Crystalline N-acetyl neuraminic acid derivatives and processes for their preparation

Abstract

Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in crystaline form, particularly in the form of a hydrate which exists as crystals having a low aspect ratio, or in the form of a hydrate which exists as crystals having a high aspect ratio.

1 . 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in crystalline form.  
     
     
         2 . 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of crystals having a low aspect ratio.  
     
     
         3 . The crystalline form as claimed in  claim 2  wherein the crystals are tabular.  
     
     
         4 . The crystalline form as claimed in any one of  claims 1  to  3  wherein substantially all water of crystallisation is lost at about 80 to 90° C.  
     
     
         5 . The crystalline form as claimed in any one of  claims 1  to  4  for which the X-ray data are as shown in Table I.  
     
     
         6 . 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of crystals having a high aspect ratio.  
     
     
         7 . The crystalline form as claimed in  claim 6  wherein the crystals are needle-shaped.  
     
     
         8 . The crystalline form as claimed in any one of claims  1 ,  6  or  7  wherein water content is stable over a broad range of relative humidity.  
     
     
         9 . The crystalline form as claimed in any one of claims  1 ,  6  to  8  wherein one mole of water of crystallisation is lost at about 84-90° C. and a further mole of water of crystallisation is lost by about 135-143° C.  
     
     
         10 . The crystalline form as claimed in any one of claims  1 ,  6  to  9  for which the X-ray data are as shown in Table II.  
     
     
         11 . The crystalline form claimed in any one of  claims 2  to  5  substantially free of the crystalline form claimed in any one of  claims 6  to  10 .  
     
     
         12 . The crystalline form claimed in any one of  claims 6  to  10  substantially free of the crystalline form claimed in any one of  claims 2  to  5 .  
     
     
         13 . A method for the preparation of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in crystalline form, which method comprises crystallisation of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid from aqueous solution.  
     
     
         14 . A method as claimed in  claim 13  for the preparation of the crystalline form as claimed in any one of  claims 2  to  5 .  
     
     
         15 . A method as claimed in  claim 14  wherein the temperature of the aqueous solution is greater than about 50° C.  
     
     
         16 . A method as claimed in  claim 15  wherein the temperature of the aqueous solution is in the range 50 to 55° C.  
     
     
         17 . A method as claimed in any one of  claims 14  to  16  wherein the aqueous solution is seeded with crystals of the crystalline form as claimed in any one of  claims 2  to  5 .  
     
     
         18 . A method as claimed in  claim 13  for the preparation of the crystalline form as claimed in any one of  claims 6  to  10 .  
     
     
         19 . A method as claimed in  claim 18  wherein the temperature of the aqueous solution is less than about 40° C.  
     
     
         20 . A method as claimed in  claim 19  wherein the temperature of the aqueous solution is in the range 20 to 30° C.  
     
     
         21 . A method as claimed in any one of  claims 18  to  20  wherein the aqueous solution is seeded with crystals of the crystalline form as claimed in any one of  claims 6  to  10 .  
     
     
         22 . A method as claimed in any one of  claims 13  to  21  comprising addition of a counter solvent to the aqueous solution.  
     
     
         23 . A method as claimed in  claim 22  wherein the counter solvent is a ketone or an alkanol.  
     
     
         24 . A method as claimed in  claim 23  wherein the counter solvent is acetone.  
     
     
         25 . A method for the preparation of the crystalline form as claimed in any one of  claims 2  to  5 , which method comprises interconversion of the crystalline form as claimed in any one of  claims 6  to  10 .  
     
     
         26 . The method as claimed in  claim 25  wherein interconversion is effected by ageing of the aqueous solution.  
     
     
         27 . The method as claimed in  claim 25  wherein the interconversion is effected by addition of a base to the aqueous solution.  
     
     
         28 . A method for the preparation of the crystalline form as claimed in any one of  claims 6  to  10 , which process comprises addition of an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid to a similar volume of a counter solvent.  
     
     
         29 . The method as claimed in  claim 28  wherein the counter solvent is acetone.  
     
     
         30 . A pharmaceutical formulation comprising 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in crystalline form and a pharmaceutically acceptable carrier therefor.  
     
     
         31 . A pharmaceutical formulation as claimed in claim  30  in the form of a powder.  
     
     
         32 . A pharmaceutical formulation as claimed in claim  30  in the form of an aqueous solution or suspension.