Process for preparing a pharmaceutical formulation of contrast agents

摘要

The invention relates to a 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%, advantageously between 0.02% and 0.3% and very advantageously between 0.025% and 0.25%, the macrocyclic chelate advantageously being chosen from DOTA, NOTA, DOTAGA, DO3A, BT-DO3A, HP-DO3A and PCTA, and is preferably DOTA, the said process comprising the following successive steps: b) preparation of a liquid pharmaceutical composition containing, firstly, the complex of macrocyclic chelate with a lanthanide, and, secondly, free macrocyclic chelate and/or free lanthanide; c) measurement in the pharmaceutical formulation obtained in step b) of the concentration of free macrocyclic chelate Cch1 and/or of free lanthanide Clan1; d) adjustment of Cch1 and/or of Clan1 so as to obtain Cch1=Ct ch1 and Clan1=0, wherein Ct ch1 is the target concentration of free macrocyclic chelate in the final liquid pharmaceutical formulation.

主权项

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 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 optionally free lanthanide;
said step b) consisting of mixing a solution of free macrocyclic chelate and of free lanthanide, 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, c1) adjusting the pH of a sample of the liquid pharmaceutical formulation obtained in step b) so that the concentration of free lanthanide Clan 1 is equal to 0; c2) measuring, in the sample of the liquid pharmaceutical formulation obtained in step c1), the concentration of free macrocyclic chelate Cch 1; d) adjusting Cch 1 and Clan 1 in the liquid pharmaceutical formulation obtained in step b) so as to obtain Cch 1=Ct ch 1 and Clan 1=0 based on the measurements obtained in step c2),
by adding free lanthanide to the liquid pharmaceutical formulation obtained in step b) if Cch 1>Ct ch 1, orby adding further free macrocyclic chelate if Cch 1