Crystalline Form of Bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] Calcium Salt

Abstract

Two polymorphic forms of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt, processes for making them and their use as HMG Co-A reductase inhibitors are described.

1 . A crystalline hydrated form of the compound bis[(E)-7-[4-(4fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt of formula I 
       
         
           
           
               
               
           
         
       
       having an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=8.8, 13.1 and 21.5°. 
     
     
         2 . The crystalline hydrated form as claimed in  claim 1  with an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=4.3, 8.8, 13.1, 13.7, 21.5, 22.8 and 28.9°. 
     
     
         3 . The crystalline hydrated form as claimed in  claim 1  with an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=4.3, 8.8, 13.1, 13.7, 15.2, 15.8, 17.5, 21.5, 21.9, 22.8, 24.5 and 28.9°. 
     
     
         4 . The crystalline hydrated form as claimed in  claim 1 , which contains about 9-10% water. 
     
     
         5 . The crystalline hydrated form as claimed in  claim 1  having an X-ray powder diffraction pattern substantially as shown in  FIG. 1 . 
     
     
         6 . A crystalline form of the compound bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt of formula I 
       
         
           
           
               
               
           
         
       
       having an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=4.4, 7.7, 9.0 and 20.7°. 
     
     
         7 . The crystalline form as claimed in  claim 6  having an X-ray powder diffraction pattern substantially as shown in  FIG. 2 . 
     
     
         8 . A pharmaceutical composition comprising the crystalline form as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . A process for formation and amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt comprising
 isolating from a solution the crystalline form as claimed in  claim 1 ; and   subsequently converting the crystalline form to an amorphous form.   
     
     
         10 . The process as claimed in  claim 9  comprising
 mixing a solution contain [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with a slurry of the crystalline form of formula 1 having an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=8.8, 13.1 and 21.5° or formula 1 having an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=4.4, 7.7, 9.0 and 20.7° in water; 
 isolating crystals of the crystalline form; and 
 subsequently converting the isolated crystals to the amorphous form. 
 
     
     
         11 . The process as claimed in  claim 10  wherein the solution containing the [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt is a waste solution. 
     
     
         12 . The process as claimed in  claim 10  wherein the mixing is carried out between 37 and 43° C. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . A process for the manufacture of the crystalline form as claimed in  claim 1  which comprises forming crystals from a saturated solution of a compound of formula (I) in aqueous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] sodium salt. 
     
     
         17 . A process for the manufacture of the crystalline form as claimed in  claim 1  which comprises seeding an aqueous solution or slurry of a compound of formula I. 
     
     
         18 . A process for the manufacture of the crystalline form as claimed in  claim 1  which comprises prolonged stirring of a solution of an amorphous form of a compound of formula I. 
     
     
         19 . A process for the manufacture of the pharmaceutical composition as claimed in  claim 8  which comprises admixing the crystalline form together with a pharmaceutically acceptable carrier. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating hyperlipidemia, hypercholesterolemia or atherosclerosis which comprises administering to a warm-blooded mammal in need thereof an effective amount of the crystalline form as claimed in  claim 1 . 
     
     
         22 . The process as claimed in  claim 11 , wherein the waste solution is a mother liquor solution from a process for formation and isolation of amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt from the corresponding sodium salt and calcium chloride. 
     
     
         23 . A pharmaceutical composition comprising the crystalline form as claimed in  claim 6  and a pharmaceutically acceptable carrier. 
     
     
         24 . A process for formation of amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt comprising
 isolating from a solution the crystalline form as claimed in  claim 6 ; and   subsequently converting the crystalline form to an amorphous form.   
     
     
         25 . A process for the manufacture of the crystalline form as claimed in  claim 6  which comprises forming crystals from a saturated solution of a compound of formula (I) in aqueous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] sodium salt. 
     
     
         26 . A process for the manufacture of the crystalline form as claimed  claim 6  which comprises seeding an aqueous solution or slurry of a compound of formula I. 
     
     
         27 . A process for the manufacture of the crystalline form as claimed in  claim 6  which comprises prolonged stirring of a solution of an amorphous form of a compound of formula I. 
     
     
         28 . A method of treating hyperlipidemia, hypercholesterolemia or atherosclerosis which comprises administering to a warm-blooded mammal in need thereof an effective amount of the crystalline form as claimed in  claim 6 .