Title: Crystal forms of lamotrigine and processes for their preparations
Abstract: The present invention relates to lamotrigine, a useful agent for anti-epilepsia. New crystal forms of lamotrigine containing molecules of the solvent in stoichiometric ratios are disclosed. The present invention also provides processes for preparing the new crystal forms of lamotrigine.
Patent Number: 6,861,426 Issued on 03/01/2005 to Garti, et al.
| Inventors:
|
Garti; Nissim (Ramot, IL);
Berkovich; Yana (Jerusalem, IL);
Dolitzky; Ben-Zion (Petach Tiqva, IL);
Aronhime; Judith (Rehovot, IL);
Singer; Claude (Kfar Saba, IL);
Liebermann; Anita (Tel-Aviv, IL);
Gershon; Neomi (Rosh Ha-Ain, IL)
|
| Assignee:
|
Teva Pharmaceutical Industries Ltd. (Petah Tiqva, IL)
|
| Appl. No.:
|
086157 |
| Filed:
|
February 27, 2002 |
| Current U.S. Class: |
514/242; 544/182 |
| Intern'l Class: |
A61K 031//35; C07D 253//07.5 |
| Field of Search: |
544/182
514/242
|
References Cited [Referenced By]
U.S. Patent Documents
| 4560687 | Dec., 1985 | Baxter et al. | 544/182.
|
| 6124308 | Sep., 2000 | Nobbs et al. | 544/182.
|
Other References
Janes et al., "Structure of Lamotrigine Methanol Solvate:
3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine-Methanol, a Novel
Anticonvulsant Drug," Acta Cryst., 1989, C45, 129-132.
Pharmacopeial Forum, vol. 24, No. 1, (Jan.-Feb. 1998) p. 5438-5440.
E. Schmitt et al "Moisture-Dependent Crystallization of Amorphous
Lamotrigine Mesylate" Journal of Pharmaceutical Sciences vol. 85, No. 11,
Nov. 1996, pp. 1215-1219.
|
Primary Examiner: Raymond; Richard L.
Attorney, Agent or Firm: Kenyon & Kenyon
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. .sctn. 1.119(e) of
Provisional Application Ser. No. 60/271,688, filed Feb. 27, 2001, the
disclosure of which is incorporated by reference in its entirety herein.
Claims
What is claimed is:
1. A solvated form of crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine comprising
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine and a solvent selected
from the group consisting of dimethylformamide, dimethylamine,
tetrahydrofuran, methyl isobutyl ketone, methyl tertiary-butyl ether,
water and acetone.
2. Crystalline form B of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine,
characterized by an X-ray powder diffraction pattern having peaks at about
10.3, 24.2, 25.0, 26.4 and 32.3.+-.0.2 degrees two-theta.
3. The crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 2,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 13.0, 15.8, 17.2, 18.5, 20.5, 21.1, 21.7, 26.1, 27.7, 29.5,
and 30.9.+-.0.2 degrees two-theta.
4. The crystalline form B of
6-(2,3,4-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 2,
being a monosolvate of dimethylformamide.
5. Crystalline form C of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine,
characterized by an X-ray powder diffraction pattern having peaks at about
10.1, 10.5, 17.1, 18.4 and 26.2.+-.0.2 degrees two-theta.
6. The crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 5,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 12.4, 13.1, 13.6, 14.4, 16.3, 21.6, 22.5, 23.1, 24.2, 27.8,
28.4, 32.7, 33.6, and 34.6.+-.0.2 degrees two-theta.
7. The crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 5,
being a sesquisolvate of dimethylformamide.
8. Crystalline form D of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine,
characterized by an X-ray powder diffraction pattern having peaks at about
14.1, 18.2, 15.9, 20.6 and 30.8+0.2 degrees two-theta.
9. The crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine of claim 8, further
characterized by the X-ray powder diffraction pattern having other peaks
at about 13.2, 14.9, 17.2, 18.0, 18.2, 19.0, 19.5, 22.7, 23.0, 23.5, 26.2,
27.0, 27.8, 28.2, 28.6, 29.0, 29.5, 31.0, 32.9 and 33.8.+-.0.2 degrees
two-theta.
10. The crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 8,
being a 2/3 solvate of dimethylformamide.
11. A crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 9.6, 13.8, 15.8,
23.1 and 26.7.+-.0.2 degrees two-theta.
12. The crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 11,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 11.6, 13.0, 14.4, 15.2, 16.2, 17.8, 18.9, 20.1, 21.8, 24.6,
25.6, 26.3, 27.3, 27.7, 28.8, 30.0, 30.7, 31.9, 32.3, 32.7, 34.3 and
35.9.+-.0.2 degrees two-theta.
