Synthesis and detection of N-sulfonated oversulfated chondroitin sulfate in marketplace heparin.
N-sulfonated oversulfated chondroitin sulfate (NS-OSCS), recently reported as a potential threat to the heparin supply, was prepared along with its intermediate derivatives. All compounds were spiked into marketplace heparin and subjected to United States Pharmacopeia (USP) identification assays for heparin (proton nuclear magnetic resonance [(1)H NMR], chromatographic identity, % galactosamine [%GalN], anti-factor IIa potency, and anti-factor Xa/IIa ratio). The U.S. Food and Drug Administration (FDA) strong-anionic exchange high-performance liquid chromatography (SAX-HPLC) method resolved NS-OSCS from heparin and OSCS and had a limit of detection of 0.26% (w/w) NS-OSCS. The %GalN test was sensitive to the presence of NS-OSCS in heparin. Therefore, current USP heparin monograph tests (i.e., SAX-HPLC and %GalN) detect the presence of NS-OSCS in heparin.
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA. Electronic address: daniel.mans@fda.hhs.gov.
Daniel J
DJ
Mans
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Hongping
H
Ye
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Jamie D
JD
Dunn
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Richard E
RE
Kolinski
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Dianna S
DS
Long
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Nisarga L
NL
Phatak
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Houman
H
Ghasriani
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
Lucinda F
LF
Buhse
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
John F
JF
Kauffman
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, St. Louis, MO 63110, USA.
David A
DA
Keire
D000837:Anion Exchange Resins; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000032:analysis* / Q000737:chemistry / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004126:Dimethylformamide / Q000737:chemistry; D004340:Drug Contamination / Q000517:prevention & control; D005688:Galactosamine / Q000032:analysis; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology; D006834:Hydrazines / Q000737:chemistry; D007202:Indicators and Reagents / Q000032:analysis* / Q000737:chemistry / Q000633:toxicity; D057230:Limit of Detection; D066244:Proton Magnetic Resonance Spectroscopy; D011786:Quality Control; D014481:United States; D014486:United States Food and Drug Administration
D000837:Anion Exchange Resins; D000925:Anticoagulants; D006834:Hydrazines; D007202:Indicators and Reagents; C029424:hydrazine; D005688:Galactosamine; D004126:Dimethylformamide; D006493:Heparin; D002809:Chondroitin Sulfates
Heparin; High-performance liquid chromatography; Nuclear magnetic resonance; Oversulfated chondroitin sulfate