Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them

Abstract

This invention relates to novel polymorphic/pseudopolymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I shown below. The invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier. The polymorphic forms of the present invention are more active, as antidiabetic and hypolipidemic agent, than the novel 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

We claim:  
     
         1 . A polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Endotherms at 181.21° C. (onset at 177.70° C.)  
 X-ray powder diffraction (2θ): 8.18, 12.40, 16.66, 18.80, 19.44, 22.32, 22.84, 23.10, 23.50, 24.72, 29.84,  
 Infrared absorption bands (cm −1 ): 3249, 3062, 1709, 1587, 1489, 1374, 1272, 1243, 1112, 1043, 919, 737, 673, 543.  
 
     
     
         2 . A polymorphic Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Endotherms at 131° C., 166.24° C. and 178.96° C.  
 Exotherm at 169.73° C.  
 X-ray powder diffraction (2θ): 6.78, 11.5, 12.08, 16.44, 19.34, 22.30, 22.72, 24.40, 26.66  
 Infrared absorption bands (cm −1 ): 3055, 1711, 1589, 1510, 1491, 1376, 1274, 1111, 1039, 810, 730, 543.  
 
     
     
         3 . A polymorphic Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Exotherm at 168.00° C.  
 Endotherm at 182.20° C. (onset at 171° C.),  
 Small endotherms at 99.66° C., 164.38° C.  
 X-ray powder diffraction (2θ): 6.80, 12.10, 15.84, 17.02, 19.40, 22.32, 22.68, 2438, 26.36,  
 Infrared absorption bands (cm −1 ): 3061, 1710, 1588, 1510, 1491, 1379, 1273, 1110, 1040, 805, 739, and 543.  
 
     
     
         4 . A polymorphic Form-IV of L-arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Small Exotherm at 171.80° C.  
 Endotherms at 149.85° C., 185.60° C. (onset at 147.78° C.)  
 Small Endotherm at 164.51° C.  
 X-ray powder diffraction (2θ): 6.78, 12.66, 15.96, 16.54, 19.34, 22.78, 24.42, 26.70, 31.70,  
 Infrared absorption bands (cm −1 ): 3056, 1711, 1589, 1493, 1381, 1274, 1242, 1101, 1060, 805, 743, and 543.7.  
 
     
     
         5 . A polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Small exotherm at 173.82° C.  
 Endotherm at 185.95° C., (onset at 178.09° C.)  
 Small endotherms at 119.81° C., 164.69° C., 172.44° C.  
 X-ray powder diffraction (2θ): 6.76, 12.10, 15.96, 17.00, 18.50, 19.40, 22.38, 22.44, 24.44, 26.30,  
 Infrared absorption bands (cm −1 ). 3266, 3055, 1711, 1589, 1510, 1492, 1379, 1274, 1175, 1111, 1040, 918, 819, 730, 676, 544.  
 
     
     
         6 . A polymorphic Form-VI of L-arginine salt of (2S) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Exotherm at 157.98° C.,  
 Endotherms at 179.11° C. and 183.69° C. (onset at 157.98° C.),  
 Small endotherm at 77.80° C.  
 X-ray powder diffraction (2θ): No diffraction peaks due to its amorphous nature,  
 Infrared absorption bands (cm −1 ): 3065, 1629,.1490, 1377, 1273, 1244, 1109, 1042, 805, 740, 539.  
 
     
     
         7 . A polymorphic Form-VII of L-arginine salt of (2S) 3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Exotherm at 132.93° C.,  
 Endotherms at 176.63° C. (onset at 169.06° C.) and 184.09° C.  
 X-ray powder diffraction (2θ): No diffraction peaks due to its amorphous nature,  
 Infrared absorption bands (cm −1 ): 3065, 1629, 1490, 1377, 1273, 1109, 1042, 740, 541.  
 
     
     
         8 . A polymorphic Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Exotherm at 158.27° C.  
 Endotherm at 178.12° C. (onset at 167.15 C.),  
 Small Endotherm at 152.72° C.  
 X-ray powder diffraction (2θ): 4.16, 11.02, 15.94, 19.50, 20.22, 22.22, 27.38,  
 Infrared absorption bands (cm −1 ): 3151, 1629, 1490, 1378, 1272, 1244, 1104, 1041, 742, 549.  
 
