗休克为主[6-7]。
以酶发酵法催化蔗糖制备右旋糖酐的反应体系中除了产物右旋糖酐外,还可能含有起始底物蔗糖、副产物果糖等糖类发酵残留物[8]。国内外现行质量标准,如《美国药典》(USP)现行版、《欧洲药典》(EP)11.0、2020年版《中国药典》等,均未对右旋糖酐类药物(如右旋糖酐70、40、20等)相关残留物进行控制。因此,为全面评估该类药物的质量及相关风险,有必要建立合适的分析方法对右旋糖酐中主要可能的糖类残留物进行分析。本研究以临床使用较为广泛的右旋糖酐40为研究对象,样品来源于国家药品监督管理局国家药品计划抽验项目,共收集到4家企业生产的原料药。采用高效液相色谱-示差折光(HPLC-RID)法,通过优化前处理过程及相关色谱条件,对原料药中的发酵副产物果糖和起始物料蔗糖进行测定,并结合不同的生产工艺进行分析,为该品种药物的工艺开发、质量评价和标准制修订提供参考。
1 材料
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1.1 主要仪器
Agilent 1260型高效液相色谱仪(配置RID检测器,美国Agilent公司);XPE205型电子天平(瑞士梅特勒-托利多公司);Milli-Q Advantage A10型超纯水系统(法国Millipore公司);JAC-5020型超声波清洗器(韩国科导公司);CT15RE型微量高速离心机(日本Hitachi公司)。
1.2 标准品、耗材及原料药
果糖对照品(批号:100231-202008)、蔗糖对照品(批号:111507-202105)、葡萄糖对照品(批号:110833-201908)(中国食品药品检定研究院);乙腈为色谱级,超纯水由实验室自制。
右旋糖酐40原料药共12批,分别生产自4家企业,每家企业3批。样品均来源于国家药品监督管理局国家药品评价性监督抽验项目,样品涉及国内各主要原料药生产单位,具有一定的代表性。
2 方法与结果
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2.1 色谱条件
采用Agilent公司ZORBAX-NH2柱(4.6 mm×250 mm,5 μm),RID检测器温度设置为40 ℃,流动相为乙腈-水(75∶25),流速1.0 mL·min-1,柱温40 ℃,进样量50 μL。
2.2 溶液的制备
2.2.1 对照品储备液
精密称取果糖、蔗糖、葡萄糖对照品各50 mg,分别置于5 mL量瓶中,用乙腈-水(50∶50)溶解并稀释至刻度,摇匀,即得对照品储备液,其质量浓度均10 mg·mL-1。
2.2.2 系统适用性溶液及对照品溶液
精密量取“2.2.1”项下各对照品储备液、果糖和蔗糖对照品储备液各1.0 mL,分别置于10 mL量瓶中,加乙腈-水(50∶50)稀释至刻度,摇匀,即得系统适用性溶液及混合对照品溶液(果糖、蔗糖质量浓度均为1.0 mg·mL-1)。
2.2.3 供试品溶液
精密称取右旋糖酐40原料药1.0 g,加水5.0 mL,加热超声30 min后,加入5.0 mL乙腈混合均匀,以10 000 r·min-1的速度离心10 min,取上清液作为供试品溶液。
2.3 方法学考察
2.3.1 线性关系考察
取“2.2.1”项下果糖、蔗糖对照品储备液逐级稀释,稀释制成质量浓度分别为0.04、0.1、0.2、0.5、1.0、1.5 mg·mL-1的系列对照品溶液。按“2.1”项下色谱条件进样分析,记录峰面积。以各对照品的质量浓度ρ(mg·mL-1)为横坐标、峰面积Y为纵坐标进行线性回归,绘制标准曲线,得到回归方程Y果糖=477 382ρ+2 727.9,r=0.999 9;Y蔗糖=491 431ρ+1 471.3,r=0.999 9,说明果糖质量浓度在0.04~1.5 mg·mL-1之间、蔗糖质量浓度在0.04~1.5 mg·mL-1之间线性关系良好。
2.3.2 专属性考察
分别精密吸取系统适用性溶液、对照品溶液、供试品溶液及空白溶液乙腈-水(50∶50),按照“2.1”项下色谱条件进样测定,记录色谱图(图1)。试验结果表明,果糖、蔗糖与葡萄糖分离度较好,果糖与蔗糖对应出峰位置无干扰,表明该法专属性良好。
2.3.3 定量限与检测限
精密量取“2.2.3”项下的对照品溶液,用乙腈-水(50∶50)逐级稀释,精密量取50 μL,注入色谱仪进样测定,计算各色谱峰的信噪比,以信噪比(S/N)约为3时的浓度为检测限,S/N约为10时的浓度为定量限。测得果糖的定量限(S/N=15.2)为0.01 mg·mL-1;检测限(S/N=3.8)为0.004 mg·mL-1;蔗糖的定量限(S/N=11.6)为0.01 mg·mL-1;检测限(S/N=3.8)为0.004 mg·mL-1。
