title: Analysis and characterization of heparin impurities.
abstract: 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.
authors.affiliation: Department of Chemistry, University of California, Riverside, CA 92521, USA.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Beni
authors.forename: John F K
authors.initials: JF
authors.lastname: Limtiaco
authors.forename: Cynthia K
authors.initials: CK
authors.lastname: Larive
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000302:isolation & purification; D002809:Chondroitin Sulfates / Q000032:analysis / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004340:Drug Contamination; D004586:Electrophoresis / Q000379:methods; D006493:Heparin / Q000737:chemistry* / Q000302:isolation & purification; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D019265:Spectroscopy, Near-Infrared / Q000379:methods; D013059:Spectrum Analysis, Raman / Q000379:methods
chemical_list: D000925:Anticoagulants; D006493:Heparin; D002809:Chondroitin Sulfates
references.citation: Proc Natl Acad Sci U S A. 1980 Nov;77(11):6551-5
references.pmid: 6935668
references.citation: Nat Biotechnol. 2008 Jun;26(6):669-75
references.pmid: 18437154
references.citation: J Chromatogr A. 2010 Jan 22;1217(4):479-88
references.pmid: 20004903
references.citation: Chem Rev. 2005 Jul;105(7):2745-64
references.pmid: 16011323
references.citation: Anal Chem. 2009 Dec 15;81(24):10116-23
references.pmid: 19911825
references.citation: Electroanalysis. 2010 Jan;22(1):26-30
references.pmid: 21151739
references.citation: J Biol Chem. 1995 Sep 29;270(39):22914-23
references.pmid: 7559427
references.citation: Biomed Chromatogr. 2002 Apr;16(2):127-33
references.pmid: 11857645
references.citation: J Pharm Biomed Anal. 2009 Apr 5;49(3):816-9
references.pmid: 19179033
references.citation: Biomaterials. 2010 Aug;31(22):5741-8
references.pmid: 20427081
references.citation: Semin Thromb Hemost. 1999;25 Suppl 3:5-16
references.pmid: 10549711
references.citation: J Pharm Biomed Anal. 2010 Sep 5;52(5):656-64
references.pmid: 20233649
references.citation: Biochem J. 1987 Jun 15;244(3):515-22
references.pmid: 3446173
references.citation: Anal Chem. 1994 Oct 15;66(20):3466-71
references.pmid: 7978318
references.citation: Analyst. 2000 May;125(5):933-8
references.pmid: 10885058
references.citation: Electrophoresis. 2008 Aug;29(15):3095-106
references.pmid: 18633943
references.citation: J Chromatogr A. 1997 Mar 28;765(2):169-79
references.pmid: 9129307
references.citation: Carbohydr Res. 1989 Mar 15;186(2):301-12
references.pmid: 2500236
references.citation: Anal Biochem. 1993 Aug 15;213(1):120-7
references.pmid: 8238864
references.citation: J Biol Chem. 1992 Dec 5;267(34):24347-55
references.pmid: 1332952
references.citation: Br J Haematol. 1995 May;90(1):1-7
references.pmid: 7786769
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16956-61
references.pmid: 19805108
references.citation: J Am Chem Soc. 2002 Jul 24;124(29):8707-18
references.pmid: 12121115
references.citation: J Chromatogr A. 2009 May 1;1216(18):4107-12
references.pmid: 19272607
references.citation: Chem Pharm Bull (Tokyo). 1990 Sep;38(9):2503-6
references.pmid: 2285982
references.citation: J Pharm Biomed Anal. 1998 Aug;17(4-5):557-616
references.pmid: 9682143
references.citation: Electrophoresis. 1997 Nov;18(12-13):2408-14
