Crystalline Form of Bis [(E)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-[methyl(methyl-sulfonyl)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-(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)=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 3  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  or  claim 6  and a pharmaceutically acceptable carrier. 
   
   
       9 . 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 1  or  claim 6 ; and   subsequently converting the crystalline form to an amorphous form.   
   
   
       10 . The process as claimed in  claim 9  comprising
 mixing a solution containing [(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 as claimed in  claim 1  or  claim 6  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  or  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. 
   
   
       17 . A process for the manufacture of the crystalline form as claimed in  claim 1  or  claim 6  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  or  claim 6  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 a the crystalline form as claimed in  claim 1  or  claim 6 . 
   
   
       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.