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Complex Stability

Complex Stability

Complex Stability of Gadolinium-Based Contrast Agents

Although a number of fundamental questions regarding the stability of GBCAs and SI increase remain to be answered, below we summarize a few relevant points that need to be understood when considering the stability of GBCAs.

The likelihood of a Gd-chelate to release Gd3+ions depends in particular on the chelate’s chemical structure and respective in vivo and in vitro stability. Based on their chemical structures, GBCAs may be divided into two groups: linear chelates and macrocyclic chelates.3


Some relevant features of GBCAs.

  Chemical Structure (charge) Protein binding Serum elimination half-life Elimination pathway
OmniscanTM Linear chelates (non-ionic) None -70 min Kidney
Magnevist® Linear chelates (ionic) None  90 min Kidney
MultiHance® Linear chelates (ionic) < 5% 72 - 102 min Kidney ≥ 96%, Bile ≤ 4%
Primovist® Linear chelates (ionic) < 15% 50 min Kidney 50%, Bile 50%
ProHance® Macrocyclic chelates None 96 min Kidney
Gadovist® 1.0 Macrocyclic chelates None  78 - 126 min Kidney


Linear Gd-Chelates

The complex stability of linear (open-chain) chelates is primarily characterized by their thermodynamic (log K) and conditional complex stability (log Kcond) calculated at pH 7.4.

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The thermodynamic stability constants describe the equilibrium between concentrations of the Gd-complex on the one hand, and concentrations of free Gd3+ ion and free ligand on the other. The constants are influenced by the net charge of the Gd complex. An ionic chelate results in stronger binding of the Gd3+ ion than a neutral or non-ionic chelate.

  • Non-ionic linear chelates are characterized by lower complex stability and require high excess of free ligand in the formulation.
  • Ionic linear chelates are characterized by higher complex stability and require only very low excess of free ligand in the formulation.



Trade name Excess ligand in formulation Thermodynamic stability
log Ktherm log Kcond

















Macrocyclic Gd-Chelates

Macrocyclic chelates differ from linear chelates regarding the kinetics of complexation and decomplexation.2

Macrocyclic Gd-Chelates


Significant activation energy is necessary to both generate and dissociate the Gd-complexes. The adequate parameter describing this kinetic process is the dissociation half-life, which describes the time needed for the decomplexation of half of the Gd-complexes in solution.2 The thermodynamic stability constants, on the other hand, can be neglected for macrocyclic GBCAs given the extremely long dissociation half-life (extrapolated > 1,000 years at pH 7.4), which is called the kinetic inertness.

  • Due to high kinetic inertness, all macrocyclic agents are highly stable under physiological conditions.2,3
  • Any differences between the macrocyclic GBCAs in dissociation half-lives measured at highly artificial conditions in vitro are extremely unlikely to result in any relevant differences in vivo2 and the extrapolated dissociation half-lives at physiological conditions for all three macrocyclic GBCAs are similar.


Kinetic stability is the most relevant parameter for macrocyclic GBCAs (ProHance®, Gadovist® 1.0 and Dotarem®).1-5



Dissociation half-life T1/2 (pH 1) T1/2 (pH 7.4, extrapolated)
ProHance® (Gd-HPDO3A) 2h, 3h > 1,000 years
Gadovist® 1.0 (BT-DO3A) 8h, 24h > 1,000 years
Dotarem® (Gd-DOTA) 9h, 26h, 60h > 1,000 years


Macrocyclic GBCAs are inert due to their high kinetic stability




Chelate stability and clinical relevance

Summary on chelate stability and clinical relevance


  1. Lohrke J, Frenzel T, Endrikat J, et al. 25 Years of Contrast-Enhanced MRI: Developments, Current Challenges and Future Perspectives. Adv Ther. 2016;33:1-28.

  2. Schmitt-Willich H. Stability of linear and macrocyclic gadolinium based contrast agents. Br J Radio. 2007;80:581-2; author reply 584-5. 

  3. Frenzel T, Lengsfeld P, Schirmer H, Hutter J, Weinmann HJ.Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol. 2008;43:817-28.

  4. Port M, Idee JM, Medina C, Robic C, Sabatou M, Corot C. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals. 2008;21:469-90.

  5. Wedeking P, Kumar K, Tweedle MF. Dissociation of gadolinium chelates in mice: relationship to chemical characteristics. Magn Reson Imaging. 1992;10:641-8.