13. The crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 11,
being a 2/3 ethanolate.
14. Crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 17.2, 18.7, 26.5,
27.0 and 28.0.+-.0.2 degrees two-theta.
15. The crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 14,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 9.7, 11.8, 12.7, 13.4, 14.6, 15.4, 20.2, 20.7, 21.3, 21.6,
22.0, 24.6, 25.1, 25.5, 28.2, 29.4, 30.1, and 31.8.+-.0.2 degrees
two-theta.
16. The crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 14,
being a 1/3 solvate of acetone.
17. A crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 17.2, 18.7, 26.5,
27.0 and 28.0.+-.0.2 degrees two-theta.
18. The crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 17,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 12.2, 13.5, 14.7, 15.1, 16.5, 16.7, 17.0, 18.5, 19.5, 20.5,
24.0, 24.6, 25.7, 26.3, 28.4, 28.9, 29.4, 30.5, 31.1, 31.8, 33.3 and
35.1.+-.0.2 degrees two-theta.
19. The crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 17
being a monosolvate of ethanol.
20. A crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 9.5, 10.0, 20.2 and
26.0.+-.0.2 degrees two-theta.
21. The crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 20,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 11.6 12.4, 13.7, 14.8, 15.9, 16.3, 16.6, 17.3, 18.5, 21.0,
21.3, 24.2, 24.4, 24.7, 25.0, 25.5, 26.4, 26.7, 27.8, 29.2, 30.4 and
35.1.+-.0.2 degrees two-theta.
22. The crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 20,
is being a monosolvate of isopropanol.
23. Crystalline form K of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 11.2, 12.9, 17.2,
21.5 and 22.3.+-.0.2 degrees two-theta.
24. The crystalline form K of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 23,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 13.5, 17.8, 18.4, 19.2, 20.4, 24.3, 25.3, 25.9, 26.7, 27.0,
28.0, 28.4, 29.0, 29.6, 30.2, 30.6, 31.4, 32.4, and 34.7.+-.0.2 degrees
two-theta.
25. The crystalline form K of
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine according to claim 23,
being a solvate of tetrahydrofuran.
26. Crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 12.9, 14.9, 18.2,
20.5, and 25.8.+-.0.2 degrees two-theta.
27. The crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, according to claim 26,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 8.3, 11.3, 11.7, 12.4, 14.1, 16.7, 17.6, 18.4, 19.0, 20.1,
21.7, 22.6, 23.6, 24.6, 26.3, 26.8, 27.8, 28.4, 28.9, 31.1, 31.9, and
33.3.+-.0.2 degrees two-theta.
28. The crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, according to claim 26,
being a monosolvate of acetone.
29. Crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized an X-ray
powder diffraction pattern having peaks at about 10.0, 16.5, 16.8, 25.5,
and 27.4.+-.0.2 degrees two-theta.
30. The crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 29,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 9.0, 11.4, 13.0, 13.8, 15.1, 17.4, 17.8, 18.6, 21.1, 21.9,
23.8, 26.5, 27.0, 28.0, 28.6, 29.0, 30.1, 32.1, 33.1, and 33.6.+-.0.2
degrees two-theta.
31. The crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine form M according to
claim 29, being a solvate of dimethylamine.
32. Crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having a peak at about 11.6, 13.4, 15.0,
26.9, and 27.7.+-.0.2 degrees two-theta.
33. The crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 32,
further characterized by the X-ray powder diffraction pattern having other
peak at about 15.9, 16.5, 19.1, 22.2, 22.4, 23.2, 23.5, 26.7, 28.6, 29.9,
30.1, 30.4, 30.7, 31.4, 31.9, 32.9, 33.3, 34.4, 35.0, and 36.2.+-.0.2
degrees two-theta.
34. The crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 32,
being a hydrate.
35. Crystalline form P of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 16.1, 18.1, 18.7,
and 26.0.+-.0.2 degrees two-theta.
36. The crystalline form P of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 35,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 8.4, 9.0, 10.1, 12.1, 13.3, 19.5, 20.4, 21.8, 22.5, 24.0,
24.4, 27.4, and 28.3.+-.0.2 degrees two-theta.
37. The crystalline form P of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 35,
being a monosolvate of dimethylformamide.
38. A crystalline form Q of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 12.4, 13.8, 14.1,
16.6, 17.4, 17.9, 20.0, 21.0, 23.6, 28.8 and 30.9.+-.0.2 degrees 2-theta.
39. The crystalline form Q of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 38,
further characterized by the X-ray powder diffraction pattern having other
typical peaks at about 9.4, 10.0, 26.7, 27.8, and 28.4.+-.0.2 degrees
two-theta.
