Pharmaceutically acceptable salt and polymorphic forms of flupirtine maleate

Abstract

New polymorphic forms of flupirtine maleate are described.

1 . Polymorph V of flupirtine maleate characterized by data selected from the group consisting of:
 a) having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in  FIG. 1 , and   b) having characteristic X-ray powder diffraction peaks (2θ): 6.5±0.2°, 9.3±0.2°, 13.4±0.2°, 18.6±0.2° and 20.1±0.2°.   
     
     
         2 . A polymorph according to  claim 1 , further characterised by X-ray powder diffraction peaks (2θ) selected from one or more of the following: 4.4±0.2°, 12.4±0.2°, 12.8±0.2°, 15.6±0.2° and 22.2±0.2°. 
     
     
         3 . Polymorph W of flupirtine maleate characterized by data selected from the group consisting of:
 a) having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in  FIG. 3  and   b) having characteristic X-ray powder diffraction peaks (2θ): 5.3±0.2°, 7.9±0.2°, 13.0±0.2°, 18.7±0.2° and 20.1±0.2°.   
     
     
         4 . A polymorph according to  claim 3 , further characterised by X-ray powder diffraction peaks (2θ) selected from one or more of the following: 6.5±0.2°, 9.2±0.2°, 10.9±0.2°, 13.4±0.2° and 15.8±0.2°. 
     
     
         5 . Polymorph Y of flupirtine maleate characterized by data selected from the group consisting of:
 a) having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in  FIG. 7  and   b) having characteristic X-ray powder diffraction peaks (2θ): 8.0±0.2°, 10.0±0.2°, 12.9±0.2°, 18.0±0.2° and 19.5±0.2°.   
     
     
         6 . A polymorph according to  claim 5 , further characterised by X-ray powder diffraction peaks (2θ) selected from one or more of the following: δ 7.0±0.2°, 7.5±0.2°, 13.9±0.2°, 16.8±0.2° and 25.8±0.2°. 
     
     
         7 . Polymorph Z of flupirtine maleate characterized by data selected from the group consisting of:
 a) having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in  FIG. 9  and   b) having characteristic X-ray powder diffraction peaks (2θ): 7.6±0.2°, 9.9±0.2°, 17.9±0.2° and 19.8±0.2°.   
     
     
         8 . A polymorph according to  claim 7 , further characterised by X-ray powder diffraction peaks (2θ) selected from one or more of the following: 5.1±0.2°, 6.9±0.2°, 12.8±0.2° and 22.2±0.2°. 
     
     
         9 . A process for the preparation of the crystalline polymorph according to  claim 1 , which comprises crystallizing 2-amino-3-carbethoxyamino-6-(4-fluoro-benzylamino)-pyridine maleate from a solution thereof in an organic solvent or a mixture of organic solvents. 
     
     
         10 . A pharmaceutical composition containing a therapeutically effective dose of a polymorphic form of flupirtine maleate according to  claim 1 . 
     
     
         11 . A method of treating a disease state prevented, ameliorated or eliminated by the administration of centrally acting non-opioid analgesics, muscle-relaxants, functional NMDA antagonists or substances that increase the expression of the protein Bcl-2, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate according to  claim 1 . 
     
     
         12 . A method for the treatment of CNS disorders, comprising administering an effective amount of the crystalline polymorph according to  claim 1 . 
     
     
         13 . A method according to  claim 12 , wherein said CNS disorder is back pain or Parkinson's disease. 
     
     
         14 . A method of treating a disease state prevented, ameliorated or eliminated by the administration of centrally acting non-opioid analgesics, muscle-relaxants, functional NMDA antagonists or substances that increase the expression of the protein Bcl-2, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate according to  claim 3 . 
     
     
         15 . A method of treating a disease state prevented, ameliorated or eliminated by the administration of centrally acting non-opioid analgesics, muscle-relaxants, functional NMDA antagonists or substances that increase the expression of the protein Bcl-2, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate according to  claim 5 . 
     
     
         16 . A method of treating a disease state prevented, ameliorated or eliminated by the administration of centrally acting non-opioid analgesics, muscle-relaxants, functional NMDA antagonists or substances that increase the expression of the protein Bcl-2, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a polymorphic form of flupirtine maleate according to  claim 7 .