Low Molecular Weight Heparin - Manufacturing Process

Manufacturing Process

Various methods of heparin depolymerisation are used in the manufacture of low-molecular-weight heparin. These are listed below:

• Oxidative depolymerisation with hydrogen peroxide. Used in the manufacture of ardeparin (Normiflo)
• Deaminative cleavage with isoamyl nitrite. Used in the manufacture of certoparin (Sandoparin)
• Alkaline beta-eliminative cleavage of the benzyl ester of heparin. Used in the manufacture of enoxaparin (Lovenox and Clexane)
• Oxidative depolymerisation with Cu2+ and hydrogen peroxide. Used in the manufacture of parnaparin (Fluxum)
• Beta-eliminative cleavage by the heparinase enzyme. Used in the manufacture of tinzaparin (Innohep and Logiparin)
• Deaminative cleavage with nitrous acid. Used in the manufacture of dalteparin (Fragmin), reviparin (Clivarin), and nadroparin (Fraxiparin)

Deaminative cleavage with nitrous acid results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannitol using a suitable reducing agent as shown in figure 1.

Likewise both chemical and enzymatic beta-elimination result in the formation of an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as shown in figure 2.