Solvent-free gadolinium contrast agents

Abstract

Disclosed herein are complexes of gadolinium metal, ligand and meglumine that are substantially free of non-aqueous solvents. In particular, solvent-free complexes of 1) gadopentetate dimeglumine and 2) gadoterate meglumine are disclosed and methods of their preparation are disclosed. In addition, methods are disclosed for purifying reactants, monitoring and controlling pH, quantifying the free gadolinium content, quantifying the concentration of gadolinium-ligand complex in aqueous solution, and procedures for producing a drug product in one step. The one step process eliminates the need to dry the gadolinium-ligand complex, which is typically highly hygroscopic. The one step process includes purification steps that do not require the use of non-aqueous solvents.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 15 / 855,570, filed Dec. 27, 2017, which claims benefit of U.S. Provisional Application No. 62 / 439,893, filed Dec. 29, 2016, both of which are hereby incorporated by reference in their entireties.TECHNICAL FIELD[0002]The present disclosure relates generally to metal chelates, particularly those of lanthanide metals, and in one specific embodiment, those of Gd(III), which are useful as contrast agents in magnetic resonance imaging for therapeutic and diagnostic applications, as well as clinical and biomedical research applications.BACKGROUND OF THE INVENTION[0003]Magnetic resonance imaging (MRI) is a powerful diagnostic method that yields three-dimensional images of body tissues in vivo. The tissue features obtained are the result of variations in the distribution of water in these tissues. MRI contrast agents administered prior to imaging alter the relaxation times of p...

AI Technical Summary

Benefits of technology

[0033]Generally, it is an object of the present invention to provide drug products and methods for synthesizing contrast agents capable of enhancing magnetic resonance images of body organs and tissues, and in particular, a ligand-gadolinium complex possessing an improved safety profile, reduced variability of product and absence of solvent contaminants. Other objects and features will be in part apparent and in part pointed out hereinafter.

Problems solved by technology

Consequently, medical contrast agents with a large pH range in the product specification present a safety concern regarding product stability and the potential for formation the release toxic Gd(III) from the complex.

The large pH range in the drug product is linked to the use of solvents in the drug purification process, which tends to remove ligand in an unpredictable fashion.

The synthetic methods attempted in the past to prepare paramagnetic metal chelates have one or more drawbacks such as the use of large excess of ligand to reduce free Gd(III) ion; or the need to carry out extensive solvent purification of product due to impurities in the original reagents.

Ironically, the biocompatible solvents used to purify the drug product can complex with the impurities they are meant to remove.

Thus, the use of gadolinium metal in vivo, for example gadolinium chloride or gadolinium oxide, is not safe and a water-soluble chelate of gadolinium must be used.

While a water soluble chelated gadolinium-based contrast agent is safer to inject in patients, the toxicity issues are not entirely solved.

However, Gd(III) ion, even if it does not form a water-insoluble compound, can still be toxic, since the reactivity of Gd(III) is very similar to Ca(II), and Ca(II) is ubiquitous in chemical pathways in the mammalian body.

Beyond this threshold concentration, any further increase in concentration results in little improvement in contrast enhancement.

Gd(III) can compete with Ca(II) in the chemical pathways of biological systems, and this substitution potential results in gadolinium toxicity to organisms.

This chelate effect can be compromised by the presence of solvent, which can form binding spheres with solvent rather than water.

Stronger acid conditions clearly results in lower complex stability.

There are additional ionic competitors besides protons that can affect complex stability.

The fact that transmetallation of gadolinium complexes results in the formation of a more unstable metal complex implies that the synthesis methodology can impact the magnitude of transmetallation.

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