40. The crystalline form Q of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 38,
being a monosolvate of monoisopropanol.
41. Crystalline form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 10.9, 12.2, 21.0,
27.3, 28.6, and 32.5.+-.0.2 degrees two-theta.
42. The crystalline form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 41,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 9.2, 15.7, 19.0, 23.5, and 25.4.+-.0.2 degrees two-theta.
43. The crystalline form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 41,
being a monosolvate of methyl-isobutyl-ketone.
44. Crystalline form S of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 13.4 and
18.7.+-.0.2 degrees two-theta.
45. The crystalline form S of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 44,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 22.4, 26.0, 27.6, and 31.3.+-.0.2 degrees two-theta.
46. The crystalline form S of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 44,
is being anhydrous.
47. Crystalline form U of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an
X-ray powder diffraction pattern having peaks at about 12.4, 19.5, 28.4,
and 32.1.+-.0.2 degrees two-theta.
48. The crystalline form U of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 47,
further characterized by the X-ray powder diffraction pattern having other
peaks at about 11.5, 15.9, 17.9, 25.4, 25.8, and 26.6.+-.0.2 degrees
two-theta.
49. The crystalline form U of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 47,
being a monosolvate of methyl tertiary-butyl ether.
50. A method of preparing a crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.3, 24.2, 25.0,
26.4 and 32.3.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine form B by adding water
at about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
51. A method of preparing crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding chloroform at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
52. A method of preparing crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding toluene at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine C.
53. A method of preparing a crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.20.2.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding acetone at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
54. A method of preparing a crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide to
form a solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
55. A method of preparing a crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 14.1, 18.2, 15.9,
20.6 and 30.8.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding water; and
c) filtering the product of step b) to obtain the crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
56. A method of preparing a crystalline form E of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 9.5, 11.5, 13.8,
23.2 and 26.7.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in methanol at about
55.degree. C.;
b) precipitating the crystalline form E of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding toluene at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form E of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
57. A method of preparing a crystalline form E1 of
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine characterized by an X-ray
powder diffraction pattern having peaks at about 9.6, 13.8, 15.8, 23.1 and
26.7.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in ethanol at about
0.degree. C.;
b) precipitating the crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding toluene at
about 55.degree. C., and
c) isolating the crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
58. A method of preparing a crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 17.2, 18.7, 26.5,
27.0 and 28.0.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in acetone at about
70.degree. C.;
b) precipitating the crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding cyclohexane at
about 0.degree. C.; and
c) isolating the crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
59. A method of preparing a crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 9.6, 10.5, 21.8,
22.2 and 27.5.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in ethanol to form a
solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
60. A method of preparing a crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 9.6, 10.5, 21.8,
22.2 and 27.5.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in isopropanol to form a
solution;
b) heating the solution at about 65.degree. C.; and
c) cooling the solution to about 25.degree. C. for about 5.5 hours;
d) filtering the cooled solution; and
e) drying the filtered solution at about 50.degree. C. for about 17 hours
at about 10 mmHg to obtain the crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
61. A method of preparing crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 9.5, 10.0, 20.2 and
26.0.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in isopropanol to form a
solution;
b) heating the solution to about 65.degree. C.;
c) cooling the solution to about 25.degree. C. for about 5.5 hours;
d) filtering the cooled solution; and
e) drying the filtered solution at about 50.degree. C. for about 17 hours
at about 10 mmHg to obtain the crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
62. A method of preparing crystalline form K of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 11.2, 12.9, 17.2,
21.5 and 22.3.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in tetrahydrofuran to
form a solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form K of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
63. A method of preparing crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 12.9, 14.9, 18.2,
20.5, and 25.8.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in acetone to form a
solution;
b) stirring the solution at about 25.degree. C. for about 24 hours;
c) concentrating the stirred solution to dryness;
d) adding acetone; and
e) filtering the product of step d) to obtain the crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
64. A method of preparing a crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.0, 16.5, 16.8,
25.5, and 27.4.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylamine to form
a solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
65. A method of preparing a crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having a peak at about 11.6, 13.4, 15.0,
26.9, and 27.7.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in water to form a
solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
66. A method of preparing a crystalline form O of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having a peak at about 9.5, 13.7, 23.0,
26.7, and 28.7.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline 6-(2,3-dichlorophenyl)
1,2,4-triazine-3,5-diamine in methanol to form a solution;
b) heating the solution at about 65.degree. C.;
c) cooling the heated solution to about 25.degree. C. for about 5.5 hours;
d) filtering the cooled solution; and
e) drying the filtered solution at about 60.degree. C. for about 17 hours
at about 10 mmHg to obtain the crystalline form O of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
67. A method of preparing a crystalline form P of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 16.1, 18.1, 18.7,
and 26.0.+-.0.2 degrees two-theta, comprising heating crystalline form C
of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine form C at about
80.degree. C. for about 1 hour to obtain the crystalline form P of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, wherein the crystalline
form C of 6-(2.3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is
characterized by an X-ray powder diffraction pattern having peaks at about
10.1, 10.5, 17.1, 18.4 and 26.2.+-.0.2 degrees two-theta.
