Abstract
Fondaparinux sodium is a synthetic pentasaccharide representing the high affinity antithrombin III binding site in heparin. It is the active pharmaceutical ingredient of the anticoagulant drug Arixtra®. The single crystal X-ray structure of Fondaparinux sodium is reported, unequivocally confirming both structure and absolute configuration. The iduronic acid adopts a somewhat distorted chair conformation. Due to the presence of many sulfur atoms in the highly sulfated pentasaccharide, anomalous dispersion could be applied to determine the absolute configuration. A comparison with the conformation of Fondaparinux in solution, as well as complexed with proteins is presented. The content of the solution reference standard was determined by quantitative NMR using an internal standard both in 1999 and in 2016. A comparison of the results allows the conclusion that this method shows remarkable precision over time, instrumentation and analysts.
Highlights
IntroductionFondaparinux sodium (referred to as ‘Fondaparinux’ in this article; Figure 1) is a synthetic pentasaccharide [1] derived from the high affinity antithrombin III binding site in heparin, modified by a methyl group at the reducing end
Fondaparinux sodium is a synthetic pentasaccharide [1] derived from the high affinity antithrombin III binding site in heparin, modified by a methyl group at the reducing end
The individual glucosamine (D, F and H) rings have adopted the conventional stable 4C1 chair iduronic acid G ring conformation has been the subject of intense debate [11,12,13,14,15,23,24,25,26]
Summary
Fondaparinux sodium (referred to as ‘Fondaparinux’ in this article; Figure 1) is a synthetic pentasaccharide [1] derived from the high affinity antithrombin III binding site in heparin, modified by a methyl group at the reducing end. It is the active pharmaceutical ingredient of GSK’s anticoagulant drug Arixtra® and a selective aXa inhibitor through antithrombin III [2] and lacks aIIa activity as a result of its low molecular weight. Complexation by proteins locks the iduronate residue in a single 2 S0 conformation both in the crystal [5,6,9,10] and in solution [16]. In the crystal of uncomplexed Fondaparinux, the Molecules 2017, 22, 1362; doi:10.3390/molecules22081362 www.mdpi.com/journal/molecules occurrenceFondaparinux, of a single iduronate conformation is foreseen
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