     
     
         9 . A polymorphic Form-IX of L-arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Endotherm at 176.67° C. (onset at 173.36° C.), (FIG. 21)  
 X-ray powder diffraction (2θ): 8.20, 12.42, 16.66, 18.80, 19.44, 22.30, 23.08, 27.38, 28.48, 29:84, (FIG. 9)  
 Infrared absorption bands (cm −1 ): 3066, 1588, 1489, 1376, 1273, 1243, 1110, 1043, 919, 805, 737, 543, (FIG. 33)  
 
     
     
         10 . A polymorphic Form-X of L-arginine, salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized-by the data described hereunder: 
 DSC: Endotherm at 184.53° C.,)  
 Exotherm at, 162.67° C.  
 X-ray powder diffraction (2θ): No diffraction peaks due to its amorphous nature,  
 Infrared absorption bands (cm −1 ): 3413, 1630, 1511, 1491, 1377, 1273, 1244, 1176, 1108, 741.  
 
     
     
         11 . A polymorphic Form-XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the data described hereunder: 
 DSC: Endotherm at 184.40° C. (onset at 177.67° C.),  
 X-ray powder diffraction (2θ): 7.38, 7.56, 11.90, 12.32, 14.80, 16.40, 19.58, 20.48, 22.34, 22.90, 23.54,  
 Infrared absorption bands (cm −1 ): 3383, 2925, 1629, 1510, 1490, 1377, 1273, 1243, 1090, 1041, 739, 539.  
 
     
     
         12 . A mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,  
       
         
           
           
               
               
           
         
       
       which is characterized by the following data: 
 DSC: Endotherms at 181.28° C., 185.31° C., (onset at 173.54° C.)  
 X-ray powder diffraction (2θ): 8.16, 12.40, 16.64, 18.78, 19.42, 22.34, 22.80. 23.08, 29.84,  
 Infrared absorption bands (cm −1 ): 3247, 3066, 1708, 1587, 1510, 1489, 1375, 1273, 1244, 1178, 1111, 1043, 805, 737, 673, 543.  
 
     
     
         13 . A pharmaceutical composition comprising any one of polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I  
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable carrier, diluent, excipient or solvate.  
     