references.pmid: 9456055
references.citation: Anal Biochem. 2008 Sep 15;380(2):229-34
references.pmid: 18572011
references.citation: Nat Rev Cancer. 2002 Jul;2(7):521-8
references.pmid: 12094238
references.citation: Nat Protoc. 2010 Jun;5(6):993-1004
references.pmid: 20448545
references.citation: J Pharm Biomed Anal. 2010 May 1;52(1):1-8
references.pmid: 20071127
references.citation: Thromb Haemost. 2009 Nov;102(5):907-11
references.pmid: 19888527
references.citation: J Pharm Biomed Anal. 2010 Mar 11;51(4):921-6
references.pmid: 19959313
references.citation: J Biomol NMR. 1999 Oct;15(2):157-68
references.pmid: 10605089
references.citation: Thromb Haemost. 2009 Nov;102(5):854-8
references.pmid: 19888519
references.citation: Electrophoresis. 2002 Apr;23(7-8):1104-9
references.pmid: 11981858
references.citation: J Pharm Biomed Anal. 2009 Apr 5;49(3):670-3
references.pmid: 19167854
references.citation: Biochem J. 1935 Aug;29(8):1817-30
references.pmid: 16745848
references.citation: J Pharm Biomed Anal. 2010 Apr 6;51(5):1060-3
references.pmid: 20036090
references.citation: J Med Chem. 2008 Sep 25;51(18):5498-501
references.pmid: 18754653
references.citation: Carbohydr Res. 2002 May 13;337(10):935-45
references.pmid: 12007476
references.citation: Biochemistry. 1972 Feb 15;11(4):563-8
references.pmid: 5062409
references.citation: Science. 1989 Mar 17;243(4897):1490-3
references.pmid: 2467380
references.citation: Clin Appl Thromb Hemost. 2009 Jul-Aug;15(4):395-401
references.pmid: 19617248
references.citation: Anal Biochem. 1997 Sep 5;251(2):219-26
references.pmid: 9299019
references.citation: J Biol Chem. 2004 Jan 23;279(4):2608-15
references.pmid: 14610083
references.citation: Anal Biochem. 2009 May 1;388(1):140-5
references.pmid: 19232311
references.citation: Science. 1971 Apr 30;172(3982):440-51
references.pmid: 4927678
references.citation: Biomaterials. 2008 Dec;29(36):4808-14
references.pmid: 18801571
references.citation: Am J Cardiol. 1998 Sep 10;82(5B):3L-10L
references.pmid: 9737473
references.citation: Anal Chem. 1988 Nov 1;60(21):2322-8
references.pmid: 2853587
references.citation: Electrophoresis. 2004 Jul;25(13):1949-63
references.pmid: 15237394
references.citation: J Pharm Biomed Anal. 2009 Feb 20;49(2):319-26
references.pmid: 19155153
references.citation: Anal Chem. 2009 Sep 1;81(17):7406-15
references.pmid: 19653663
references.citation: Electrophoresis. 1990 Jan;11(1):23-8
references.pmid: 1690641
references.citation: Chembiochem. 2007 Mar 5;8(4):391-4
references.pmid: 17243186
references.citation: J Pharm Sci. 1992 Aug;81(8):823-7
references.pmid: 1328601
references.citation: N Engl J Med. 2008 Jun 5;358(23):2457-67
references.pmid: 18434646
references.citation: J Pharm Sci. 2009 Nov;98(11):4017-26
references.pmid: 19642166
references.citation: Glycobiology. 2002 Sep;12(9):117R-25R
references.pmid: 12213784
references.citation: Chem Commun (Camb). 2008 Oct 7;(37):4469-71
references.pmid: 18802593
references.citation: J Chromatogr A. 2001 Apr 20;914(1-2):277-91
references.pmid: 11358222
references.citation: Yakugaku Zasshi. 2009 Oct;129(10):1255-64
references.pmid: 19797882
references.citation: J Pharm Sci. 1989 Feb;78(2):101-4
references.pmid: 2541240
references.citation: J Med Chem. 2003 Jun 19;46(13):2551-64
references.pmid: 12801218
references.citation: J Pharm Sci. 2009 Oct;98(10):3540-7
