Oxidative degradation products of atorvastatin calcium

Abstract

The present invention relates to oxidative degradation products of atorvastatin calcium and the process of the preparation thereof. The present invention also relates to atorvastatin calcium substantially free of oxidative degradation products and the pharmaceutical compositions containing such atorvastatin calcium.

1 - 48 . (canceled) 
   
   
       49 . 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1aphenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)hydroxy-butyric acid. 
   
   
       50 . 4-(4-Fluoro-phenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid phenylamide. 
   
   
       51 . 4-[1b-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl ]-3-(R)hydroxy-butyric acid. 
   
   
       52 . Substantially pure atorvastatin calcium containing less than about 0.29 weight % of oxidative degradation products 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1bisopropyl-6a-phenyl-1a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-azacyclopropa[a]inden-3-yl ]-3-(R)-hydroxy-butyric acid, 4-(4-Fluoro-phenyl)-2,4dihydroxy-2-isopropyl-5-phenyl-3,6-dioxa-bicyclo[3.1.0]hexane-1-carboxylic acid phenylamide, 4-[1b-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6aphenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl ]-3-(R)hydroxy-butyric acid and 3-(4-Fluoro-benzoyl)-2-isobutyryl-3-phenyl-oxirane-2carboxylic acid phenylamide. 
   
   
       53 . Substantially pure atorvastatin calcium containing less than about 0.09 weight % 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1aphenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)hydroxy-butyric acid. 
   
   
       54 . Substantially pure atorvastatin calcium containing less than about 0.05 weight % 4-(4-Fluoro-phenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid phenylamide. 
   
   
       55 . Substantially pure atorvastatin calcium containing less than about 0.09 weight % 4-[1b-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6aphenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)hydroxy-butyric acid. 
   
   
       56 . Substantially pure atorvastatin calcium which comprises less than about 0.06 weight % 3-(4-Fluoro-benzoyl)-2-isobutyryl-3-phenyl-oxirane-2-carboxylic acid phenylamide. 
   
   
       57 . A pharmaceutical composition comprising substantially pure atorvastatin calcium which comprises less than about 0.6 weight % of oxidative degradation products 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1aphenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)hydroxy-butyric acid, 4-(4-Fluoro-phenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6dioxa-bicyclo[3.1.0]hexane-1-carboxylic acid phenylamide, 4-[1b-(4-Fluoro-phenyl)6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-azacyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid and 3-(4-Fluoro-benzoyl)-2isobutyryl-3-phenyl-oxirane-2-carboxylic acid phenylamide. 
   
   
       58 . A pharmaceutical composition comprising substantially pure atorvastatin calcium which comprises less than about 0.2 weight % 4-[6-(4-Fluoro-phenyl)-6hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-azacyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid and at least one pharmaceutically acceptable excipient. 
   
   
       59 . A pharmaceutical composition comprising substantially pure atorvastatin calcium which comprises less than about 0.1 weight % 4-(4-Fluoro-phenyl)-2,4dihydroxy-2-isopropyl-5-phenyl -3,6-dioxa-bicyclo[3,1.0]hexane-1-carboxylic acid phenylamide and at least one pharmaceutically acceptable excipient. 
   
   
       60 . A. pharmaceutical composition comprising substantially pure atorvastatin calcium comprising less than about 0.2 weight % 4-[1b-(4-Fluoro-phenyl)-6-hydroxy6-isopropyl-1a-phenyl-6a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-azacyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid and at least one pharmaceutically acceptable excipient. 
   
   
       61 . A pharmaceutical composition comprising substantially pure atorvastatin calcium comprising less than about 0.1 weight % 3-(4-Fluoro-benzoyl)-2-isobutyryl3-phenyl-oxirane-2-carboxylic acid phenylamide and at least one pharmaceutically acceptable excipient.