Method for producing a liquid pharmaceutical preparation
A method for producing a liquid pharmaceutical preparation which contains a complex consisting of DOTA and gadolinium and a base such as L-lysine or meglumine, includes the following steps: a) An aqueous solution containing free DOTA, free gadolinium and a base such as L-lysine or meglumine is produced. b) The yield of free DOTA and free gadolinium is determined in the solution obtained according to step a). c) Free gadolinium and/or free DOTA is added in order to adjust a stoichiometric excess of free DOTA in the solution. d) The complexation is executed at an increased temperature. e) Additional base such as L-lysine or meglumine is added in order to adjust the pH value. f) The final volume of the preparation is adjusted.
1. A method for producing a liquid pharmaceutical preparation that contains a complex that consists of DOTA and gadolinium as well as a base the method comprising the following steps :
a) producing an aqueous solution that consists of DOTA, gadolinium, and a base,
b) determining the content of free DOTA and free gadolinium in the solution obtained according to step a),
c) adding free gadolinium and/or free DOTA in order to adjust a content of free DOTA of 200-1500 ppm in the solution that is obtained according to step a), relative to the complex, whereby the addition of free DOTA and free gadolinium is carried out in such a way that there is no free gadolinium in the preparation,
d) carrying out complexing at elevated temperature,
e) adding more of the base in order to adjust the pH, and
f) setting the final volume.
2. The method according to claim 1 , wherein for producing the solution according to step a), first DOTA is dissolved in water at elevated temperature, and then gadolinium is added.
3. The method according to claim 1 , wherein the complexing is completed by further addition of the base.
4. The method according to claim 1 , wherein step a) is carried out at a temperature of between 60° C. and 95° C.
5. The method according to claim 1 , wherein the solution is stirred when steps a) and/or d) is/are carried out.
6. The method according to claim 1 , wherein in step c), the addition of free gadolinium and/or free DOTA is carried out in two or more than two partial amounts.
7. The method according to claim 1 , wherein free DOTA is added in the form of a solution and/or free gadolinium is added in the form of a solution.
8. The method according to claim 1 , wherein the gadolinium is added as an oxide (Gd 2 O 3 ) and in the oxidation stage +III.
9. The method according to claim 1 , wherein the concentration of free DOTA in the preparation is 180-2000 ppm relative to the complex.
10. The method according to claim 1 , wherein the concentration of free gadolinium in the preparation is less than 10 ppm.
11. The method according to claim 1 , wherein the pH in step e) is adjusted to a value of between 7.0 and 7.2.
12. The method of claim 1 , wherein the base is meglumine or L-lysine.
13. The method of claim 3 , wherein the base added is meglumine or L-lysine.
14. The method according to claim 2 , wherein the complexing is completed by further addition of the base.
15. The method according to claim 2 , wherein step a) is carried out at a temperature of between 60° C. and 95° C.
16. The method according to claim 3 , wherein step a) is carried out at a temperature of between 60° C. and 95° C.
17. The method according to claim 2 , wherein the solution is stirred when steps a) and/or d) is/are carried out.
18. The method according to claim 3 , wherein the solution is stirred when steps a) and/or d) is/are carried out.
19. The method according to claim 4 , wherein the solution is stirred when steps a) and/or d) is/are carried out.
20. The method according to claim 2 , wherein in step c), the addition of free gadolinium and/or free DOTA is carried out in two or more than two partial amounts.