Method for detecting trifluridine- and/or tipiracil-related substance

Patent metadata

Field	Value
Publication number	US-10866219-B2
Application number	US-201815952367-A
Country	US
Kind code	B2
Filing date	Apr 13, 2018
Priority date	Dec 22, 2017
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

This invention provides a method that is capable of detecting a trifluridine-related substance and a tipiracil-related substance contained in a sample containing trifluridine or a salt thereof and tipiracil or a salt thereof using the same procedure. The method is for detecting a trifluridine-related substance or a tipiracil-related substance or both, the method comprising the step of subjecting a sample containing trifluridine or a salt thereof and tipiracil or a salt thereof to high-performance liquid chromatography using a mobile phase composed of an organic phase and an aqueous phase.

First claim

The invention claimed is:

1. A method for detecting a trifluridine-related substance or a tipiracil-related substance or both,
subjecting a sample containing trifluridine or a salt thereof and tipiracil or a salt thereof to high-performance liquid chromatography with a mobile phase comprising an organic phase and an aqueous phase; and
detecting at least one trifluridine-related or tipiracil-related substance contained in the sample,
wherein the at least one trifluridine-related or tipiracil-related substance includes 2′ deoxy-5-methoxycarbonyluridine being a related substance 4.

2. The method according to claim 1 , wherein
the detecting comprises detecting related substances 2 and 5 as well as the related substances 1, 3 and 4 contained in the sample, the related substance 1 is trifluorothymine, the related substance 2 is 2-iminopyrrolidine, the related substance 3 is 5-chloro-6-{(2-oxopyrrolidin-1-yl)methyl}pyrimidine-2,4-(1H,3H)-dione, and the related substance 5 is 5-carboxyuracil.

3. The method according to claim 2 , wherein the subjecting comprises performing the high-performance liquid chromatography such that the difference in retention time between the related substance 3 and trifluridine is 1.0 minute or longer.

4. The method according to claim 2 , wherein the percentage of the organic phase with respect to the entire mobile phase at retention times of the related substances 1 to 5, trifluridine, and tipiracil is within a range of 7 to 15% by volume.

5. The method according to claim 2 , wherein the organic phase comprises methanol.

6. The method according to claim 2 , wherein the aqueous phase comprises phosphoric acid or a salt thereof, or a mixture thereof.

7. The method according to claim 2 , wherein the difference between the maximum value and the minimum value of the percentage of the organic phase in the entire mobile phase at the retention times of the related substances 1, 3, and 4 and trifluridine is 5% by volume or less with respect to the entire mobile phase.

8. The method according to claim 2 , wherein the mobile phase has a pH of 2.0 to 5.0.

9. The method according to claim 3 , wherein the percentage of the organic phase with respect to the entire mobile phase at retention times of the related substances 1 to 5, trifluridine, and tipiracil is within a range of 7 to 15% by volume.

10. The method according to claim 3 , wherein the organic phase comprises methanol.

11. The method according to claim 4 , wherein the organic phase comprises methanol.

12. The method according to claim 3 , wherein the aqueous phase comprises phosphoric acid or a salt thereof, or a mixture thereof.

13. The method according to claim 4 , wherein the aqueous phase comprises phosphoric acid or a salt thereof, or a mixture thereof.

14. The method according to claim 3 , wherein the difference between the maximum value and the minimum value of the percentage of the organic phase in the entire mobile phase at the retention times of the related substances 1, 3, and 4 and trifluridine is 5% by volume or less with respect to the entire mobile phase.

15. The method according to claim 4 , wherein the difference between the maximum value and the minimum value of the percentage of the organic phase in the entire mobile phase at the retention times of the related substances 1, 3, and 4 and trifluridine is 5% by volume or less with respect to the entire mobile phase.

16. The method according to claim 3 , wherein the mobile phase has a pH of 2.0 to 5.0.

17. The method according to claim 4 , wherein the mobile phase has a pH of 2.0 to 5.0.

18. The method according to claim 1 , wherein the mobile phase has a pH of 2.6 to 2.8.

19. The method according to claim 1 , wherein the detecting comprises detecting at least one trifluridine-related substance and at least one tipiracil-related substance, and trifluorothymine is detected as a trifluridine-related substance, 5-chloro-6-{(2-oxopyrrolidin-1-yl)methyl}pyrimidine-2,4-(1H,3H)-dione is detected as a tipiracil-related substance, and 2′-deoxy-5-methoxycarbonyluridine is detected a trifluridine-related substance.

20. The method according to claim 1 , wherein the detecting further comprises detecting at least one selected from the group consisting of trifluorothymine being a related substance 1, and 5-chloro-6-{(2-oxopyrrolidin-1-yl)methyl}pyrimidine-2,4-(1H,3H)-dione being a related substance 3.

21. The method according to claim 1 , wherein the detecting further comprises detecting at least one selected from the group consisting of trifluorothymine being a related substance 1,2-iminopyrrolidine being a related substance 2,5-chloro-6-{(2-oxopyrrolidin-1-yl)methyl}pyrimidine-2,4-(1H,3H)-dione being a related substance 3, and 5-carboxyuracil being a related substance 5.

Assignees

• Taiho Pharmaceutical Co Ltd

Inventors

• Tokimitsu Yoshinori

Classifications

• B01J20/28083 Primary

  being in the range 2-50 nm, i.e. mesopores · CPC title

• B01J20/291

  Gel sorbents · CPC title

• G01N30/02 Primary

  Column chromatography · CPC title

• B01J20/287

  Non-polar phases; Reversed phases · CPC title

• B01D15/366

  Ion-pair, e.g. ion-pair reversed phase · CPC title