     
         14 . A process for the preparation of the polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 1 , which comprises: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,    (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),    (iii) stirring the reaction mixture at a temperature of 40-80° C. for a period in the range of 18-30 h to obtain a white crystalline precipitate,    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-0.16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         15 . A process for the preparation of the polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 1 , which comprises: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods, and dissolving in an organic solvent,    (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in: step (i),    (iii) stirring the reaction mixture at room temperature for a period in the range of 90-100 h to obtain a white crystalline precipitate,    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         16 . A process for the preparation of the polymorphic Form-II of L-arginine salt of (2S) 3-[4-2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyropanoic acid, having the characteristics defined in  claim 2 , which comprises: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in acetone,    (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),    (iii) stirring the reaction mixture at room temperature for a period in the range of 18-30 h to obtain a-white crystalline precipitate    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         17 . A process for the preparation of the polymorphic Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 3 , which comprises: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in 1,4-dioxane,    (ii) adding L-arginine dissolved in Water slowly with constant stirring to the solution obtained in step (i),    (iii) stirring the reaction mixture at room temperature for a period in the range of 18-30 h to obtain a white crystalline precipitate    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying wider vacuum at a temperature of-40-45° C. for a period in the range of 4-16 h to yield Form-III of L-arginine salt of (2S) 3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         18 . A process for the preparation of the polymorphic Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 4 , which comprises: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in dimnethyl sulfoxide,    (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),    (iii) stirring the reaction mixture at room temperature for a period in the range of 18-30 h to obtain a white crystalline precipitate    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v.) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         19 . A process for the preparation of the polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 5 , which compnses: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in dimethyl formamide,    (ii)-adding L-arginine dissolved in water slowly with constant stifling in the solution obtained in step (i),    (iii) stirring the reaction mixture at room temperature for a period in the range of 18-30 h to obtain a white crystalline precipitate,    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (vi) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         20 . A process for the preparation of the polymorphic Form-VI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 6 , which comprises: 
 (i) dissolving any of the polymorphic Forms I-V of L-arginine salt of (2S) 3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, in water and    (ii) freeze drying the resulting solution to yield an amorphous white powder of Form-VI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         21 . A process for the preparation of the polymorphic Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 7 , which comprises: 
 (i) dissolving any of -the polymorphic Forms I-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, in methanol and    (ii) evaporating the resulting solution under vacuum to obtain an amorphous white powder of Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         22 . A process for the preparation of the polymorphic Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in claim 8, which comprises: 
 (i) synthesizing (2S) 3-[4-[2phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,    (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),    (iii) stirring the reaction mixture at a temperature of 40-80° C. for a period in the range of 18-30 h to obtain a white crystalline precipitate,    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,    (vi) refluxing the Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-dioxane for a period in the range of 8-16 h and    (vii) filtering and drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         23 . A process for the preparation of the polymorphic Form-IX of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid; having the characteristics defined in  claim 9 , which comprises 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,    (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution in I; is obtained in step (i),    (iii) stirring the reaction mixture at a temperature of 40-80° C. for a period in the range of 18-30 h to obtain a white crystalline precipitate,    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,    (vi) refluxing the Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-dioxane for a period in the range of 8-16 h,    (vii) filtering and drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,    (viii) refluxing the Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-11-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained in step (vii) above in isopropyl alcohol for a period in the range of 8-16 h and    (viii) filtering and drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-IX of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         24 . A process for the preparation of the polymorphic Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 10 , which comprises: 
 (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,    (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),    (iii) stirring the reaction mixture at a temperature of 40-80° C. for a period in the range of 18-30 h to obtain a white crystalline precipitate,    (iv) filtering the white crystalline precipitate obtained in step (iii) above and    (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and    (vi) heating the polymorphic Form-I obtained in step (v) at 185° C. and cooling it to room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazn-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         25 . A process for the preparation of the polymorphic. Form-XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 1  1, which comprises: 
 (i) synthesizing (29) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent,  
 (ii) adding L-arginine dissolved in water slowly with constant stirring to the solution obtained in step (i),  
 (iii) stirring the reaction mixture at a temperature of 40-80° C. for a period in the range of 18-30 h to obtain a white crystalline precipitate,  
 (iv) filtering the white crystalline precipitate obtained in step (iii) above and  
 (v) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,  
 (vi) heating the polymorphic Form-I obtained in step (v) to 185° C. and cooling it to room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and  
 (vii) heating the polymorphic Form-X obtained in step (vi) to 175° C. and cooling it to room temperature to yield Form-XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)etloxylphenyl]-2-ethoxypropanoic acid.  
 
     
     
         26 . A process for the preparation of the mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 11 , which comprises: 
 (i) synthesizing (2S) 3-[4-[-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, employing known methods and dissolving in an organic solvent    (ii) adding L-arginine dissolved in water slowly with constant stirring in the solution obtained in step (i),    (iii) stirring the reaction mixture at room temperature for a period in the range of 18-30 h to separate white crystalline powder,    (iv) filtering the white crystalline powder obtained in step (iii) and    (v) drying under vacuum at a temperature of 4045° C. for a period in the range of 4-16 h to yield mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         27 . A process for the preparation of polymorphic Form I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the characteristics defined in  claim 1 , which comprises: 
 (i) suspending any of the polymorphic Form II to XI or the mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in isopropyl alcohol and stirring in dark conditions at room temperature for a period of 35-50 h,    (ii) filtering and washing with isoporpyl alcohol and    (iii) drying under vacuum at a temperature of 40-45° C. for a period in the range of 4-16 h to yield polymorphic Form of I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.    
     
     
         28 . A pharmaceutical composition comprising a mixture of any of polymorphic Forms I to XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula (I) aid a pharmaceutically acceptable carrier, diluent, excipient or solvate.  
     
     
         29 . A process as claimed in claims  14  and  22  to  26 , wherein the organic solvents arc selected from acetonitrile, ethanol, methanol, 1,4-dioxane, and isopropanol.  
     