68. A method of preparing a amorphous
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine comprising heating
crystalline form J of 6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine at
about 80.degree. C. for about 1 hour, wherein the crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is characterized by an
X-ray powder diffraction pattern having peaks at about 9.5, 10.0, 20.2 and
26.0.+-.0.2 degrees two-theta.
69. A method of preparing crystalline form Q of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 12.4, 13.8, 14.1,
16.6, 17.4, 20.0, 21.0, 23.6, 28.8 and 30.9.+-.0.2 degrees two-theta,
comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in isopropanol to form a
solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature; and
d) filtering the product of step c) to obtain the crystalline form of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5 diamine.
70. A method of preparing crystalline form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, comprising the steps
of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in
methyl-isobutyl-ketone to form a solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature;
d) stirring the cooled solution; and
e) filtering the product of step d) to obtain the crystalline el form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
71. A method of preparing crystalline form S of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 13.4 and
18.7.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylcarbinol to
form a solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature;
d) stirring the cooled solution; and
e) filtering the product of step d) to obtain the crystalline form S of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
72. A method of preparing crystalline form U of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 12.4, 19.5, 28.4,
and 32.1.+-.0.2 degrees two-theta, comprising the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in methyl tertiary-butyl
ether to form a solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature;
d) stirring the cooled solution; and
e) filtering the product of step d) to obtain the crystalline form U of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
73. A method for preparing an anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, comprising heating at
least one crystalline solvate of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine selected from the group
consisting of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
crystalline form B characterized by an X-ray powder diffraction pattern
having peaks at about 10.3, 24.2, 25.0, 26.4 and 32.3.+-.0.2 degrees
two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form C
characterized by an X-ray powder diffraction pattern having peaks at about
10.1, 10.5, 17.1, 18.4 and 26.2.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form D
characterized by an X-ray powder diffraction pattern having peaks at about
14.1, 18.2, 15.9, 20.6 and 30.8.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form F
characterized by an X-ray powder diffraction pattern having peaks at about
17.2, 18.7, 26.5, 27.0 and 28.0.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form K
characterized by an X-ray powder diffraction pattern having peaks at about
11.2, 12.9, 17.2, 21.5 and 22.3.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form L
characterized by an X-ray powder diffraction pattern having peaks at about
12.9, 14.9, 18.2, 20.5, and 25.8.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form M
characterized by an X-ray powder diffraction pattern having peaks at about
10.0, 16.5, 16.8, 25.5, and 27.4.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form N
characterized by an X-ray powder diffraction pattern having a peak at
about 11.6, 13.4, 15.0, 26.9, and 27.7.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form P
characterized by an X-ray powder diffraction pattern having peaks at about
16.1, 18.1, 18.7, and 26.0.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form R
characterized by an X-ray powder diffraction pattern having peaks at about
10.9, 12.2, 21.0, 27.3, 28.6, and 32.5.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form S
characterized by an X-ray powder diffraction pattern having peaks at about
13.4 and 18.7.+-.0.2 degrees two-theta and
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form U
characterized by an X-ray powder diffraction pattern having peaks at about
12.4, 19.5, 28.4, and 32.1.+-.0.2 degrees two-theta,
at an elevated temperature sufficient to remove a solvent from the
crystalline solvate of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
to produce the anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
74. The method of claim 73, wherein the crystalline solvate of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is heated at about
110.degree. C. for about 2 hours.
75. The method of claim 73, wherein the crystalline solvate of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is heated at about
110.degree. C. for about 1 hour.
76. The method of claim 73, wherein the crystalline solvate of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is heated at about
150.degree. C. for about 1/2 hour.
77. The method of claim 75, wherein the crystalline solvate of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is the crystalline form
L of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
78. The method of claim 75, wherein the crystalline solvate of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is the crystalline form
N of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine form N.
