Patent ID: 9655983
Date: 2017-05-23
CPC Classifications: A61K,A61P,G01N

Claim:
1. An 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%, wherein the process comprises the following successive steps: (b) preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide, and: free lanthanide, and optionally free macrocyclic chelate; said step (b) consisting of mixing a solution of free macrocyclic chelate and free lanthanide wherein the lanthanide/macrocyclic chelate mol/mol ratio is between 1.001 and 1.3; (c1) adjusting the pH of a sample of the liquid pharmaceutical formulation obtained in step (b) so that the concentration of free macrocyclic chelate C (c2) measuring in the sample of the liquid pharmaceutical formulation obtained in step (c1) the concentration of free lanthanide C (d) adjusting the concentration of free macrocyclic chelate C 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 in the final liquid pharmaceutical formulation; wherein the complex of macrocyclic chelate with a lanthanide is the meglumine salt of the DOTA-gadolinium complex, the macrocyclic chelate is DOTA and the lanthanide is gadolinium; wherein the operating steps (b) and (d) of the process occur in the same reactor; and wherein the liquid pharmaceutical formulation is an injectable solution.