Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel process for preparing other forms

Abstract

The present invention provides novel forms of atorvastatin designated Forms VI, VIII, IX, X, XI and XII and novel processes for their preparation as well as processes for preparing atorvastatin Forms I, II, IV, V and amorphous atorvastatin.

1 . A process for preparing atorvastatin hemi-calcium Form XII characterized by a powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8, 18.2, and 19.0±0.2 degrees 2θ comprising the steps of:
 a) suspending [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester in ethanol,   b) deprotecting the [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester by adding hydrochloric acid to the suspension, thereby forming a solution of atorvastatin ester derivatives in ethanol,   c) adding calcium hydroxide to the solution, thereby forming a solution of atorvastatin hemi-calcium in ethanol,   d) optionally removing any excess calcium hydroxide, and   e) precipitating atorvastatin hemi-calcium from the solution as Form XII characterized by a powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0±0.2 degrees 2θ.   
     
     
         2 . A pharmaceutical composition comprising solid atorvastatin hemi-calcium Form XII characterized by a powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0±0.2 degrees 2θ and a pharmaceutically acceptable excipient. 
     
     
         3 . A pharmaceutical dosage form comprising solid atorvastatin hemi-calcium Form XII characterized by a powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0±0.2 degrees 2θ. 
     
     
         4 . The pharmaceutical dosage form of claim  7  which contains 2.5 mg to 80 mg of atorvastatin hemi-calcium Form XII characterized by a powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0±0.2 degrees 2θ.