Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE

In 2008, heparin (active pharmaceutical ingredient, API) lots were associated with anaphylactoid-type reactions. Oversulfated chondroitin sulfate (OSCS), a semi-synthetic glycosaminoglycan (GAG), was identified as a contaminant and dermatan sulfate (DS) as an impurity. While DS has no known toxicity...

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Main Authors: Zhenqing Zhang, Boyangzi Li, Jiraporn Suwan, Fuming Zhang, Zhenyu Wang, Haiying Liu, Barbara Mulloy, Robert J. Linhardt
Format: Journal
Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/49434
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spelling th-cmuir.6653943832-494342018-08-16T02:17:01Z Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE Zhenqing Zhang Boyangzi Li Jiraporn Suwan Fuming Zhang Zhenyu Wang Haiying Liu Barbara Mulloy Robert J. Linhardt Pharmacology, Toxicology and Pharmaceutics In 2008, heparin (active pharmaceutical ingredient, API) lots were associated with anaphylactoid-type reactions. Oversulfated chondroitin sulfate (OSCS), a semi-synthetic glycosaminoglycan (GAG), was identified as a contaminant and dermatan sulfate (DS) as an impurity. While DS has no known toxicity, OSCS was toxic leading to patient deaths. Heparins, prepared before these adverse reactions, needed to be screened for impurities and contaminants. Heparins were analyzed using high-field1H-NMR spectroscopy. Heparinoids were mixed with a pure heparin and analyzed by1H-NMR to assess the utility of1H-NMR for screening heparin adulterants. Sensitivity of heparinoids to deaminative cleavage, a method widely used to depolymerize heparin, was evaluated with polyacrylamide gel electrophoresis to detect impurities and contaminants, giving limits of detection (LOD) ranging from 0.1% to 5%. Most pharmaceutical heparins prepared between 1941 and 2008 showed no impurities or contaminants. Some contained DS, CS, and sodium acetate impurities. Heparin prepared in 2008 contained OSCS contaminant. Heparin adulterated with heparinoids showed additional peaks in their high-field1H-NMR spectra, clearly supporting NMR for monitoring of heparin API with an LOD of 0.5-10%. Most of these heparinoids were stable to nitrous acid treatment suggesting its utility for evaluating impurities and contaminants in heparin API. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association. 2018-08-16T02:17:01Z 2018-08-16T02:17:01Z 2009-01-01 Journal 15206017 00223549 2-s2.0-70349648765 10.1002/jps.21729 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=70349648765&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/49434
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Pharmacology, Toxicology and Pharmaceutics
spellingShingle Pharmacology, Toxicology and Pharmaceutics
Zhenqing Zhang
Boyangzi Li
Jiraporn Suwan
Fuming Zhang
Zhenyu Wang
Haiying Liu
Barbara Mulloy
Robert J. Linhardt
Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE
description In 2008, heparin (active pharmaceutical ingredient, API) lots were associated with anaphylactoid-type reactions. Oversulfated chondroitin sulfate (OSCS), a semi-synthetic glycosaminoglycan (GAG), was identified as a contaminant and dermatan sulfate (DS) as an impurity. While DS has no known toxicity, OSCS was toxic leading to patient deaths. Heparins, prepared before these adverse reactions, needed to be screened for impurities and contaminants. Heparins were analyzed using high-field1H-NMR spectroscopy. Heparinoids were mixed with a pure heparin and analyzed by1H-NMR to assess the utility of1H-NMR for screening heparin adulterants. Sensitivity of heparinoids to deaminative cleavage, a method widely used to depolymerize heparin, was evaluated with polyacrylamide gel electrophoresis to detect impurities and contaminants, giving limits of detection (LOD) ranging from 0.1% to 5%. Most pharmaceutical heparins prepared between 1941 and 2008 showed no impurities or contaminants. Some contained DS, CS, and sodium acetate impurities. Heparin prepared in 2008 contained OSCS contaminant. Heparin adulterated with heparinoids showed additional peaks in their high-field1H-NMR spectra, clearly supporting NMR for monitoring of heparin API with an LOD of 0.5-10%. Most of these heparinoids were stable to nitrous acid treatment suggesting its utility for evaluating impurities and contaminants in heparin API. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association.
format Journal
author Zhenqing Zhang
Boyangzi Li
Jiraporn Suwan
Fuming Zhang
Zhenyu Wang
Haiying Liu
Barbara Mulloy
Robert J. Linhardt
author_facet Zhenqing Zhang
Boyangzi Li
Jiraporn Suwan
Fuming Zhang
Zhenyu Wang
Haiying Liu
Barbara Mulloy
Robert J. Linhardt
author_sort Zhenqing Zhang
title Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE
title_short Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE
title_full Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE
title_fullStr Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE
title_full_unstemmed Analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>H-NMR and PAGE
title_sort analysis of pharmaceutical heparins and potential contaminants using<sup>1</sup>h-nmr and page
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=70349648765&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/49434
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