HEPARIN SALTS Elemental analysis of typical batches of heparin results in 24.0 - 25% carbon, 3.4 - 3.6% hydrogen, 1.9 - 2.3% nitrogen, and 9.5 - 11.0% sulfur. Heparin salts are strongly anionic polyelectrolytes that effectively bind and release of micro-ions. Activity measurements made with an ion-specific electrode show that only 66 percent of the sodium ions in sodium heparin are bound. Heparin sodium may be converted into different salt forms by passage through appropriately charged cation-exchange resins. Mass spectrometry show a greater than 99% efficiency of the cation exchange process. Of all cations, lithium is most similar to hydrogen and binds to heparin particularly strongly. The rate of heparin-catalyzed thrombin-antithrombin (TAT) interaction, however, is apparently less in the presence of lithium than in the presence of sodium or potassium ions in solutions of similar ionic strength. Of all the cations, lithium binds to heparin with particularly high affinity. Heparin sodium also appears somewhat more resistant to dehydration than heparin lithium. It has been suggested that lyophilized or crystallized lithium heparin is the best anticoagulant for use in blood because it avoids interference with sodium determinations of heparin sodium. Replacement of lithium ions by equivalents of calcium in aqueous solution at pH 7.0 results in a decrease in pH, suggesting a direct involvement of the carboxy groups of heparin in cation interactions. The pH, therefore, may change slightly during blood gas analysis due to the effect of calcium or calcium. Divalent cations such as calcium and zinc bind more strongly to heparin than monovalent counterions. NMR data conclude that calcium ions also are located at specific chelated sites within the heparin molecule. Also, zinc ions bind preferentially to heparin rather than other glycosaminoglycans.Much of its polysaccharide structure can be represented as a repeating, trisulfated disaccharide and regions containing disulfated disaccharides and disaccharides lacking a sulfate on C-6 of the glucosamine residue are typically present. Activity measurements made with an ion-specific electrode showed that only 66 percent of the sodium ions in heparin are bound. A pentasaccharide containing the unique trisulfated glucosamine residue has high affinity for antithrombin (AT). The binding of heparin to AT accelerates the rate of thrombin inhibition by AT which accounts for the anticoagulant action of heparin. Approximately 30% of the heparin chain contains the pentasaccharide sequence required for binding to AT. The remaining 70% has no AT-dependent anticoagulant activity but catalyzes the inhibition of thrombin by heparin cofactor II. During the clotting process, heparin also will catalyze the inhibition of factor Xa by AT. BENZALKONIUM HEPARIN [HB-0318] is a water-insoluble salt of heparin sodium USP of porcine intestinal mucosa and benzalkonium chloride NF. Positive amine radicals of primary, secondary and tertiary amines and quaternary ammonium compounds electrostatically bind to negative sulfate radicals of heparin. Quaternary ammonium salts physically bind to adsorptive surfaces because of potent surface-active properties. Benzalkonium Heparin coatings may be further stabilized by exposure to gamma radiation, gas plasma or an electron beam energy source. References
Amplatz K. A simple non-thrombogenic coating. Invest Radiol 1971; 6: 280-8. HEPARIN AMMONIUM [HA-0306] is produced from heparin sodium by cation exchange chromatography pursuant to FDA Drug Master File 8003. References Gerstner JA, Cramer SM. Heparin as a nontoxic displacer for anion-xxchange protein displacement systems. BioPharm 1992; 5: 42-5. HEPARIN CALCIUM [HC-0304] is manufactured pursuant to FDA Drug Master File 7951 from heparin sodium USP of porcine intestinal mucosa. Its quality is guaranteed to meet or exceed the compendial standards of the European, Japanese and U.S. Pharmacopeia. References
Cade JF, Andrews JT, Stubbs AE. Comparison of Sodium and Calcium Heparin in Prevention
of Venous Thromboembolism. Aust NZ J Med 1982; 12: 501-4. HEPARIN LITHIUM [HL-0307] is prepared from heparin sodium of porcine intestinal mucosa by cation exchange chromatography. It is the anticoagulant of choice when determining specific analytes in whole blood, and is guaranteed to meet the standards of quality for additives to blood collection devices recommended by the National Committee for Clinical Laboratory Standards. Lithium binds to heparin with particularly high affinity. The rate of heparin-catalyzed thrombin-antithrombin interaction, however, is apparently less in the presence of lithium than in the presence of sodium or potassium ions in solutions of similar ionic strength. Heparin Lithium is the least likely to interfere with other ions, especially when balanced with calcium or zinc chloride. References
Pedersen LC, Jorgensen M. Biochem J 1983; 211: 91-97. HEPARIN SODIUM [PH-0300] of porcine intestinal mucosa is a bulk drug substance having a molecular weight ranging from 3,000 to 30,000 Daltons with an average of about 12,500. Its strength, quality and purity meet the specifications of the United States Pharmacopeia. In addition, its porcine raw material tests negative for prion antigens and is purified using a process validated for the removal of TSE infectious agents and viral infectivity due to retroviruses, enterohepatic viruses and porcine parvovirus. Heparin Sodium USP defines chemical specifications and not necessarily the intended use of the product which may be as a bulk drug substance for further manufacture, as an ingredient for the collection and analysis of blood, as a component of nonthrombogenic coatings for blood-interacting medical devices, as an affinity ligand in the purification of heparin-binding proteins, or as a starting material for low molecular weight heparins and heparin lyases. References
Dunstone JR. Ion-Exchange Reactions between Acid Mucopolysaccharides and Various Cations.
Biochem J 1962; 85: 336-51. HEPARIN ZINC LITHIUM [LZ-0308] is produced from Heparin Sodium of porcine intestinal mucosa by cation exchange chromatography. It is an anticoagulant specifically designed for the potentiometric determination of electrolytes in blood. Of all cations, lithium is most similar to hydrogen and binds to heparin particularly strongly. Divalent cations such as calcium and zinc bind more strongly to heparin than monovalent counterions. Also, zinc ions bind preferentially to heparin rather than other glycosaminoglycans. References
Parrish RF, Fair WR. Selective Binding of zinc ions to heparin rather than to other
glycosaminoglycans. Biochem J 1981; 193: 407-10. STEARALKONIUM HEPARIN [SK-0317] is a water-insoluble salt of heparin sodium of porcine intestinal mucosa and stearyldimethylbenzylammonium chloride. References
Gott VL, Whiffin JD, Dutton RC. Heparin bonding on colloidal graphite surfaces. Science 1963;
142: 1297-8.
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