Synthesis methods and compositions of low intermediate and low dichelate intermediate contrast agents

A method of making a lanthanide series contrast agent, wherein the lanthanide series contrast agent comprises at least one atom of lanthanide series metal and at least one macrocyclic chelate, said method comprising:

• (a) reacting a macrocyclic chelate with a lanthanide series metal oxide in water at a temperature and reaction time sufficient to provide a lanthanide series metal ion:macrocyclic chelate complex, wherein the macrocyclic chelate is 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and has <10 ppm impurities containing a cyclen ring, and wherein the lanthanide series metal is gadolinium;
• (b) monitoring the reaction of the macrocyclic chelate with the lanthanide series metal oxide to determine a content of metastable intermediates, wherein the metastable intermediates are partially chelated complexes of the lanthanide series metal ion:macrocyclic chelate complex;
• (c) returning to (a) if the content of metastable intermediates determined by (b) exceeds 500 parts per million relative to a total amount of the lanthanide series metal ion:macrocyclic chelate complexes present;
• and
• (d) reacting the lanthanide series metal ion:macrocyclic chelate complex with a base at a temperature and reaction time sufficient to provide a complex of lanthanide series metal ion, macrocyclic chelate, and base in an aqueous formulation, wherein the aqueous formulation comprises less than about 500 parts per million of metastable intermediates relative to a total amount of the lanthanide series metal ion:macrocyclic chelate complexes present in the aqueous formulation,
• wherein the method is performed without use of solvents.