79. A crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.3, 24.2, 25.0,
26.4 and 32.3.+-.0.2 degrees two-theta produced by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide a
about 70.degree. C.;
b) precipitating the crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding water at about
0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form B of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
80. A crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, produced by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline sed form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding chloroform at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
81. A crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, produced by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding toluene at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
82. A crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, produced by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding acetone at
about 0.degree. C.; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
83. A crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta, produced by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide to
form a solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form C of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
84. A crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 14.1, 18.2, 15.9,
20.6 and 30.8.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylformamide at
about 70.degree. C.;
b) precipitating the crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding water; and
c) filtering the product of step b) to obtain the crystalline form D of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
85. A crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 9.6, 13.8, 15.8,
23.1 and 26.7.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in ethanol at about
55.degree. C.;
b) precipitating the crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding toluene at
about 0.degree. C., and
c) isolating the crystalline form E1 of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
86. A crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 17.2, 18.7, 26.5,
27.0 and 28.0.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in acetone at about
70.degree. C.;
b) precipitating the crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding cyclohexane at
about 0.degree. C.; and
c) isolating the crystalline form F of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
87. A crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 17.2, 18.7, 26.5,
27.0 and 28.0.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in ethanol to form a
solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
88. A crystalline form H of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 17.2, 18.7, 26.5,
27.0 and 28.0.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in isopropanol to form a
solution;
b) heating the solution at about 65.degree. C.; and
c) cooling the heated solution to about 25.degree. C. for about 5.5 hours;
d) filtering the cooled solution; and
e) drying the filtered solution at about 50.degree. C. for about 17 hours
at about 10 mmHg to obtain the crystalline form H of
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine.
89. A crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 9.5, 10.0, 20.2 and
26.0.+-.0.2 degrees two-theta, prepared by a process which comprises the
steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in isopro panol to form
a solution;
b) heating the solution to about 65.degree. C.;
c) cooling the heated solution to about 25.degree. C. for about 5.5 hours;
d) filtering the cooled solution; and
e) drying the filtered solution at about 50.degree. C. for about 17 hours
at about 10 mmHg to obtain the crystalline form J of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
90. A crystalline form K of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 11.2, 12.9, 17.2,
21.5 and 22.3.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in tetrahydrofuran to
form a solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form K of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
91. A crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 12.9, 14.9, 18.2,
20.5, and 25.8.+-.0.2 degrees two-theta prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in acetone to form a
solution;
b) stirring the solution at about 25.degree. C. for about 24 hours;
c) concentrating the stirred solution to dryness;
d) adding acetone to the product of step c); and
e) filtering the product of step d) to obtain the crystalline form L of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
92. A crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.0, 16.5, 16.8,
25.5, and 27.4.+-.0.2 degrees two-theta prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine in dimethylamine to form
a solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form M of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
93. A crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having a peak at about 11.6, 13.4, 15.0,
26.9, and 27.7.+-.0.2 degrees two-theta, prepared by a process which
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine in water to form a
solution;
b) stirring the solution at about 25.degree. C. for about 24 hours; and
c) filtering the product of step b) to obtain the crystalline form N of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
94. A crystalline form P of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 16.1, 18.1, 18.7,
and 26.0.+-.0.2 degrees two-theta, prepared by a process comprises heating
crystalline form C of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine at
about 80.degree. C. for about 1 hour, wherein the crystalline form C of
6-(2.3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is characterized by an
X-ray powder diffraction pattern having peaks at about 10.1, 10.5, 17.1,
18.4 and 26.2.+-.0.2 degrees two-theta.
95. A crystalline form Q of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 12.4, 13.8, 14.1,
16.6, 17.4, 17.9, 20.0, 21.0, 23.6, 28.8 and 30.9.+-.0.2 degrees 2-theta,
prepared by a process which comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in isopropanol to form a
solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature; and
d) filtering the product of step c) to obtain the crystalline form Q of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
96. A crystalline form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an
X-ray powder diffraction pattern having peaks at about 10.9, 12.2, 21.0,
27.3, 28.6, and 32.5.+-.0.2 degrees two-theta, prepared by a process
comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in
methyl-isobutyl-ketone to form a solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature;
d) stirring the cooled solution; and
e) filtering the product of step d) to obtain the crystalline form R of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
97. A crystalline form S of
6-(2,3-dichlorophenyl)1,2,4-triazine-3,5-diamine characterized by an X-ray
powder diffraction pattern having peaks at about 13.4 and 18.7.+-.0.2
degrees two-theta prepared by a process which comprises the steps of:
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in dimethylcarbinol to
form a solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
c) cooling the heated solution to room temperature;
d) stirring the cooled solution; and
e) filtering the product of step d) to obtain the crystalline form S of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
98. A crystalline form U of
6(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine characterized by an X-ray
powder diffraction pattern having peaks at about 12.4, 19.5, 28.4, and
32.1.+-.0.2 degrees two-theta, prepared by the process comprising
a) dissolving anhydrous crystalline
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in methyl tertiary-butyl
ether to form a solution;
b) heating the solution at about 65.degree. C. for about 5 minutes;
cooling the heated solution to room temperature;
stirring the cooled solution; and
filtering the product of step d) to obtain the crystalline ee form U of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.
