, Volume 28, Issue 4, pp 615–635 | Cite as

Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose

  • Susann Neiser
  • Daniel Rentsch
  • Urs Dippon
  • Andreas Kappler
  • Peter G. Weidler
  • Jörg Göttlicher
  • Ralph Steininger
  • Maria Wilhelm
  • Michaela Braitsch
  • Felix Funk
  • Erik Philipp
  • Susanna Burckhardt


The advantage of the new generation IV iron preparations ferric carboxymaltose (FCM), ferumoxytol (FMX), and iron isomaltoside 1000 (IIM) is that they can be administered in relatively high doses in a short period of time. We investigated the physico-chemical properties of these preparations and compared them with those of the older preparations iron sucrose (IS), sodium ferric gluconate (SFG), and low molecular weight iron dextran (LMWID). Mössbauer spectroscopy, X-ray diffraction, and Fe K-edge X-ray absorption near edge structure spectroscopy indicated akaganeite structures (β-FeOOH) for the cores of FCM, IIM and IS, and a maghemite (γ-Fe2O3) structure for that of FMX. Nuclear magnetic resonance studies confirmed the structure of the carbohydrate of FMX as a reduced, carboxymethylated, low molecular weight dextran, and that of IIM as a reduced Dextran 1000. Polarography yielded significantly different fingerprints of the investigated compounds. Reductive degradation kinetics of FMX was faster than that of FCM and IIM, which is in contrast to the high stability of FMX towards acid degradation. The labile iron content, i.e. the amount of iron that is only weakly bound in the polynuclear iron core, was assessed by a qualitative test that confirmed decreasing labile iron contents in the order SFG ≈ IS > LMWID ≥ FMX ≈ IIM ≈ FCM. The presented data are a step forward in the characterization of these non-biological complex drugs, which is a prerequisite to understand their cellular uptake mechanisms and the relationship between the structure and physiological safety as well as efficacy of these complexes.


Intravenous iron Iron sucrose Ferric carboxymaltose Iron isomaltoside 1000 Ferumoxytol Low molecular weight iron dextran 



Double quantum filtered correlation spectroscopy


Ethylenediaminetetraacetic acid


Ferric carboxymaltose


U.S. Food and Drug Administration




Gel-filtration chromatography




Goodness of fit


Heteronuclear multiple-bond correlation


High molecular weight iron dextran


Heteronuclear single quantum correlation


Iron isomaltoside 1000


Iron sucrose


Iron sucrose similar




Low molecular weight iron dextran


Number average molecular weight


Weight average molecular weight


z-average molecular weight


Non-biological complex drugs


Nuclear magnetic resonance


Non-transferrin bound iron




Polyglucose sorbitol carboxymethylether


Quadrupole splitting


Standard deviation


Selected area electron diffraction


Carboxymethylation substitution degree


Sodium ferric gluconate


Standard hydrogen electrode


Transmission electron microscopy


Total correlation spectroscopy




United States Pharmacopeia


X-ray absorption near edge structure


X-ray diffraction



We thank Werner Agster, Zorica Nikolic, Roland Riederer, and Maja Thum (all Vifor (International) Ltd.) for technical assistance. We are also grateful to Ralf Weigel from ANKA–Synchrotron Radiation Facility, Karlsruhe Institute for Technology (KIT), for constructing the cell for liquid samples used in Fe K-edge XANES spectroscopy. Dr. Peter Geisser, Vifor (International) Ltd., is thanked for valuable discussions.

Conflict of interest

S. Neiser, M. Wilhelm, M. Braitsch, F. Funk, E. Philipp, and S. Burckhardt are employees of Vifor (International) Ltd. D. Rentsch investigated the structure of the carbohydrate components by NMR, U. Dippon and A. Kappler examined the core structures by Mössbauer spectroscopy, P. Weidler investigated the core structures by XRD, and J. Göttlicher and R. Steininger examined the core structures by Fe K-edge XANES. The measurements for these studies were paid for by Vifor (International) Ltd.

Supplementary material

10534_2015_9845_MOESM1_ESM.doc (288 kb)
Supplementary material 1 (DOC 288 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Susann Neiser
    • 1
  • Daniel Rentsch
    • 2
  • Urs Dippon
    • 3
  • Andreas Kappler
    • 3
  • Peter G. Weidler
    • 4
  • Jörg Göttlicher
    • 5
  • Ralph Steininger
    • 5
  • Maria Wilhelm
    • 1
  • Michaela Braitsch
    • 1
  • Felix Funk
    • 1
  • Erik Philipp
    • 1
  • Susanna Burckhardt
    • 1
  1. 1.Chemical and Preclinical Research and DevelopmentVifor (International) Ltd.St. GallenSwitzerland
  2. 2.Swiss Federal Laboratories for Materials Science and Technology (Empa)DübendorfSwitzerland
  3. 3.Geomicrobiology, Center for Applied GeosciencesUniversity of TübingenTübingenGermany
  4. 4.Institute of Functional Interfaces, Karlsruhe Institute of Technology (KIT)Eggenstein-LeopoldshafenGermany
  5. 5.ANKA–Synchrotron Radiation FacilityKarlsruhe Institute for Technology (KIT)Eggenstein-LeopoldshafenGermany

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