Preparation of high-purity gadobutrol

Patent metadata

Field	Value
Publication number	US-10072027-B2
Application number	US-201214112994-A
Country	US
Kind code	B2
Filing date	Apr 17, 2012
Priority date	Apr 21, 2011
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

What is described is a process for producing high-purity gadobutrol in a purity (according to HPLC) of more than 99.7 or 99.8 or 99.9% and the use for preparing a pharmaceutical formulation for parenteral administration. The process is carried out using specifically controlled crystallization conditions. The more recent developments in the field of the gadolinium-containing MR contrast agents (EP 0448191 B1, CA Patent 1341176, EP 0643705 B1, EP 0986548 B1, EP 0596586 B1) include the MRT contrast agent gadobutrol (Gadovist® 1.0) which has been approved for a relatively long time in Europe and more recently also in the USA under the name Gadavist®.

First claim

The invention claimed is:

1. Gadobutrol in a purity (according to HPLC) of more than 99.9%, comprising less than 0.01% of free gadolinium(III) ions,
a residual ethanol solvent content of less than 200 ppm, and a proportion of butrol ligand, N-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, of less than 0.03%,
wherein the gadobutrol is in the form of a polymorph I monohydrate I.

2. Gadobutrol of claim 1 , having a water content of from 3.0% to 3.5%.

3. A pharmaceutical formulation for parenteral administration comprising gadobutrol having a purity of more than 99.9%,
wherein the gadobutrol is crystallized from ethanol: water having a water content of from 10.5% to 12.0% to provide the gadobutrol with a purity (according to HPLC) of more than 99.9%, and
wherein the gadobutrol comprises less than 0.01% of free gadolinium(III) ions, a residual ethanol solvent content of less than 200 ppm, and a proportion of butrol ligand, N-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, of less than 0.03%, and
wherein the gadobutrol is in the form of a polymorph I monohydrate I.

4. A pharmaceutical formulation for parenteral administration comprising gadobutrol according to claim 1 .

5. The pharmaceutical formulation of claim 4 , wherein the formulation further comprises from 0.08% to 0.14% of calcobutrol.

6. The pharmaceutical formulation of claim 5 , wherein the total amount of calcobutrol and free butrol ligand in the formulation is less than 0.14% of the pharmaceutical formulation.

7. The pharmaceutical formulation of claim 3 , wherein the formulation further comprises from 0.08% to 0.14% of calcobutrol.

8. The pharmaceutical formulation of claim 7 , wherein the total-amount of calcobutrol and free butrol ligand in the formulation is less than 0.14% of the pharmaceutical formulation.

Assignees

• Platzek Johannes
• Trentmann Wilhelm
• Bayer Ip Gmbh

Inventors

• Platzek Johannes
• Trentmann Wilhelm

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D257/02 Primary

  not condensed with other rings · CPC title

• C07F5/003 Primary

  without C-Metal linkages · CPC title

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K49/108

  the metal complex being Gd-DOTA · CPC title