99. A pharmaceutical composition comprising a therapeutically effective
amount of at least one solid selected from the group consisting of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form B
characterized by an X-ray powder diffraction pattern having peaks at about
10.3, 24.2, 25.0, 26.4 and 32.3.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form C
characterized by an X-ray powder diffraction pattern having peaks at about
10.1, 10.5, 17.1, 18.4 and 26.2.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form D
characterized by an X-ray powder diffraction pattern having peaks at about
14.1, 18.2, 15.9, 20.6 and 30.8.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form F
characterized by an X-ray powder diffraction pattern having peaks at about
17.2, 18.7, 26.5, 27.0 and 28.0.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form K
characterized by an X-ray powder diffraction pattern having peaks at about
11.2, 12.9, 17.2, 21.5 and 22.3.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form L
characterized by an X-ray powder diffraction pattern having peaks at about
12.9, 14.9, 18.2, 20.5, and 25.8.+-.0.2 degrees two-theta,
6*(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form M
characterized by an X-ray powder diffraction pattern having peaks at about
10.0, 16.5, 16.8, 25.5, and 27.4.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form N
characterized by an X-ray powder diffraction pattern having a peak at
about 11.6, 13.4, 15.0, 26.9, and 27.7.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form P
characterized by an X-ray powder diffraction pattern having peaks at about
16.1, 18.1, 18.7, and 26.0.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form R
characterized by an X-ray powder diffraction pattern having peaks at about
10.9, 12.2, 21.0, 27.3, 28.6, and 32.5.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form S
characterized by an X-ray powder diffraction pattern having peaks at about
13.4 and 18.7.+-.0.2 degrees two-theta and
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form U
characterized by an X-ray powder diffraction pattern having peaks at about
12.4, 19.5, 28.4, and 32.1.+-.0.2 degrees two-theta; and
a pharmaceutically acceptable excipient.
100. A method for treating a patient suffering from epilepsia by
administering a therapeutically effective amount of at least one solid
selected from the group consisting of
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form B
characterized by an X-ray powder diffraction pattern having peaks at about
10.3, 24.2, 25.0, 26.4 and 32.3.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form C
characterized by an X-ray powder diffraction pattern having peaks at about
10.1, 10.5, 17.1, 18.4 and 26.2.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form D
characterized by an X-ray powder diffraction pattern having peaks at about
14.1, 18.2, 15.9, 20.6 and 30.8.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form F
characterized by an X-ray powder diffraction pattern having peaks at about
17.2, 18.7, 26.5, 27.0 and 28.0.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form K
characterized by an X-ray powder diffraction pattern having peaks at about
11.2, 12.9, 17.2, 21.5 and 22.3.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form L
characterized by an X-ray powder diffraction pattern having peaks at about
12.9, 14.9, 18.2, 20.5, and 25.8.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form M
characterized by an X-ray powder diffraction pattern having peaks at about
10.0, 16.5, 16.8, 25.5, and 27.4.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form N
characterized by an X-ray powder diffraction pattern having a peak at
about 11.6, 13.4, 15.0, 26.9 and 27.7.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form P
characterized by an X-ray powder diffraction pattern having peaks at about
16.1, 18.1, 18.7, and 26.0.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form R
characterized by an X-ray powder diffraction pattern having peaks at about
10.9, 12.2, 21.0, 27.3, 28.6, and 32.5.+-.0.2 degrees two-theta,
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form S
characterized by an X-ray powder diffraction pattern having peaks at about
9.5, 10.0, 20.2 and 26.0.+-.0.2 degrees two-theta and
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine crystalline form U
characterized by an X-ray powder diffraction pattern having peaks at about
12.4, 19.5, 28.4, and 32.1.+-.0.2 decrees two-theta.
Description
FIELD OF THE INVENTION
The present invention relates to new crystal forms of lamotrigine, related
pharmaceutical composition, and processes for their preparation.
BACKGROUND OF THE INVENTION
Lamotrigine is known as 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
or 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine and has the following
chemical formula (I).
##STR1##
Lamotrigine is an anti-epileptic drug of the phenyltriazine class and is
chemically unrelated to other existing anti-epileptic drugs. This drug is
produced by Glaxo Wellcome and is sold under the trademark LAMICTAL.RTM..
LAMICTAL.RTM. is produced in the form of chewable dispersible tablets and
is available in different strengths (from 2 mg to 200 mg).
