Crystal forms of lamotrigine and processes for their preparations

• US 20050171107A1
• Filed: 01/31/2005
• Published: 08/04/2005
• Est. Priority Date: 02/27/2001
• Status: Active Grant

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Liebermann, Anita, Aronhime, Judith, Garti, Nissim, Singer, Claude, Dolitzky, Ben-Zion, Berkovich, Yana, Gershon, Neomi
• Granted Patent: US 7,390,807 B2
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: C07D 253/075 Two hetero atoms, in positions 3 and 5

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.

Claims

1-17. -17. (canceled)

18. 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.

19. The crystalline form E of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 18, further characterized by an X-ray powder diffraction pattern having 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 and 32.2±

0.2 degrees two-theta.

21. The crystalline form E of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 18, wherein the crystalline form E of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is a 2/3 methanolate.

20. Crystalline form E of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an X-ray powder diffraction pattern as in FIG. 4.

22-62. -62. (canceled)

63. Crystalline form O 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, 13.7, 23.0, 26.7, and 28.7±

0.2 degrees two-theta.

64. The crystalline form O of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 63, further characterized by an X-ray powder diffraction pattern having 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, and 34.8±

0.2 degrees two-theta.

66. The crystalline form O of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine according to claim 63, wherein the crystalline form O of 6-(2.3-dichlorophenyl)-1,2,4-triazine-3,5-diamine is a 2/3 methanolate.

65. Crystalline form O of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, characterized by an X-ray powder diffraction pattern as in FIG. 13.

67-91. -91. (canceled)

92. A pharmaceutical composition comprising a therapeutically effective amount of a solvated crystalline form of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine selected from the group consisting of 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 and crystalline form O 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, 13.7, 23.0, 26.7, and 28.7±

0.2 degrees two-theta.

93. A method for treating a patient suffering from epilepsia by administering a therapeutically effective amount of a crystalline form of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine selected from the group consisting of lamotrigine forms 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 and crystalline form O 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, 13.7, 23.0, 26.7, and 28.7±

0.2 degrees two-theta.

94-99. -99. (canceled)

100. A method for preparing 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

     1) dissolving anhydrous 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in methanol at about 55°

C.; and

     2) precipitating the crystalline form E of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine by adding toluene at about 0°

C. to obtain the crystalline form E of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.

101-109. -109. (canceled)

110. 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 peaks at about 9.5, 13.7, 23.0, 26.7, and 28.7±

0.2 degrees two-theta, comprising the steps of

     1) dissolving anhydrous 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine in methanol to form a solution;

     2) heating the solution to at about 65°

C.;

     3) cooling the solution to about 25°

C. for about 5.5 hours;

     4) filtering the solution; and

     5) drying the solution at about 60°

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.

111-116. -116. (canceled)

117. A method for preparing 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 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 and crystalline form O 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, 13.7, 23.0, 26.7, and 28.7±

0.2 degrees two-theta at an elevated temperature sufficient to remove methanol from the crystalline solvate to produce the anhydrous crystalline 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine.

118. A method for preparing anhydrous crystalline 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, comprising heating at least one crystalline 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine solvate of a solvent selected from the group consisting of dimethylformamide, dimethylamine, methanol, ethanol, isopropyl alcohol, tetrahydrofuran and acetone.