2.3.4 重复性试验
选取同一批次右旋糖酐40原料药,按“2.2.4”项下方法平行制备6份供试品溶液,按“2.1”项下色谱条件进样测定,计算同一样品中果糖、蔗糖的含量。果糖测定结果(n=6)平均值分别为0.11%,其RSD(n=6)值为0.7%;蔗糖均未检出,表明本方法的重复性良好。
2.3.5 稳定性试验
选取同一批右旋糖酐40原料药样品制备而成的供试品溶液和对照品溶液,分别于0、4、12、24、48 h按“2.1”项下色谱条件测定,结果供试品溶液中果糖峰面积RSD(n=45)为1.1%,蔗糖均未检出;对照品溶液中,果糖峰面积相对标准偏差(RSD)(n=45)为0.9%,蔗糖峰面积RSD(n=45)为1.2%;峰面积RSD值均小于2.0%(n=45),表明对照品溶液、供试品溶液在48 h内稳定性良好。
2.3.6 回收率试验
精密称取果糖、蔗糖对照品适量,用乙腈-水(50∶50)溶解并稀释制成浓度约为10 mg·mL-1的对照品储备液。精密称取右旋糖酐40原料药约1.0 g,分别加水3.5、4.0、4.5、4.9 mL,加热、超声使溶解后,分别精密量取混合储备液1.5、1.0、0.5、0.1 mL,混匀,再各自加入5 mL乙腈混合均匀,以10 000 r·min-1的速度离心10 min,取上清液分别作150%、100%、50%、10%回收率供试液。各浓度平行3份,按“2.1”项下色谱条件进行检测,计算加标回收率,结果见表1。
2.3.7 耐用性试验
分别采用不同型号色谱柱、流动相比例、柱温、流速、检测器温度等参数作耐用性考察,具体条件见表2,各条件下含量结果与标准条件比较,RSD小于2.0%,表明方法耐用性良好。
2.4 结果
按“2.1”项下色谱条件进行检测,按外标法进行计算,对12批次右旋糖酐40原料药的测定结果进行汇总(表3)。
3 讨论
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样品中果糖等糖类物质含量的测定方法很多,如蒸发光散射检测(ELSD)[9]、RID[10]、电雾式检测(CAD)[11]、质谱法[12]或柱前衍生法[13]等。其中柱前衍生法、质谱法相对灵敏度略高,但柱前衍生法存在操作繁琐和衍生不一定完全、质谱法存在仪器较昂贵等缺点,ELSD和CAD等则需载气辅助,因此选择使用相对较简单的RID检测器。但RID方法灵敏度往往略低,无法很好地满足右旋糖酐药物中糖类残留物质的检测要求。
为保证方法具有较高的灵敏度,本研究采用了加大供试品溶液浓度的处理方式,但是由于高浓度的右旋糖酐溶液具有一定的黏性,且易造成色谱柱的污染,故选择等体积的乙腈进行沉淀处理。利用右旋糖酐40在热水中易溶,在乙腈或乙腈-水混合溶液等溶剂中溶解性较差的特性,采用热水制备高浓度右旋糖酐40供试液,待全部溶解后加入等体积乙腈进行沉淀,将右旋糖酐40沉淀后离心,取上清液作为供试品溶液。此方法在保证大量的右旋糖酐40沉淀的同时,可使上清液澄清透明,便于进样分析。在优化前处理方法时,称取右旋糖酐40适量,加水5.0 mL,加热溶解后,比较分别加入2.5、5.0、7.5 mL乙腈混合均匀后制备的供试品溶液。加入2.5 mL乙腈处理离心后,制备的供试品溶液易发生浊光现象,较难制备澄清液体;加入7.5 mL乙腈处理离心后,制备的液体较澄清,但最后定容体积较5.0 mL变大,导致方法灵敏度下降。故最后选择5.0 mL乙腈进行供试品溶液的前处理。
为进一步提高方法灵敏度,将进样体积提高至50 μL,并对色谱条件进行优化,所建立的方法检测限为0.004 mg·mL-1,约相当于样品中残留量的0.004%,较好地满足了药品中有关物质控制的限量要求。本方法对流动相比例也进行了优化,在柱温及检测池温度为40 ℃时,将流动相乙腈-水比例分别设置为75∶25与80∶20,前者使系统适用性溶液中的各待测物分离度更好,且出峰更快,故选择乙腈-水75∶25作为流动相。
