Anal Chem 2015 Aug 18;8716:8424-32. doi: 10.1021/acs.analchem.5b01788.

One-hour screening of adulterated heparin by simplified peroxide digestion and fast RPIP-LC-MS(2).

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Early detection of potential contaminants in heparin, an extensively used anticoagulant in drug formulations and medical devices, is critical to ensuring public health. In response to heparin adulteration by oversulfated chondroitin sulfates (OSCS) that was associated with adverse events including deaths in 2007-2008, many methods have been developed to detect OSCS in heparin. However, an analytical challenge for quality screenings has been to speed up these measurements to address the complex distribution scheme of heparin in today's global market. Here an approach based on mass spectrometry is described that enables the measurement of adulterated heparin in 1 h, significantly shortening the time frame of screening for potential contaminants. The methodology is based on simplified peroxide digestion that rapidly depolymerizes large polysaccharide chains to small oligosaccharides followed by fast liquid chromatography mass spectrometry to determine sample purity. We find that rapid peroxide digestion generates abundant C- and Y-type oligosaccharides that can be used to differentiate parent glycosaminoglycans via unsupervised multivariate analysis, including heparin, chondroitin sulfate A, dermatan sulfate, and the infamous OSCS. With quantitation demonstrated at 1% (w/w), or 50 ng, OSCS in heparin and the lower limit of detection estimated at ∼0.20% (w/w), or ∼10 ng, OSCS in heparin, the technology was sufficiently sensitive to differentiate real-life, "authentic" adulterated heparin samples and to quantify this contaminant with an error <10% relative standard deviation. The methodologies presented here are deliberately simple to foster adoption and increase the analytical throughput of mass spectrometric screening in the routine quality assessment of heparin and other types of compounds of this molecular family.

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