Process for preparing a pharmaceutical formulation of contrast agents

Industrial process for preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide and a mol/mol amount of free macrocyclic chelate of between 0.002% and 0.4%, said process comprising the following successive steps:

• b) preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide, and:
• free macrocyclic chelate,
• and/or free lanthanide;
• said step b) consisting of mixing a solution of free macrocyclic chelate and of free lanthanide, so as to obtain complexation of the lanthanide by the macrocyclic chelate, the amounts of free macrocyclic chelate and of free lanthanide being such that the macrocyclic chelate/lanthanide mol/mol ratio is between 1.001 and 1.3 and all the lanthanide is complexed and that Cch 1>Ct ch 1,
• with Cch 1 representing the concentration of free macrocyclic chelate, and
• Ct ch 1 representing the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical formulation, Ct ch 1 being selected in the range of between 0.002% and 0.4% mol/mol;
• c) measuring, in a sample of the liquid pharmaceutical formulation obtained in step (b), Cch 1, the concentration of free lanthanide Clan 1 being equal to 0 by adjusting the pH of the sample of liquid pharmaceutical formulation;
• d) adjusting Cch 1 and Clan 1 in the liquid pharmaceutical formulation by adding free lanthanide to the liquid pharmaceutical formulation obtained in step b), so as to obtain Cch 1=Ct ch 1 and Clan 1=0,
• wherein the amount of free macrocyclic chelate in the final liquid pharmaceutical formulation corresponds to the proportion of free macrocyclic chelate relative to the amount of complexed macrocyclic chelate DOTA-Gd in the final liquid pharmaceutical formulation in mol/mol,
• wherein the macrocyclic chelate is DOTA and the lanthanide is gadolinium,
• and wherein the operating steps b) and d) of the process occur in the same reactor.