Crystalline form of bis [(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl] (3r,5s)-3, 5-dihydroxyhept-6-enoicacid] 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 the formula I  
     
       
         
         
             
             
         
       
     
     having an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=8.8, 13.1 and 21.5°.  
   
   
       2 . A 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 . A 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 . A crystalline hydrated form as claimed in  claim 1 ,  claim 2  or  claim 3  which contains about 9-10% water.  
   
   
       5 . A 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 a compound of formula I (as shown in  claim 1)  having an X-ray powder diffraction pattern with peaks at 2-theta (2θ)=4.4, 7.7, 9.0 and 20.7°.  
   
   
       7 . A crystalline form of a compound of formula I (as shown in  claim 1)  having an X-ray powder diffraction pattern substantially as shown in FIG. 2.  
   
   
       8 . A pharmaceutical composition comprising a crystalline form as claimed in any one of the preceding claims, together with 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 isolation of a crystalline form as defined in any one of  claims 1  to  5  from a solution and subsequent conversion to the amorphous form.  
   
   
       10 . A 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-6enoic acid]calcium salt with a slurry of a crystalline form as described in any one of  claims 1  to  5  in water, isolation of crystals of a crystalline form as described in any one of  claims 1  to  5  and subsequent conversion of the isolated crystals to the amorphous form.  
   
   
       11 . A process as claimed in  claim 10  wherein the 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 is a waste solution such as 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.  
   
   
       12 . A process as claimed in  claim 10  or  claim 11  wherein the mixing is carried out between 37 and 43° C.  
   
   
       13 . The use of a crystalline form as claimed in any one of  claims 1  to  5  as a processing aid for 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.  
   
   
       14 . The use as claimed in  claim 13  as a processing aid for recovery 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 waste solutions.  
   
   
       15 . The use of a crystalline form as claimed in any one of  claims 1  to  5  as an intermediate in the manufacture 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.  
   
   
       16 . A process for the manufacture of a crystalline form as claimed in any one of  claims 1  to  5  which comprises forming crystals from a saturated solution of a compound of formula (I) as defined in  claim 1 , 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 a crystalline form as claimed in any one of  claims 1  to  5  which comprises seeding an aqueous solution or slurry of a compound of formula I (as defined in  claim 1) .  
   
   
       18 . A process for the manufacture of a crystalline form as claimed in any one of  claims 1  to  5  which comprises prolonged stirring of a solution of an amorphous form of a compound of formula I (as defined in  claim 1) .  
   
   
       19 . A process for the manufacture of a pharmaceutical composition as claimed in  claim 8  which comprises admixing a crystalline form as defined in any one of  claims 1  to  5  together with a pharmaceutically acceptable carrier.  
   
   
       20 . The use of a crystalline form as claimed in any one of  claims 1  to  5  in the manufacture of a medicament.  
   
   
       21 . A method of treating a disease condition wherein inhibition of HMG CoA reductase is beneficial which comprises administering to a warm-blooded mammal an effective amount of a crystalline form as claimed in any one of  claims 1  to  5 .