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

Area of Science:

• Analytical Chemistry
• Pharmacology
• Radiochemistry

Background:

• Gadolinium-based contrast agents (GBCAs) are crucial for Magnetic Resonance Imaging (MRI).
• Ensuring the purity of GBCAs, such as the tetrameric macrocyclic agent Gadoquatrane, is vital for patient safety and drug efficacy.
• Synthesis of complex GBCAs can lead to various Gd-containing by-products that require precise quantification.

Purpose of the Study:

• To develop and validate a sensitive analytical method for quantifying Gd complexes in GBCAs.
• To establish a method capable of detecting and quantifying multinuclear Gd complexes and other by-products in Gadoquatrane.
• To provide a powerful alternative to existing methods like HPLC-UV for pharmaceutical quality control.

Main Methods:

• High-Performance Liquid Chromatography-Inductively Coupled Plasma-Mass Spectrometry (HPLC-ICP-MS) was developed.
• The method utilizes external calibration with a generic Gd standard for accurate quantification.
• The technique was applied to analyze a Gadoquatrane sample from early process development.

Main Results:

• The HPLC-ICP-MS method demonstrated high sensitivity and accuracy for Gd complex quantification.
• Six different multimeric Gd-containing by-products were quantitatively detected in the Gadoquatrane sample.
• A limit of quantification (LOQ) of 38 nmol/L for monomeric Gd complexes was achieved, enabling detection as low as 0.004 mass%.

Conclusions:

• The developed HPLC-ICP-MS method is a robust tool for assessing unknown Gd-containing by-products in GBCAs at trace levels.
• This method significantly aids in optimizing synthesis processes and establishing drug substance control strategies.
• The ability to quantify by-products without synthesizing reference compounds accelerates pharmaceutical development timelines.