Screening of Heparin API by Near Infrared Reflectance and Raman Spectroscopy

Spencer, John; Kauffman, John F.; Reepmeyer, John C.; Gryniewicz, Connie M.; Ye, Wei; Toler, Duckhee Y.; Buhse, Lucinda F.; Westenberger, Benjamin J.

doi:10.1002/jps.21660

Cited by 34 publications

(32 citation statements)

References 22 publications

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“…Since the initial report discovery and structural elucidation of OSCS in heparin (13), a number of analytical tools and methods have been used in the overall analysis and are described in a series of recent publications, including NMR (23)(24)(25), MS (26), IR-Raman (27,28), CE (29 -31), HPLC (32), biosensor (33), and bioassays (34 -36). Also, the structural assignment of OSCS has been independently confirmed by other independent investigations (41), providing additional support to the fact that OSCS is the major contaminant within suspect heparin lots.…”

Section: Discussionmentioning

confidence: 99%

Orthogonal analytical approaches to detect potential contaminants in heparin

Guerrini

Zhang

Shriver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Heparin is a widely used anticoagulant and antithrombotic agent. Recently, a contaminant, oversulfated chondroitin sulfate (OSCS), was discovered within heparin preparations. The presence of OSCS within heparin likely led to clinical manifestations, most prevalently, hypotension and abdominal pain leading to the deaths of several dozens of patients. Given the biological effects of OSCS, one continuing item of concern is the ability for existing methods to identify other persulfonated polysaccharide compounds that would also have anticoagulant activity and would likely elicit a similar activation of the contact system. To complete a more extensive analysis of the ability for NMR and capillary electrophoresis (CE) to capture a broader array of potential contaminants within heparin, we completed a systematic study of NMR, both mono-and bidimensional, and CE to detect both various components of sidestream heparin and their persulfonated derivatives. We show that given the complexity of heparin samples, and the requirement to ensure their purity and safety, use of orthogonal analytical techniques is effective at detecting an array of potential contaminants that could be present.anticoagulant ͉ capillary electrophoresis ͉ contamination ͉ NMR ͉ oversulfated chondroitin

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Section: Discussionmentioning

confidence: 99%

Orthogonal analytical approaches to detect potential contaminants in heparin

Guerrini

Zhang

Shriver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…12,13 However, development of additional, orthogonal assays that can rapidly and sensitively detect the presence of potential contaminants, if present, is warranted. To this end, there have been several reports of potential methods, including ion exchange HPLC, 10 quantitative capillary electrophoresis, 14 inhibition of Taq polymerase in a real-time PCR, 15 a fluorescent receptor array, 16 and use of potentiometric polyanion sensors.…”

mentioning

confidence: 99%

Competitive Inhibition of Heparinase by Persulfonated Glycosaminoglycans: A Tool to Detect Heparin Contamination

et al. 2011

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Heparin and the low molecular weight heparins are extensively used as medicinal products to prevent and treat the formation of venous and arterial thrombi. In early 2008, administration of some heparin lots was associated with the advent of severe adverse effects, indicative of an anaphylactoid-like response. Application of orthogonal analytical tools enabled detection and identification of the contaminant as oversulfated chondroitin sulfate (OSCS) was reported in our earlier report. Herein, we investigate whether enzymatic depolymerization using the bacterially derived heparinases, given the structural understanding of their substrate specificity, can be used to identify the presence of OSCS in heparin. We also extend this analysis to examine the effect of other persulfonated glycosaminoglycans (GAGs) on the action of the heparinases. We find that all persulfonated GAGs examined were effective inhibitors of heparinase I, with IC50 values ranging from approximately 0.5–2 µg/mL. Finally, using this biochemical understanding, we develop a rapid, simple assay to assess the purity of heparin using heparinase digestion followed by size-exclusion HPLC analysis to identify and quantify digestion products. In the context of the assay, we demonstrate that less than 0.1% (w/w) of OSCS (and other persulfonated polysaccharides) can routinely be detected in heparin.

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“…An advantage of both NIR and Raman spectroscopy is that they can be used to characterize solid heparin samples and detect OSCS contamination above 1% [48]. A nondestructive NIR method has been extended beyond impurity analysis as a potential tool for heparin potency determination [49].…”

Section: New Analytical Methods For Heparin Impurity Analysismentioning

confidence: 99%

Analysis and characterization of heparin impurities

2010

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This review discusses recent developments in analytical methods available for the sensitive separation, detection and structural characterization of heparin contaminants. The adulteration of raw heparin with oversulfated chondroitin sulfate (OSCS) in 2007–2008 spawned a global crisis resulting in extensive revisions to the pharmacopeia monographs on heparin and prompting the FDA to recommend the development of additional physicochemical methods for the analysis of heparin purity. The analytical chemistry community quickly responded to this challenge, developing a wide variety of innovative approaches, several of which are reported in this special issue. This review provides an overview of methods of heparin isolation and digestion, discusses known heparin contaminants, including OSCS, and summarizes recent publications on heparin impurity analysis using sensors, near-IR, Raman, and NMR spectroscopy, as well as electrophoretic and chromatographic separations.FigureSchematic illustrating the process for heparin impurity characterization

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Screening of Heparin API by Near Infrared Reflectance and Raman Spectroscopy

Cited by 34 publications

References 22 publications

Orthogonal analytical approaches to detect potential contaminants in heparin

Orthogonal analytical approaches to detect potential contaminants in heparin

Competitive Inhibition of Heparinase by Persulfonated Glycosaminoglycans: A Tool to Detect Heparin Contamination

Analysis and characterization of heparin impurities

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