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.

1 - 21 . (canceled) 
     
     
         22 . A gadolinium contrast agent comprising a complex of Gd(III) ion, ligand and meglumine in an aqueous formulation suitable for injection in a mammal, wherein:
 the formulation comprises not more than 0.025% by weight of free ligand;   the formulation comprises less than 100 parts per million of free Gd(III) ion; and   the formulation comprises less than 50 parts per million of non-aqueous solvent.   
     
     
         23 . The gadolinium contrast agent of  claim 22 , wherein the formulation comprises less than 10 parts per million of free Gd(III) ion 
     
     
         24 . The gadolinium contrast agent of  claim 22 , wherein the formulation comprises less than 1 part per million of free Gd(III) ion. 
     
     
         25 . The gadolinium contrast agent of  claim 22 , wherein the formulation comprises less than 0.5 part per million of free Gd(III) ion. 
     
     
         26 . The gadolinium contrast agent of  claim 22 , wherein the formulation comprises less than 0.1 part per million of free Gd(III) ion. 
     
     
         27 . The gadolinium contrast agent of  claim 22 , wherein the formulation comprises less than 1 part per million of non-aqueous solvent. 
     
     
         28 . The contrast agent of  claim 22 , wherein the complex is gadopentetate dimeglumine. 
     
     
         29 . The contrast agent of  claim 22 , wherein the complex is gadoterate meglumine. 
     
     
         30 . The contrast agent of  claim 22 , wherein the formulation comprises less than 0.020% by weight of free ligand. 
     
     
         31 . The contrast agent of  claim 22 , wherein the formulation has a pH in the range of from about 7.2 to about 7.5. 
     
     
         32 . The contrast agent of  claim 22 , wherein the complex has a conditional thermodynamic stability constant, at pH 7.4, in the range of from about 18.1 to about 18.6. 
     
     
         33 . The contrast agent of  claim 22 , comprising less than 10 parts per million of non-Gd pentetic acid complexes. 
     
     
         34 . A method of making a gadolinium contrast agent, comprising intermixing Gadolinium oxide, ligand, meglumine and water in the absence of a non-aqueous solvent to form an aqueous formulation suitable for injection in a mammal, wherein:
 the formulation comprises not more than 0.025% by weight of free ligand;   the formulation comprises less than 100 parts per million of free Gd(III) ion; and   the formulation comprises less than 50 parts per million of non-aqueous solvent.   
     
     
         35 . The method of  claim 34 , wherein the formulation comprises less than 10 parts per million of free Gd(III) ion 
     
     
         36 . The gadolinium contrast agent of  claim 34 , wherein the formulation comprises less than 1 part per million of free Gd(III) ion. 
     
     
         37 . The method of  claim 34 , wherein the complex is in a hydrated state of at least 1% by weight water during each method step. 
     
     
         38 . The method of  claim 34 , comprising the steps of: i) preparing an aqueous solution of the ligand, ii) preparing a gadolinium:ligand complex in water, iii) verifying free gadolinium content in the complex, iv) verifying gadolinium:ligand complex formation, v) preparing a gadolinium:ligand meglumine solution, and vi) filtering the gadolinium:ligand meglumine solution. 
     
     
         39 . The method of  claim 34 , wherein the ligand is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). 
     
     
         40 . The method of  claim 34 , wherein the ligand is pentetic acid. 
     
     
         41 . A method of reducing the risk of nephrogenic systemic fibrosis in a patient receiving a gadolinium contrast agent comprising administering to the patient the gadolinium contrast agent of  claim 22 .