Quantification of Gd species in a tetrameric Gd-based contrast agent using HPLC-ICP-MS

Abstract

This study presents a newly developed high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) method for quantification of Gd complexes in a tetrameric, macrocyclic Gd-based MRI contrast agent (GBCA). Since for the multimeric GBCA Gadoquatrane, currently in Phase III clinical development, mainly multinuclear Gd complexes are expected as by-products from the route of synthesis, HPLC-ICP-MS is suitable for the quantitative determination of these Gd species. The developed HPLC-ICP-MS method offers high sensitivity and accurate quantification based on external calibration with a generic Gd standard and is thus a powerful alternative to routinely used HPLC-UV in the pharmaceutical industry. The method allows for quantitatively detecting six different multimeric Gd-containing by-products in a Gadoquatrane sample taken from the early process development. A limit of quantification (LOQ) of 38 nmol/L is achieved for monomeric Gd complexes, which allows the quantitative determination of Gd species at levels as low as 0.004 mass% in the product. With this method, unknown Gd-containing by-products in GBCAs even at trace levels can be well assessed regarding their relevance in the further synthesis process optimization and in the drug substance control strategy. The elaborative synthesis of reference compounds for quantification of unknowns may be omitted, which can significantly accelerate the synthesis process optimization.