STABLE CRYSTAL FORM OF TIPIRACIL HYDROCHLORIDE AND CRYSTALLIZATION METHOD FOR THE SAME

• US 20180291005A1
• Filed: 05/02/2018
• Published: 10/11/2018
• Est. Priority Date: 06/17/2013
• Status: Active Grant

• Current Assignee: Taiho Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Taiho Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: KAZUNO, Hideki, MUTSUMI, Tomonobu
• Granted Patent: US 10,457,666 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

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°, 17.2°, 17.8°, 23.3°, 27.1°, and 29.3° as a diffraction angle (2θ±0.2°).

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°

, 17.2°

, 17.8°

, 23.3°

, 27.1°

, and 29.3°

as a diffraction angle (2θ

±

0.2°

).

2. Crystal Form I of claim 1, exhibiting peaks at three or more angles of 11.6°

, 17.2°

, 17.8°

, 23.3°

, 27.1°

, and 29.3°

as a diffraction angle (2θ

±

0.2°

).

3. Crystal Form I of claim 2, exhibiting peaks at angles of 11.6°

, 17.2°

, 17.8°

, 23.3°

, 27.1°

, and 29.3°

as a diffraction angle (2θ

±

0.2°

).

4. Crystal Form I of claim 1, exhibiting an endothermic peak determined by thermogravimetry-differential thermal analysis at a temperature of around 262°

C.

5. Crystal Form I of claim 1, which shows, in single-crystal analysis, the following crystal data:

Crystal system;

monoclinic system

Space group;

P2₁/n (No.

     14)

Lattice constant;

a=11.6006 (9) Å

b=10.3106 (11) Å

c=10.3036 (10) Å

.

α

=90°

β

=101.951 (7)°

γ

=90°

Unit lattice volume;

1205.7 (2) Å

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 1 of claim 1 after 6-month stability test at 40°

C., exhibiting powder X-ray peaks at two or more angles selected from the group consisting of 11.6°

, 17.2°

, 17.8°

, 23.3°

, 27.1°

, and 29.3°

as a diffraction angle (2θ

±

0.2°

).

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°

C. followed by cooling.

11. The method of claim 10, comprising subjecting the solution to a crystallization at a temperature of 44 to 50°

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°

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°

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°

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.