目前国内主流商业化右旋糖酐40原料药供应商共有3家,分别为国内供应商A、B、C。右旋糖酐40原料均由蔗糖经发酵后生成的高分子葡萄糖聚合物经处理精制而得。目前主流生产工艺有2种,分别为醇沉法和膜过滤法,具体工艺步骤见图2。蔗糖作为起始物料,经过多个不同阶段的纯化工艺后,其残余含量均未检出。果糖作为主要发酵副产物,其在发酵过程中与右旋糖酐等量产生,其在原料药中残留的概率相对较高。结合测定结果,可以看出采用膜过滤工艺的右旋糖酐40原料药中的果糖残留含量较低,而采用醇沉工艺的样品由于具体工艺(尤其是醇沉和精制步骤)参数的差异,不同企业测定结果差异较大,但是同一企业不同批次间差异较小。结合笔者前期不同工艺的相对分子质量与相对分子质量分布项目的质量差异研究[7],不同生产工艺药物的糖类残留量与药品质量存在一定的相关性。
4 结论
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小分子糖类极性大,在反相色谱柱上几乎没有保留,且没有紫外吸收[14-15]。本研究利用氨基柱为固定相,结合RID检测器,建立了右旋糖酐40原料药中主要糖类残留物果糖和蔗糖的测定方法。经验证,该方法的重复性、稳定性、回收率及线性关系均良好,方法简便、快速,能准确定量评价右旋糖酐40原料药中的残留糖类成分。
目前右旋糖酐制备主要是发酵后通过酸法或酶法等水解后,进行相对分子质量划分,再通过醇沉法或膜过滤法进行纯化获得,广泛应用于食品、医药等行业[16-17]。不同的生产纯化工艺获得的产品质量良莠不齐,且相较于其他领域,右旋糖酐40作为注射剂原料的产品,对产品的质量要求更为严格。而目前右旋糖酐类注射液的不良反应较多[18-20],现有多个药典质量标准中需控制的相对分子质量与相对分子质量分布等相关项目均无法很好地区分和表征不同来源右旋糖酐的内在质量差异[21]。作为注射用原料药,右旋糖酐系列原料药药典质量标准中均缺乏有关物质的控制,对工艺中的起始物料、发酵副产物、降解物质等相关杂质均缺乏合适的项目控制。本研究通过比较多个来源的原料,找到具有一定质量区分度的指标来表征右旋糖酐40的内在关键质量,可在一定程度上表征不同来源样品的纯度质量差异,同时也为相关药品国家质量标准的制修订提供了参考。
基金
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  • 国家药品抽验评价项目资助
  • 浙江省药品监督管理局科技计划资助(2021005)
  • 浙江省药品监督管理与产业发展研究会项目资助(ZYH2021001)
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2024年第59卷第9期
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文章信息
doi: 10.11669/cpj.2024.09.009
  • 接收时间：2023-08-21
  • 首发时间：2025-11-25
  • 出版时间：2024-05-08
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  • 收稿日期：2023-08-21
基金
国家药品抽验评价项目资助
浙江省药品监督管理局科技计划资助(2021005)
浙江省药品监督管理与产业发展研究会项目资助(ZYH2021001)
作者信息
    1 浙江省食品药品检验研究院, 国家药品监督管理局仿制药评价关键技术重点实验室,浙江省药品接触材料质量控制研究重点实验室, 杭州 310052
    2 中国药科大学, 南京 211198
    3 浙江省医疗器械审评中心, 杭州 310001

通讯作者:

*黄巧巧,女,副主任药师 研究方向:药品质量控制、医疗器械技术审评 Tel: (0571) 86459413;
郑金琪,男,主任药师 研究方向:药品质量控制 Tel:(0571) 86459413
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https://castjournals.cast.org.cn/joweb/zgyxzz/CN/10.11669/cpj.2024.09.009
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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
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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
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