Presence of other rare earth metals in gadolinium-based contrast agents

Gadolinium-based contrast agents (GBCA) are widely used to enhance tissue contrast during magnetic resonance imaging (MRI) procedures. However, free Gadolinium (Gd) is undesirable as a drug substance, due to its high toxicity. Consequently, a coordinating ligand is required to keep it in solution and to increase tolerance. In order to achieve an adequate performance, GBCA must be administered in relatively large amounts. Chelate amounts are around 13-20 g and for Gd alone, this may amount to 3.3 g. Taking into account the route of administration, impurities in GBCA may be significant. Gadolinium occurs in nature along with 16 other elements known collectively as rare earth metals (RE), which are found throughout the earth's crust in minerals such as monazite. Gadolinium oxide corresponds to 0.7-4.0% of the RE present in minerals, and the sum concentration of RE in minerals is around 4%. Rare earth metals are difficult to separate, as the chemical and physical properties of one RE are significantly similar to those of others. In this study, the presence of other RE in GBCA formulations was investigated. Different lots of Magnevist®, Viewgam®, OptiMARK®, Omniscan®, Dotarem®, and Gadovist® were analyzed. Inductively-coupled plasma mass spectrometry and atomic absorption spectrometry were used for RE determination. Procedure optimization included sample decomposition and method validation for element determination. The results showed that Sc, Y, La, Ce, Pr, Nd, Eu, Tb, Tm, Dy, Ho, and Er were present in the 22 samples analyzed. Terbium, Thulium, Europium, and Lanthanum were, on average, found in the highest amounts, which were 0.42 mg/L, 0.17 mg/L, 0.17 mg/L, and 0.16 mg/L, respectively. These results could be attributed to the similarity among Europium, Gadolinium, and Terbium. They are in sequence in the periodic table and therefore present very close ionic radii, restricting their separation. Considering the sum of all RE, Viewgam® was the most contaminated formulation (mean of 2.16 mg/L) and Magnevist® the least (mean of 0.64 mg/L). Although the RE are chemically similar, the other RE do not perform as Gd as a contrast agent; therefore, their presence in formulations may be a matter of concern.