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Last Updated: March 29, 2024

Claims for Patent: 10,457,666


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Summary for Patent: 10,457,666
Title:Stable crystal form of tipiracil hydrochloride and crystallization method for the same
Abstract: Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride exhibiting powder X-ray peaks at two or more angles selected from the group consisting of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.).
Inventor(s): Kazuno; Hideki (Tsukuba, JP), Mutsumi; Tomonobu (Kodama-gun, JP)
Assignee: TAIHO PHARMACEUTICAL CO., LTD. (Chiyoda-ku, JP)
Application Number:15/969,434
Patent Litigation and PTAB cases: See patent lawsuits and PTAB cases for patent 10,457,666
Patent Claims: 1. Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride exhibiting powder X-ray peaks at two or more angles selected from the group consisting of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.), and having a purity of at least 90% by mass.

2. Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride exhibiting peaks at three or more angles of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.), and having a purity of at least 90% by mass.

3. Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride exhibiting peaks at angles of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.), and having a purity of at least 90% by mass.

4. Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride exhibiting an endothermic peak determined by thermogravimetry-differential thermal analysis at a temperature of around 262.degree. C., exhibiting powder X-ray peaks at two or more angles selected from the group consisting of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.), and having a purity of at least 90% by mass.

5. Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride which exhibits powder X-ray peaks at two or more angles selected from the group consisting of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.), has a purity of at least 90% by mass, and shows, in single-crystal analysis, the following crystal data: Crystal system: monoclinic system Space group: P2.sub.1/n (No. 14) Lattice constant: a=11.6006 (9) .ANG. b=10.3106 (11) .ANG. c=10.3036 (10) .ANG. .alpha.=90.degree. .beta.=101.951 (7).degree. .gamma.=90.degree. Unit lattice volume: 1205.7 (2) .ANG..sup.3.

6. Crystal Form I of claim 1, in an anhydrous form.

7. Crystal Form I of claim 1, having a purity of at least 99% by mass.

8. Crystal Form I of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride after 6-month stability test at 40.degree. C., exhibiting powder X-ray peaks at two or more angles selected from the group consisting of 11.6.degree., 17.2.degree., 17.8.degree., 23.3.degree., 27.1.degree., and 29.3.degree. as a diffraction angle (2.theta..+-.0.2.degree.), and having a purity of at least 90% by mass.

9. A pharmaceutical composition comprising crystal Form I of claim 8, trifluridine and a pharmaceutically acceptable carrier.

10. A method of producing crystal Form I of claim 1, comprising subjecting a solution having 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride dissolved in a water-ethanol mixed solvent to crystallization at a temperature of at least 40.degree. C. followed by cooling.

11. The method of claim 10, comprising subjecting the solution to a crystallization at a temperature of 44 to 50.degree. C. for at least 1.5 hours followed by cooling.

12. The method of claim 10, comprising subjecting the solution to a crystallization at a temperature of 50 to 63.degree. C. for at least 0.5 hours followed by cooling.

13. The method of claim 10, comprising subjecting the solution to a crystallization at a temperature of 44 to 50.degree. C. for 1.5 to 7 hours followed by cooling.

14. The method of claim 13, wherein the solution is subjected to the crystallization temperature for 1.5 to 3 hours.

15. The method of claim 10, comprising subjecting the solution to a crystallization at a temperature of 50 to 63.degree. C. for 0.5 to 7 hours followed by cooling.

16. The method of claim 15, wherein the solution is subjected to the crystallization temperature for 0.5 to 3 hours.

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