references.pmid: 19117047
references.citation: Nat Prod Rep. 2009 Mar;26(3):313-21
references.pmid: 19240943
references.citation: J Med Chem. 2008 Dec 25;51(24):7663-5
references.pmid: 19055319
references.citation: Biochem J. 1984 Aug 1;221(3):697-705
references.pmid: 6477495
references.citation: Eur J Pharm Sci. 2010 Jul 11;40(4):297-304
references.pmid: 20399266
references.citation: Anal Biochem. 2009 May 15;388(2):317-21
references.pmid: 19289093
references.citation: Nat Prod Rep. 2002 Jun;19(3):312-31
references.pmid: 12137280
references.citation: Anal Chem. 2008 Dec 15;80(24):9845-7
references.pmid: 19007240
references.citation: Trends Pharmacol Sci. 1995 Jun;16(6):198-204
references.pmid: 7652929
references.citation: Mol Cell Biochem. 1982 Oct 29;48(3):161-82
references.pmid: 6757715
references.citation: Biochemistry. 1976 Sep 7;15(18):3932-42
references.pmid: 9127
references.citation: Anal Biochem. 1985 Nov 1;150(2):325-31
references.pmid: 4091260
references.citation: Nat Biotechnol. 2008 Jun;26(6):624-6
references.pmid: 18536681
references.citation: Biochem J. 1985 Sep 15;230(3):665-74
references.pmid: 2933029
references.citation: Nat Chem Biol. 2006 Apr;2(4):195-6
references.pmid: 16532012
references.citation: Anal Biochem. 1994 Aug 15;221(1):182-8
references.pmid: 7985791
references.citation: Anal Biochem. 1991 Dec;199(2):249-55
references.pmid: 1812791
references.citation: Angew Chem Int Ed Engl. 2002 Feb 1;41(3):391-412
references.pmid: 12491369
references.citation: Anal Bioanal Chem. 2009 Jan;393(1):155-69
references.pmid: 18841350
references.citation: Carbohydr Res. 1998 Jan;306(1-2):35-43
references.pmid: 9691438
references.citation: Anal Biochem. 2007 Dec 1;371(1):118-20
references.pmid: 17679101
references.citation: Biochem J. 2004 Apr 15;379(Pt 2):217-27
references.pmid: 14759226
references.citation: J Pharm Biomed Anal. 2010 Feb 5;51(3):733-5
references.pmid: 19782493
references.citation: J Pharm Biomed Anal. 2008 Jan 7;46(1):30-5
references.pmid: 18024047
references.citation: Nucleic Acids Res. 1991 Nov 11;19(21):6051
references.pmid: 1719488
references.citation: Yakugaku Zasshi. 2008 Oct;128(10):1513-5
references.pmid: 18827473
references.citation: N Engl J Med. 2008 Dec 18;359(25):2674-84
references.pmid: 19052120
references.citation: Biologicals. 2010 Sep;38(5):539-43
references.pmid: 20452241
references.citation: J Chromatogr A. 2003 Oct 3;1014(1-2):215-23
references.pmid: 14558627
references.citation: J Pharm Biomed Anal. 2009 May 1;49(4):1060-4
references.pmid: 19211212
references.citation: J Pharm Sci. 1995 Mar;84(3):360-4
references.pmid: 7616378
references.citation: J Pharm Biomed Anal. 2010 Nov 2;53(3):302-8
references.pmid: 20417048
references.citation: Anal Biochem. 2010 Jun 15;401(2):236-41
references.pmid: 20211145
references.citation: Appl Environ Microbiol. 1981 Feb;41(2):360-5
references.pmid: 7235692
references.citation: J Chromatogr A. 2001 Oct 12;932(1-2):65-74
references.pmid: 11695869
references.citation: Biochim Biophys Acta. 1983 Sep 9;740(4):466-75
references.pmid: 6882767
references.citation: J Pharm Biomed Anal. 2008 Sep 10;48(1):13-9
references.pmid: 18678460
references.citation: Anal Chem. 2001 May 15;73(10):2310-6
references.pmid: 11393857
references.citation: Anal Biochem. 2004 Mar 1;326(1):33-41
references.pmid: 14769333