Purification of X-ray contrast agents

Patent metadata

Field	Value
Publication number	US-9938233-B2
Application number	US-201314442203-A
Country	US
Kind code	B2
Filing date	Nov 19, 2013
Priority date	Dec 19, 2012
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

The present invention relates to a process for purification of iodinated X-ray contrast agents and in particular to purification of crude dimeric contrast agents, such as Iodixanol and Ioforminol. More particularly, the invention relates to purification of such X-ray contrast agents using membrane technology to remove monomeric impurities.

First claim

The invention claimed is:

1. A process of purifying a crude dimeric X-ray contrast agent product that comprises monomeric compound impurities and salts and a dimeric agent that is the dimer of the monomeric compound, the process comprising a first step of
i) passing a solution of the crude product across a membrane (M1) such that the monomeric compound impurities and the salts cross the membrane (permeate, P1) and the dimeric X-ray contrast agent passes over the membrane (retentate, R1), to provide a purified dimeric X-ray contrast agent,
wherein the monomeric compound impurities are compounds having a molecular weight between 435 and 900 Da, and
wherein M1 has a cut-off size between 950 and 1200 Da.

2. The process of claim 1 , wherein the dimeric X-ray contrast agent has a molecular weight of 1400-1700 Da.

3. The process of claim 1 , wherein the dimeric X-ray contrast agent is loforminol or Iodixanol.

4. The process of claim 1 , wherein the monomeric compound impurities have a molecular weight between 700 and 850 Da.

5. The process of claim 1 , wherein the retentate (R1) of the step (i) is retained and collected.

6. The process of claim 1 , wherein the purified dimeric X-ray contrast agent obtained holds a purity of at least 98%.

7. The process of claim 1 , wherein there is less than 2% of the monomeric compound impurities and salts left in R1 after the process is conducted.

8. The process of claim 1 , further comprising a second step
ii) wherein the permeate from step i) (P1) is passed across another membrane (M2) such that salts cross this membrane (permeate, P2) and the monomeric compound impurities passes over the membrane (retentate, R2), and wherein the retentate R2 is retained.

9. The process of claim 8 , wherein the permeate (P1) from step i), or the retentate (R2) from step (ii), is subject to another round of purification by repeating step (i) of the process to recover dimeric X-ray contrast agent lost in the first round.

10. The process of claim 8 , wherein the retentate R2 is transferred to the crude product and mixed with this crude product, or is combined with a feed stream from the crude product, before repeating step i).

11. A composition comprising a dimeric contrast agent purified according to the process as claimed in claim 1 , together with at least one physiologically tolerable carrier or excipient.

12. A process of purifying a crude dimeric X-ray contrast agent product that comprises monomeric compound impurities and salts and a dimeric agent that is the dimer of the monomeric compound, the process comprising a first step of
i) passing a solution of the crude product across a membrane (M1) such that the monomeric compound impurities and the salts cross the membrane (permeate, P1) and the dimeric X-ray contrast agent passes over the membrane (retentate, R1),
wherein the retentate (R1) of the step (i) is retained and collected to provide a purified dimeric X-ray contrast agent, and wherein the dimeric X-ray contrast agent has a molecular weight of 1400-1700 Da, and
wherein there is less than 2% of the monomeric compound impurities and salts left in R1 after the process is conducted, and
wherein M1 has a cut-off size between 950 and 1200 Da.

13. The process of claim 12 , wherein the dimeric X-ray contrast agent is loforminol or Iodixanol.

14. The process of clam 12 , wherein the purified dimeric X-ray contrast agent obtained holds a purity of at least 98%.

15. The process of claim 12 , wherein a membrane (M1) is used having a cut-off size between 950 and 1200 Da.

16. The process of claim 12 , further comprising a second step
ii) wherein the permeate from step i) (P1) is passed across another membrane (M2) such that salts cross this membrane (permeate, P2) and the monomeric compound impurities passes over the membrane (retentate, R2), and wherein the retentate R2 is retained.

17. The process of claim 16 , wherein the permeate (P1) from step i), or the retentate (R2) from step (ii), is subject to another round of purification by repeating step (i) of the process to recover dimeric X-ray contrast agent lost in the first round.

18. The process of claim 16 , wherein the retentate R2 is transferred to the crude product and mixed with this crude product, or is combined with a feed stream from the crude product, before repeating step i).

19. A composition comprising a dimeric contrast agent purified according to the process as claimed in claim 12 , together with at least one physiologically tolerable carrier or excipient.

20. The process of clam 12 , wherein the purified dimeric X-ray contrast agent obtained holds a purity of at least 99.0%.

Assignees

• Ge Healthcare As

Inventors

• Cervenka Jan
• Thaning Mikkel
• Olsson Andreas
• Glogard Christian

Classifications

• C07C237/46

  having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring · CPC title

• A61K49/0438

  Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol · CPC title

• A61K49/0447

  Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound · CPC title

• C07C231/24 Primary

  Separation; Purification · CPC title