The crystallographic structure of lamotrigine methanolate is known (Acta
Cryst., (1989, C45, 129-132)).
No indication was found in the literature concerning the existence of other
types of crystal forms of lamotrigine. There is a need to develop various
crystal forms of lamotrigine for better formulation.
OBJECTS AND SUMMARY OF THE INVENTION
An object of the present invention is to provide new solvated forms and
hydrate forms of lamotrigine.
Another object of the present invention is to provide process for obtaining
an anhydrous form A by heating to prepare solvated and hydrate forms of
lamotrigine.
The present invention provides a new crystal form B of lamotrigine (a
solvate of DMF), characterized by an X-ray powder diffraction pattern
having strong peaks at about 10.3, 24.2, 25.0, 26.4, 32.3.+-.0.2 degrees
two-theta, and other typical peaks at about 13.0, 15.8, 17.2, 18.5, 20.5,
21.1, 21.7, 26.1, 27.7, 29.5, 30.9.+-.0.2 degrees two-theta.
The present invention provides a new crystal form C of lamotrigine (a
solvate of DMF), characterized by an X-ray powder diffraction pattern
having a strong peak at about 10.1, 10.5, 17.2, 18.4, 26.6.+-.0.2 degrees
two-theta, and other typical peaks at about 12.4, 13.1, 13.6, 14.4, 16.3,
21.6, 22.5, 23.1, 24.4, 27.4, 27.8, 28.4, 32.7, 33.6, 34.6.+-.0.2 degrees
two-theta.
The present invention provides a new crystal form D of lamotrigine (a
solvate of DMF), characterized by an X-ray powder diffraction pattern
having a strong peak at about 14.1, 15.9, 18.2, 20.6, 30.8.+-.0.2 degrees
two-theta and other typical peaks at about 13.2, 14.9, 17.2, 18.0, 19.0,
19.5, 22.7, 23.0, 23.5, 26.2, 27.0, 27.8, 28.2, 28.6, 29.0, 29.5, 31.0,
32.9, 33.8.+-.0.2 degrees two-theta.
The present invention provides a new crystal form E of lamotrigine (a
methanolate), characterized by an X-ray powder diffraction pattern having
a strong peak at about 9.5, 11.5, 13.8, 23.2, 26.7.+-.0.2 degrees
two-theta and other typical peaks at about 13.0, 14.3, 14.9, 15.7, 17.9,
19.4, 20.9, 24.5, 25.6, 27.3, 32.2.+-.0.2 degrees two-theta.
The present invention provides a new crystal form E1 of lamotrigine (an
ethanolate), characterized by an X-ray powder diffraction pattern having a
strong peak at about 9.6, 13.8, 15.8, 23.1, 26.7.+-.0.2 degrees two-theta
and other typical peaks at about 11.6, 13.0, 14.4, 15.2, 16.2, 17.8, 18.9,
20.1, 21.8, 24.6, 25.6, 26.3, 27.3, 27.7, 28.8, 30.0, 30.7, 31.9, 32.3,
32.7, 34.3, 35.9.+-.0.2 degrees two-theta.
The present invention provides a new crystal form F of lamotrigine (an
acetonate), characterized by an X-ray powder diffraction pattern having a
strong peak at about 17.2, 18.7, 26.5, 27.0, 28.0.+-.0.2 degrees two-theta
and other typical peaks at about 9.7, 11.8, 12.7, 13.4, 14.6, 15.4, 20.2,
20.7, 21.3,21.6, 22.0, 24.6, 25.1, 25.5, 28.2, 29.4, 30.1, 31.8.+-.0.2
degrees two-theta.
The present invention provides a new crystal form H of lamotrigine (an
ethanolate), characterized by an X-ray powder diffraction pattern having
strong peaks at about 9.6, 10.5, 21.8, 22.2, 27.5.+-.0.2 degrees two-theta
and other peaks at about 12.2, 13.5, 14.7, 15.1, 16.5, 16.7, 17.0, 18.5,
19.5, 20.5, 24.0, 24.6, 25.7, 26.3, 28.4, 28.9, 29.4, 30.5, 31.1, 31.8,
33.3, 35.1.+-.0.2 degrees two-theta.
The present invention provides a new crystal form J of lamotrigine (an
isopropanolate), characterized by an X-ray powder diffraction pattern
having strong peaks at about 9.5, 10.0, 20.2, 26.0.+-.0.2 degrees
two-theta and other peaks at about 11.6 12.4, 13.7, 14.8, 15.9, 16.3,
16.6, 17.3, 18.0, 18.5, 20.4, 21.0, 21.3, 24.2, 24.4, 24.7, 25.0, 25.5,
26.4, 26.7, 27.6, 27.8, 28.3, 28.7, 29.2, 30.4, 30.6, 35.1.+-.0.2 degrees
two-theta.
