Stable crystal form of tipiracil hydrochloride and crystallization method for the same

• US 10,138,223 B2
• Filed: 11/16/2016
• Issued: 11/27/2018
• 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
• Primary Examiner(s): Heyer, Dennis
• Application Number:
  US15/352,858
• Publication Number:
  US 20170057949A1
• Time in Patent Office: 741 Days
• Field of Search: None
• 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

An objective of the present invention is to obtain a stable crystal form of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride. The present invention provides a crystal of 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride exhibiting characteristic peaks at angles of 11.6°, 17.2°, 17.8°, 23.3°, 27.1°, and 29.3° as a diffraction angle (2θ±0.1°) in powder X-ray diffraction.

Claims

1. A polymorph, comprising a crystal of 5-chloro-6-(2-minopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride in a purity of 95% by mass or more,

wherein the crystal exhibits peaks at two or more of 10.5°

, 19.6°

, 23.7°

, 26.2°

, and 31.2°

which are characteristic peaks of Crystal III as a diffraction angle (2θ

±

0.2°

) in powder X-ray diffraction.

2. The polymorph according to claim 1, wherein the crystal exhibits peaks at angles of 10.5°

, 19.6°

, 23.7°

, 26.2°

, and 31.2°

as a diffraction angle (2θ

±

0.2°

) in powder X-ray diffraction.

3. The polymorph according to claim 1, wherein the crystal exhibits an endothermic peak determined by thermogravimetry-differential thermal analysis at a temperature of around 245°

C.

4. The polymorph according to claim 1, wherein the crystal shows, in single-crystal analysis, the following crystal data:

Crystal system;

monoclinic system

Space group;

P2₁

Lattice constant;

a=10.3221 (14) Å

b=9.8634 (13) Å

c=11.6643 (16) Å

α

=90°

β

=100.317°

γ

=90°

Unit lattice volume;

1169.5 (3) Å

.

5. The polymorph according to claim 1, wherein the crystal is in an anhydrous form.

6. A pharmaceutical composition comprising the polymorph according to claim 1 and a pharmaceutically acceptable carrier.

7. The polymorph according to claim 1, wherein the crystal exhibits peaks at three or more of 10.5°

, 19.6°

, 23.7°

, 26.2°

, and 31.2°

as a diffraction angle (2θ

±

0.2°

)in powder X-ray diffraction.

8. The polymorph according to claim 1, comprising the crystal in a purity of 99% by mass or more.

9. The polymorph according to claim 8, wherein the crystal exhibits peaks at three or more of 10.5°

, 19.6°

, 23.7°

, 26.2°

, and 31.2°

as a diffraction angle (2θ

±

0.2°

)in powder X-ray diffraction.

10. The polymorph according to claim 8, wherein the crystal exhibits peaks at angles of 10.5°

, 19.6°

, 23.7°

, 26.2°

, and 31.2°

as a diffraction angle (2θ

±

0.2°

)in powder X-ray diffraction.

11. The polymorph according to claim 8, wherein the crystal exhibits an endothermic peak determined by thermogravimetry-differential thermal analysis at a temperature of around 245°

C.

12. The polymorph according to claim 8, wherein the crystal shows, in single-crystal analysis, the following crystal data:

Crystal system;

monoclinic system

Space group;

P2₁

Lattice constant;

a=10.3221 (14) Å

b=9.8634 (13) Å

c=11.6643 (16) Å

α

=90°

β

=100.317°

γ

=90°

Unit lattice volume;

1169.5 (3) Å

.

13. The polymorph according to claim 8, wherein the crystal is in an anhydrous form.