Abstract: Macrocyclic gadolinium-based contrast agents (GCA) are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species quickly release free Gd3+ ions upon delivery into the body. Aqueous or dry/solid GCA with near zero metastable species content and methods of synthesizing the same are disclosed.

Abstract: The present disclosure relates to pharmaceutical formulations of contrast agents used in magnetic resonance imaging (MRI) and methods of making and purifying the same. More specifically, disclosed are such pharmaceutical formulations of chelate complexes with lanthanide metal ions, such as gadolinium ions, as well as methods for obtaining and purifying the same. In particular, the pharmaceutical formulations are free or substantially free of water molecules coordinated with the lanthanide metal chelate complexes and provide pharmaceutical compositions that are more stable and release less lanthanide ion, specifically gadolinium ion, into the human body when injected as MRI contrast agents as compared to other typically used MRI contrast agents.

Abstract: Gadolinium based contrast agents (GCA) incorporating linear ligand chelation are fundamentally different from GCAs incorporating macrocyclic ligands. The macrocyclic GCAs are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. The synthesis of linear GCAs do not form metastable complexes. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species are not regulated and quickly release free Gd3+ ions upon administration into the body. Gadolinium based contrast agents with near zero metastable species content and methods of synthesizing the same are disclosed. Gadolinium based contrast agents with long dissociation time in the body, and low free Gd3+ ion formation are obtained using a synthesis method which departs in novel ways from the traditional free Gd3+-based synthesis methods.

Abstract: Gadolinium based contrast agents (GCA) incorporating linear ligand chelation are fundamentally different from GCAs incorporating macrocyclic ligands. The macrocyclic\GCAs are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. The synthesis of linear GCAs do not form metastable complexes. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species are not regulated and quickly release free Gd3+ ions upon administration into the body. Gadolinium based contrast agents with near zero metastable species content and methods of synthesizing the same are disclosed. Gadolinium based contrast agents with long dissociation time in the body, and low free Gd3+ ion formation are obtained using a synthesis method which departs in novel ways from the traditional free Gd3+-based synthesis methods.

Abstract: Macrocyclic gadolinium-based contrast agents (GCA) are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species quickly release free Gd3+ ions upon delivery into the body. Aqueous or dry/solid GCA with near zero metastable species content and methods of synthesizing the same are disclosed.

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.

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.