Determination of calcium in gadolinium-based contrast agents using inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) in the cool plasma/N2O reaction mode

Calcium (Ca), as an impurity, can affect the efficacy and safety of gadolinium-based contrast agents (GBCAs) through ligand competition, precipitation formation, or biological interference. To meet the requirements of GBCA analysis and testing and ensure the quality and safety of GBCAs, a novel strategy was proposed to determine Ca content in GBCAs using inductively coupled plasma tandem mass spectrometry (ICP-MS)/MS. The sample was directly analyzed using ICP-MS/MS after dilution with 2 % nitric acid. Under cool plasma conditions, the formation of ⁴⁰Ar⁺ was reduced by inhibiting the ionization of the plasma gas Ar at low temperatures. In the MS/MS mode, with N₂O as the reaction gas, and based on the case that ⁴⁰Ca¹⁶O⁺ was generated through the O-atom transfer reaction between ⁴⁰Ca⁺ and N₂O (⁴⁰Ca⁺ + N₂O → ⁴⁰Ca¹⁶O⁺ + N₂) and that other interfering ions did not undergo the mass shift reaction with N₂O, spectral interference was eliminated using the mass shift method. The accuracy, reliability, and precision of the method were evaluated by analyzing standard reference materials (NIST SRM 1640a and NIST SRM 1643f) and performing spike recovery. The limit of detection (LOD) of Ca was as low as 1.35 ng L⁻¹ (obtained for ⁴⁰Ca), the relative standard deviation was 1.8 %–2.7 %, and the spike recovery was 98.6 %–102 %. Thus, a systematic method was established using ICP-MS/MS to accurately quantify the challenging element Ca in GBCAs and to highlight its potential in other fields.