Crystalline forms of atorvastatin

Abstract

The present invention is directed to new crystalline forms of Atorvastatin calcium (2:1), referred to hereinafter as polymorphic Forms X, A, B1, B2, C, D and E. The present invention also is directed to crystalline Form A of Atorvastatin calcium (2:1) that is stable against the formation of the AED impurity. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and pharmaceutical compositions comprising the crystalline forms.

1 . A crystalline form of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has the X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 31.0 (w), 18.6(m), 17.0 (w), 15.3 (w), 12.8 (w), 11.2 (m), 9.6 (s), 9.3 (w), 8.6 (w), 7.4 (m), 6.5 (vw), 6.2 (w), 5.47 (w), 5.21 (m), 4.64 (vs), 4.46 (s), 4.14 (m), 3.97 (m), 3.74 (m), 3.62 (w), 3.38 (w), 3.10 (m); wherein (vs)=very strong intensity; (s)=strong intensity; (m)=medium intensity; (w)=weak intensity; (w)=very weak intensity.  
     
     
         2 . The crystalline form of  claim 1 , that is stable against the formation of Atorvastatin calcium epoxy dihydroxy (AED).  
     
     
         3 . The crystalline form of  claim 2 , that contains less than about 0.01% (w/w) AED after storage at a temperature of about 40° C. at a relative humidity of about 75% for at least about 1 month.  
     
     
         4 . The crystalline form of  claim 2 , that contains less than about 0.01% (w/w) AED after storage at a temperature of about 25° C. at a relative humidity of about 60% for at least about 6 months.  
     
     
         5 . The crystalline form of atorvastatin hemi-calcium of any one of claims  2  to 4, that is an isopropanolate or an ethanolate.  
     
     
         6 . A process for the preparation of the crystalline form according to  claim 1 , which comprises suspending a crystalline form of Atorvastatin calcium which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9 (s), 20.9 (w), 18.9 (w), 16.1 (w), 11.1 (m), 10.5 (m), 9.1 (m), 5.53 (m), 5.07 (w), 4.77 (vw), 4.55 (m), 4.13 (w), 3.69 (w); or amorphous Atorvastatin calcium in an alcohol containing a small amount of water and treating the suspension at a temperature between 10 and 60° C.  
     
     
         7 . A process for the preparation of the crystalline form according to  claim 1 , which comprises treating a solution of Atorvastatin lactone in a mixture of isopropanol and water with calcium hydroxide.  
     
     
         8 . A pharmaceutical composition comprising an effective amount of the crystalline form according to  claim 1 , and a pharmaceutically acceptable carrier.