PROCESS FOR PRODUCING A CONTRAST AGENT

Abstract

Disclosed is a process for producing a contrast agent-containing pharmaceutical preparation, which contains as the contrast agent a complex of a lanthanide, in particular gadolinium, and a macrocyclic chelate, in particular DOTA.

Claims

1. Method for producing a liquid, in particular aqueous, preparation containing, as contrast agent, in particular as contrast agent for magnetic resonance, a complex of a lanthanide and a macrocyclic chelate, the preparation containing free macrocyclic chelate, the method comprising: a) dissolving macrocyclic chelate in water, b) adding a lanthanide, c) adding a base, d) carrying out the complexing of the lanthanide with the macrocyclic chelate, in the presence of the base, at a pH above 5.5, in particular at a pH between 6.5 and 8.0, e) adjusting the pH of the solution obtained after step d) to a value below 5.0, f) adjusting the pH to a value above 6.5, and g) diluting the solution obtained after step g) to the specified final volume.

2. The method according to claim 1, wherein gadolinium is used as lanthanide.

3. The method according to claim 1, wherein the lanthanide is used as oxide, in particular gadolinium as gadolinium oxide.

4. The method according to claim 1, wherein DOTA is used as the macrocyclic chelate.

5. The method according to claim 1, wherein in step c) an organic base is added.

6. The method according to claim 5, wherein the base is added in step c) in a deficit with respect to the lanthanide used.

7. The method according to claim 1, wherein DOTA is used to adjust the pH in step e).

8. The method according to claim 1, wherein the pH in step f) is adjusted to a value between 6.5 and 8.0, in particular to a value between 6.8 and 7.5.

9. The method according to claim 1, wherein the adjustment of the pH in step f) is carried out with a base, in particular with meglumine.

10. The method according to claim 1, wherein lanthanide and the macrocyclic chelate are used in molar amounts different from one another or in equal molar amounts.

11. The method according to claim 10, wherein the macrocyclic chelate is used in a deficit with respect to the lanthanide used.

12. The method according to claim 1, wherein chelate, in particular DOTA, in particular up to a content of 500 to 799 ppm, is added after step e).

13. The method according to claim 1, wherein the base, in particular meglumine, is present in a stoichiometric deficit with respect to the lanthanide used and in a stoichiometric surplus with respect to the macrocyclic chelate used.

14. The method according to claim 1, wherein the lanthanide is in a stoichiometric surplus with respect to the macrocyclic chelate when step d) is carried out.

15. The method of claim 1, wherein step f) is performed to adjust the pH to a value above 7.0.

16. The method of claim 1, wherein step f) is performed to adjust the pH to a value between 7.0 and 7.5.

17. The method according to claim 2, wherein the lanthanide is used as oxide, in particular gadolinium as gadolinium oxide.

18. The method according to claim 2, wherein DOTA is used as the macrocyclic chelate.

19. The method according to claim 3, wherein DOTA is used as the macrocyclic chelate.

20. The method of claim 5, wherein the organic base is meglumine.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] Examples of the method according to the invention are given below:

Example 1: Amounts: DOTA: 97.0%, Meglumine: 99.8%

[0072] 104.22 g DOTA (the weight is corrected according to the water content and calculated to 97.0%) are dissolved in approx. 300 ml water at a temperature of from 75 C. to 80 C. 45.59 g of gadolinium oxide (the weight was corrected according to the purity) are added and the mixture is stirred at a temperature of at least 75 C. for at least one hour. 43.71 g meglumine are then added to the solution, which is then stirred at a temperature of least at 75 C. for at least one hour. The pH of the solution is approx. 7. By adding a defined amount of DOTA, the pH of the solution is adjusted to approx. 6 (for example pH=6.3). DOTA is added to the solution in small portions with the aim of adjusting the pH to below 5.5, preferably to below 5.0. After the pH of 4.9 is reached, DOTA corresponding to 660 ppm is also added to the solution. The pH of 4.4 is then adjusted to using meglumine. The reaction mixture is made up to a total volume of 500 ml, filtered and autoclaved.

Example 2: Amounts: DOTA: 98.0%, Meglumine: 99.7%

[0073] 106.20 g DOTA (the weight is corrected according to the water content and calculated to 98.0%) are dissolved in approx. 300 ml water at a temperature of from 75 C. to 30 C. 45.59 g of gadolinium oxide (the weight was corrected according to the purity) are added and the mixture is stirred at a temperature of at least 75 C. for at least one hour. 48.66 g meglumine are then added to the solution, which is then stirred at a temperature of least at 75 C. for at least one hour. The pH of the solution is approx. 7. By adding a defined amount of DOTA, the pH of the solution is adjusted to approx. 6 (pH=6.1). DOTA is added to the solution in small portions with the aim of adjusting the pH to below 5.5, preferably to below 5.0. After the pH of 4.4 is reached, DOTA corresponding to 620 ppm is also added to the solution. The pH of 3.9 is then adjusted to 7.1 using meglumine.

[0074] The reaction mixture is made up to a total volume of 500 ml, filtered and autoclaved.

Example 3: Amounts: DOTA: 98.0%, Meglumine: 99.5%

[0075] 106.20 g DOTA (the weight is corrected according to the water content and calculated to 98.0%) are dissolved in approx. 300 ml water at a temperature of from 75 C. to 80 C. 45.59 g of gadolinium oxide (the weight was corrected according to the purity) are added and the mixture is stirred at a temperature of at least 75 C. for at least one hour. 48.56 g meglumine are then added to the solution, which is then stirred at a temperature of least at 75 C. for at least one hour. The pH of the solution is approx. 7. By adding a defined amount of DOTA, the pH of the solution is adjusted to approx. 6 (pH=5.9). DOTA is added to the solution in small portions with the aim of adjusting the pH to below 5.5, preferably to below 5.0. After the pH of 4.7 is reached, DOTA corresponding to 910 ppm is also added to the solution. The pH of 4.1 is then adjusted to 7.1 using meglumine. The reaction mixture is made up to a total volume of 500 ml, filtered and autoclaved.

TABLE-US-00001 Free DOTA amount in the autoclaved Example number Mixture number final product (ppm) Example 1 E-17-0087-G 934 Example 2 E-17-0086-G 797 Example 3 E-17-0077-G 460

[0076] The above-mentioned indicator reaction to determine the ratio of DOTA and meglumine and to check the equilibrium in the solution can be carried out in all cases in a supportive manner, so that fluctuations in the starting proportions of the three starting materialsmixed in a preparation vesselcan be well tracked.

[0077] As shown in the examples, the final content of excess DOTA can be adjusted to approx. 200 to 2000 ppm in the method according to the invention.

[0078] In the case of industrial amounts, the filling to the total volume is a step in which, with well-defined starting amounts, the adjustment to the final volume often requires only a small change, thus eliminating the need to readjust the amount of free DOTA.

[0079] If necessary, a corresponding adjustment can be made on a laboratory scale before the autoclaving.

[0080] In summary, an embodiment of the invention can be described as follows:

[0081] A method for producing a contrast-agent-containing pharmaceutical preparation, which contains, as contrast agent, a complex of a lanthanide, in particular gadolinium, and a macrocyclic chelate, in particular DOTA, is described.