Pharmaceutical compositions of a thiazolidinedione derivative and their use as antidiabetics

Abstract

A polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the “Polymorph”) characterised in that it: (i) provides an infra red spectrum containing peaks at 1360, 1326, 1241, 714 and 669 cm −1 ; and/or (ii) provides a Raman spectrum containing peaks at 1581, 768, 670, 271 and 226 cm −1 ; and/or (iii) provides a solid-state nuclear magnetic resonance spectrum containing peaks at chemical shifts substantially as set out in Table I; and/or (iv) provides an X-ray powder diffraction (XRPD) pattern containing peaks substantially as set out in Table II; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine.

1 . A polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the “Polymorph”) characterised in that it: 
 (i) provides an infra red spectrum containing peaks at 1360, 1326, 1241, 714 and 669 cm −1 ; and/or  
 (ii) provides a Raman spectrum containing peaks at 1581, 768, 670, 271 and 226 cm −1 ; and/or  
 (iii) provides a solid-state nuclear magnetic resonance spectrum containing peaks at chemical shifts substantially as set out in Table I; and/or  
 (iv) provides an X-ray powder diffraction (XRPD) pattern containing peaks substantially as set out in Table II.  
 
     
     
         2 . A Polymorph according to  claim 1 , which provides an infra red spectrum substantially in accordance with FIG. I.  
     
     
         3 . A Polymorph according to  claim 1  or  claim 2 , which provides a Raman spectrum substantially in accordance with FIG. II.  
     
     
         4 . A Polymorph according to any on of  claims 1  to  3 , which provides a solid-state nuclear magnetic resonance spectrum substantially in accordance with FIG. III.  
     
     
         5 . A Polymorph according to any one of  claims 1  to  4 , which provides an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. IV.  
     
     
         6 . A Polymorph according to any one of  claims 1  to  5 , in isolated form.  
     
     
         7 . A Polymorph according to any one of  claims 1  to  6 , in pure form.  
     
     
         8 . A Polymorph according to any one of  claims 1  to  7 , in crystalline form.  
     
     
         9 . A process for preparing a Polymorph according to  claim 1 , characterised in that: 
 (a) a slurry of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (hereinafter also referred to as “Compound (I)” or the “Original Polymorph”) in aqueous ethanol containing up to about 2.5% w/v water, is heated for an extended period of time; after which time the Polymorph is recovered from the denatured ethanol; or    (b) Compound (I) is admixed with denatured ethanol, heated to an elevated temperature, over an extended period of time, after which time the Polymorph is recovered from the solvent; or    (c) Compound (I) in denatured ethanol containing up to 2.5% w/v water at 55° C. is seeded with the Polymorph then cooled to a temperature in the range of from 20° C. to 25° C. to provide the Polymorph; the Polymorph is then recovered from the solvent.    
     
     
         10 . A pharmaceutical composition comprising an effective, non-toxic amount of a Polymorph according to  claim 1  and a pharmaceutically acceptable carrier therefor.  
     
     
         11 . A Polymorph according to  claim 1 , for use as an active therapeutic substance.  
     
     
         12 . A Polymorph according to  claim 1 , for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.  
     
     
         13 . The use of Polymorph for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.  
     
     
         14 . A method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of Polymorph to a human or non-human mammal in need thereof.