The present invention provides a new crystal form K of lamotrigine (a
solvate of THF), characterized by an X-ray powder diffraction pattern
having strong peaks at about 11.2, 12.9, 17.2, 21.5, 22.3.+-.0.2 degrees
two-theta and other peaks at about 13.5, 17.8, 18.4, 19.2, 20.4, 24.3,
25.3, 25.9, 26.7, 27.0, 28.0, 28.4, 29.0, 29.6, 30.2, 30.6, 31.4, 32.4,
34.7.+-.0.2 degrees two-theta.
The present invention provides a new crystal form L of lamotrigine (a
solvate of acetonate), characterized by an X-ray powder diffraction
pattern having strong peaks at about 12.9, 14.9, 18.2, 20.5, 25.8.+-.0.2
degrees two-theta, and other typical peaks at about 8.3, 11.3, 11.7, 12.4,
14.1, 16.7, 17.6, 18.4, 19.0, 20.1, 21.7, 22.6, 23.6, 24.6, 26.3, 26.8,
27.8, 28.4, 28.9, 31.1, 31.9, 33.3.+-.0.2 degrees two-theta.
The present invention provides a crystal form M of lamotrigine (a solvate
of DMA), characterized by an X-ray powder diffraction pattern having
strong peaks at about 10.0, 16.5, 16.8, 25.5, 27.4.+-.0.2 degrees
two-theta, and other typical peaks at about 9.0, 11.4, 13.0, 13.8, 15.1,
17.4, 17.8, 18.6, 21.1, 21.9, 23.8, 26.5, 27.0, 28.0, 28.6, 29.0, 30.1,
32.1, 33.1, 33.6.+-.0.2 degrees two-theta
The present invention provides a crystal form N of lamotrigine (hydrate),
characterized by an X-ray powder diffraction pattern having strong peaks
at about 11.6, 13.4, 15.0, 26.9, 27.7.+-.0.2 degrees two-theta, and other
typical peaks at about 15.9, 16.5, 19.1, 22.2, 22.4, 23.2, 23.5, 26.7,
28.6, 29.9, 30.1, 30.4, 30.7, 31.4, 31.9, 32.9, 33.3, 34.4, 35.0,
36.2.+-.0.2 degrees two-theta.
The present invention provides a new crystal form O of lamotrigine (a
solvate of methanolate), characterized by an X-ray powder diffraction
pattern having strong peaks at about 9.5, 13.7, 23.0, 26.7, 28.7.+-.0.2
degrees two-theta, and other typical peaks at about 8.5, 11.4, 14.2, 15.7,
18.0, 18.9, 24.2, 25.6, 25.9, 27.7, 30.0, 30.7, 32.6, 34.3, 34.8.+-.0.2
degrees two-theta.
The present invention provides a crystal form P of lamotrigine (a solvate
of DMF), characterized by an X-ray powder diffraction pattern having
strong peaks at about 16.1, 18.1, 18.7, 26.0.+-.0.2 degrees two-theta, and
other typical peaks at 8.4, 9.0, 10.1, 12.1, 13.3, 19.5, 20.4, 21.8, 22.5,
24.0, 24.4, 27.4, 28.3.+-.0.2 degrees two-theta.
The present invention provides a crystal form Q of lamotrigine (a
monosolvate of isopropanolate), characterized by an X-ray powder
diffraction pattern having strong peaks at about 12.4, 13.8, 14.1, 16.6,
17.4, 17.9, 20.0, 21.0, 23.6, 28.8, 30.9.+-.0.2 degrees two-theta and
other typical peaks at about 9.4, 10.0, 26.7, 27.8, and 28.4.+-.0.2
degrees two-theta.
The present invention provides a crystal form R of lamotrigine (a
monosolvate of methyl-isobutyl-ketone), characterized by an X-ray powder
diffraction pattern having strong peaks at about 10.9, 12.2, 21.0, 27.3,
28.6, 32.5.+-.0.2 degrees and other typical peaks at about 8.2, 15.7,
19.0, 23.5 and 25.4.+-.0.2 degrees two-theta.
The present invention provides a crystal form S of lamotrigine (anhydrous),
characterized by an X-ray powder diffraction pattern having strong peaks
at about 13.4, and 18.7.+-.0.2 degrees two-theta and other typical peaks
at about 22.4, 26.0, 27.6, and 31.3.+-.0.2 degrees two-theta.
The present invention provides a crystal form U of lamotrigine (a
monosolvate of MTBE), characterized by an X-ray powder diffraction pattern
having strong peaks at about 12.4, 19.5, 28.
