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. 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 X of [R—(R*,R*)]-2-(4-fluorophenyl)-beta,delta-di-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has an X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9, 11.1, 10.5, 9.1, 4.55. 
   
   
       2 . A crystalline Form B1 of [R—(R*,R*)]-2-(4-fluorophenyl)-beta,delta-di-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has an X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 12.1, 10.1, 5.27, 4.89, 4.68, 4.46, 4.22. 
   
   
       3 . A crystalline Form B2 of [R—(R*,R*)]-2-(4-fluorophenyl)-beta,delta-di-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has an X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 12.3, 10.4, 5.28, 4.88, 4.55, 4.27. 
   
   
       4 . A crystalline Form C of [R—(R*,R*)]-2-(4-fluorophenyl)-beta,delta-di-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has an X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 28.8, 24.0, 11.3, 4.59, 3.70. 
   
   
       5 . A crystalline Form D of [R—(R*,R*)]-2-(4-fluorophenyl)-beta,delta-di-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has an X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 31.0, 16.9, 10.3, 4.84. 
   
   
       6 . A crystalline Form E of [R—(R*,R*)]-2-(4-fluorophenyl)-beta,delta-di-hydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt that has an X-ray powder diffraction pattern with a characteristic peak expressed in d-values (Å) at 26.8. 
   
   
       7 . A process for the preparation of a crystalline form according to  claim 1 , which comprises drying a solution of Atorvastatin calcium in methanol, with or without presence of a non-solvent. 
   
   
       8 . A process for the preparation of a crystalline form according to  claim 2 , which comprises suspending a crystalline form that has the X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9, 11.1, 10.5, 9.1, 4.55 or the amorphous form of Atorvastatin calcium in acetonitrile containing a further organic solvent, and treating the suspension at temperatures between 10 and 50° C. 
   
   
       9 . A process for the preparation of a crystalline form according to  claim 3 , which comprises suspending a crystalline form that has the X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9, 11.1, 10.5, 9.1, 4.55 or the amorphous form of Atorvastatin calcium in acetonitrile, and treating the suspension at temperatures between 10 and 50° C. 
   
   
       10 . A process for the preparation of a crystalline form according to  claim 4 , which comprises suspending a crystalline form that has the X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9, 11.1, 10.5, 9.1, 4.55 or the amorphous form of Atorvastatin calcium in a mixture of isopropanol and water and treating the suspension at ambient temperature. 
   
   
       11 . A process for the preparation of a crystalline form according to  claim 5 , which comprises suspending a crystalline form that has the X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9, 11.1, 10.5, 9.1, 4.55 or the amorphous form of Atorvastatin calcium in a mixture of ethanol and water and treating the suspension at temperatures between 20 to 60° C. 
   
   
       12 . A process for the preparation of a crystalline form according to  claim 6 , which comprises dissolving a crystalline form that has the X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9, 11.1, 10.5, 9.1, 4.55 or the amorphous form of Atorvastatin calcium in a mixture of 2-butanone and ethyl acetate and/or heptane and evaporating of the solvent. 
   
   
       13 . A solid pharmaceutical composition comprising an effective amount of a crystalline form according to any one of  claims 1 ,  2 - 5 , or  6  and a pharmaceutically acceptable carrier. 
   
   
       14 . The crystalline form of  claim 1  further characterized by PXRD peaks expressed in d-values (Å) at 20.9, 18.9, 16.1, 5.53, 5.07, 4.77, 4.13, 3.69. 
   
   
       15 . The crystalline form of  claim 2  further characterized by PXRD peaks expressed in d-values (Å) at 27.9, 17.0, 14.2, 8.6, 7.1, 6.1, 3.90, 3.70, 2.36. 
   
   
       16 . The crystalline form of  claim 3  further characterized by PXRD peaks expressed in d-values (Å) at 28.1, 17.2, 14.0, 8.6, 7.5, 7.0, 3.88, 3.73. 
   
   
       17 . The crystalline form of  claim 4  further characterized by PXRD peaks expressed in d-values (Å) at 17.1, 9.8, 8.3, 7.7, 6.9, 5.64, 5.21, 4.39, 4.16. 
   
   
       18 . The crystalline form of  claim 5  further characterized by PXRD peaks expressed in d-values (Å) at 33.7, 7.7, 6.4. 
   
   
       19 . The crystalline form of  claim 6  further characterized by PXRD peaks expressed in d-values (Å) at 9.4, 4.6. 
   
   
       20 . The process of  claim 7  comprising drying a solution of Atorvastatin calcium in methanol in the presence of a non-solvent. 
   
   
       21 . The process of  claim 8  comprising suspending the amorphous form of Atorvastatin calcium in acetonitrile containing a further organic solvent. 
   
   
       22 . The process of  claim 9  comprising suspending the amorphous form of Atorvastatin calcium in acetonitrile and treating the suspension at temperatures between 10 and 50° C. 
   
   
       23 . The process of  claim 10  comprising suspending the amorphous form of Atorvastatin calcium in a mixture of isopropanol and water and treating the suspension at ambient temperature. 
   
   
       24 . The process of  claim 11  comprising suspending the amorphous form of Atorvastatin calcium in a mixture of ethanol and water and treating the suspension at temperatures between 20 to 60° C. 
   
   
       25 . The process of  claim 12  comprising dissolving the amorphous form of Atorvastatin calcium in a mixture of 2-butanone and ethyl acetate and/or heptane and evaporating the solvent.