     
         30 . A pharmaceutical composition as claimed in  claim 13 , in the form of a tablot, capsule, powder, syrup, solution or suspension.  
     
     
         31 . A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  to a patient in need thereof.  
     
     
         32 . A method according to  claim 31 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomexulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.  
     
     
         33 . A method according to  claim 31  for the treatment and I or prophylaxis. of disorders related to Syndrome X, which comprises administering an agonist of PPARα and/or PPARγ of formula (I).  
     
     
         34 . A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma comprising administering a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13  and  30 .  
     
     
         35 . A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemnia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  in combination/concomittant with HMG CoA reductase inhibitors or fibrates or nicotinic acid or cholestyrarine or colestipol or probucol which may be administered together or within such a period as to act synergistically together to a patient in need thereof.  
     
     
         36 . A method according to  claim 35 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.  
     
     
         37 . A method according to  claim 35  for the treatment and/or prophylaxis of disorders related to Syndrome X, which comprises administering a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  in combination with HMG CoA reductase inhibitors or fibrates or nicotinic acid or cholestyramine or colestipol or probucol which may be administered together or within such a period as to act synergistically together.  
     
     
         38 . A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma, which comprises administering a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2 ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  in combination/concomittant with HMG CoA reductase inhibitors or fibrates or nicotinic acid or cholestyramine or colestipol or probucol which may be administered together or within such a period as to act synergistically together to a patient in need thereof.  
     
     
         39 . A method according to  claim 35  for the treatment and/or prophylaxis of disorders related to Syndrome X, which comprises administering to a patient in need thereof an agonist of PPARα and/or PPARγ of formula (I) as claimed in claims  1 - 12  or a pharmaceutical composition according to  claim 13  or  30  and HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyra mine, colestipot or probucol or their combination within such a period as to act synergistically.  
     
     
         40 . Use of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  for preventing or treating hyperlipidemia, hypercholesteremia, hyperglycomia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism.  
     
     
         41 . Use of a polymorphic Form according to  claim 40 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive uephrosclerosis, retinopathy, nepbropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.  
     
     
         42 . Use of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  for reducing plasma glucose, triglycrides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.  
     
     
         43 . Use of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  in combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol which may be administered together or within such a period as to act synergistically together for preventing or treating hyperlipidemia, hypercholesterernia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism to a patient in need thereof.  
     
     
         44 . Use of a polymorphic Form according to  claim 43 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian, syndrome (PCOS), useful as aldose reductase. inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.  
     
     
         45 . Use of a polymnorphic Form selected from Form I to M or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  in combination/conconittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in the plasma.  
     
     
         46 . Use of a polymorphic Form selected from Form I to M or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  for preparing a medicament for preventing or treating hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism.  
     
     
         47 . Use of a polymorphic form according to  claim 37 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syrndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.  
     
     
         48 . Use of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  for preparing a medicament for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.  
     
     
         49 . Use of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  for preparing a medicament in combination/concomittant with UMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramife, colestipol or probucol for preventing or treating hyperlipemia, hypercholesteremria, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiolggical mechanism.  
     
     
         50 . Use of a polymorphic form according to  claim 49 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (COS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.  
     
     
         51 . Use of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(henoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  for preparing a medicament in. combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotini acid, cholestyramine, colestipol or probucol for reducing plasma glucose:, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in the plasma.  
     
     
         52 . A medicine for preventing or treating hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering an effective amount of a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30 .  
     
     
         53 . A medicine according to  claim 52 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.  
     
     
         54 . A medicine for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma comprising an effective amount of a polymorphic Form selected from Form. I to XI or a mixture of polymorphic Form I and X -of L-argnine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30 .  
     
     
         55 . A medicine for preventing or treating hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  and HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol.  
     
     
         56 . A medicine according to  claim 55 , wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotoriic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.  
     
     
         57 . A medicine for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma, which comprises a polymorphic Form selected from Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in claims  1 - 12  or a pharmaceutical composition as claimed in claims  13 ,  28  and  30  and HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyranine, colestipol or probucol.