Magnetic resonance imaging (MRI) procedures require gadolinium-based contrast agents (GBCAs) to improve their effectiveness. The paramagnetic characteristics of Gadolinium (Gd³⁺) are demonstrated through its half-filled f orbital that carries seven unpaired electrons to improve MRI image quality through its modification of water molecule T1 and T2 relaxation times. GBCAs rely on a paramagnetic gadolinium core together with a ligand-based structure that mitigates gadolinium’s potential toxicity. The multinucleated ligands fulfill two functions: they promote gadolinium excretion while simultaneously protecting against toxicity.
Besides enhancing MRI diagnostics, GBCAs have been linked to health complications that include acute kidney injury together with gadolinium encephalopathy, culminating in the development of nephrogenic systemic fibrosis (NSF) and scleroderma-spectrum disorders.
Scientific studies publishing evidence of gadolinium-NSF correlations started in 2006, and researchers demonstrated that bone marrow fibrocytes serve as fibrotic mediators. Reports of gadolinium accumulation in humans and animals demonstrated its long-term storage patterns, especially within brain tissue, as observed following linear and macrocyclic GBCA exposure in both patient and animal populations, including those exposed to ProHance and Gadovist types. Medical experts, through autopsy investigations, have documented trace amounts of gadolinium in the brain tissue of individuals who received MRI scans during their childhood years.
The study used pharmaceutical-grade Dotarem and Omniscan provided by Guerbet and GE Healthcare, together with chemicals purchased from Millipore-Sigma and Fisher Scientific, through which they obtained oxalic acid, BSA, potassium hydroxide, potassium chloride, and gadoteric acid. Different parameters required for the gadoteric acid solution were obtained through a water-based acid solution combined with sodium hydroxide as a dissolving agent. The Eppendorf Biospectrometer processed spectrophotometric measurements, while the pH evaluation relied on a Mettler Toledo Seven Compact and Expert-Pro ISM electrode. The total volume of the liquid was 1.5 ml. The precipitation measurements were evaluated at a wavelength of 605 nm. The contrast agent was added immediately, followed by vortex mixing, and spectral measurements were taken after the addition of all components.
At 25°C, Omniscan (166.6 mM) rapidly reacts with oxalic acid (333.3 mM) to produce a white solid precipitate. The white precipitate formed by GdCl₃ resembles Gd₂(C₂O₄)₃ through its formation of small crystalline shapes under 10 μm. Therefore, XPS elemental analysis revealed carbon (9.57 ± 0.05%) and hydrogen (2.59 ± 0.04%) with no nitrogen detected. Laboratory results match the data observed when creating Gd₂(C₂O₄)₃ using GdCl3 along with oxalic acid.
The reaction between Dotarem solution and oxalic acid progresses in two reaction steps. The first reaction produced no signal at 605 nm, so the process resulted in a delay period before precipitation started. The measurement of the initial reaction rate depends on the delay time because spectrophotometric quantification analysis becomes possible.
The interaction of Dotarem with oxalic acid is characterized by decreasing delay time (td) and the observed precipitation rate (kprecip) upon increasing temperature. Activation energies from calculations provide 18.9 kJ/mol for the first step and 25.0 kJ/mol for the precipitation step, both lower than for water exchange.
The rise in oxalic acid levels between 33.3 mM to 333.3 mM decreases the amount of time needed for precipitation (td) but increases the measured rate of precipitation (kprecip). Increasing the concentration of Dotarem from 33.3 mM to 166.7 mM produces a decrease in delay time(td) and an increase in the observed precipitation rate (kprecip).
The rise in oxalic acid levels between 33.3 mM to 333.3 mM decreases the amount of time needed for precipitation (td) but increases the measured rate of precipitation (kprecip). Increasing the concentration of Dotarem from 33.3 mM to 166.7 mM produces a decrease in delay time and an increase in the observed precipitation rate. The speed of Dotarem precipitation with oxalic acid increases significantly when BSA concentrations between 0.0% w/v and 8.3% w/v are added to the solution.
The presence of protein BSA in increasing concentrations leads to elevated precipitation rates (observed and measured) during the reaction phase. Initial pH measurements show that the solution containing Dotarem and oxalic acid maintains a value of 1.27. Raising the solution pH to 2.19 causes kprecip to lower but leaves td unaffected. No precipitates appear at pH values above 2.19 without BSA present, yet 1.67% BSA reintroduces some precipitation at these pH conditions.
References: Henderson IM, Benevidez AD, Mowry CD, et al. Precipitation of gadolinium from magnetic resonance imaging contrast agents may be the brass tacks of toxicity. Magnetic Resonance Imaging. 2025;119:110383. doi:10.1016/j.mri.2025.110383
