Oxidative degeneration 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 . A process for the preparation of a compound selected from the group consisting of 4-[6-(4-fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoyl-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)-2 isobutyryl-3-phenyl-oxirane-2-carboxylic acid phenylamide comprising exposing a solution of an atorvastatin salt to sunlight or artificial sunlight. 
   
   
       2 . The process according to  claim 1  wherein the atorvastatin salt is selected from the group consisting of atorvastatin calcium, atorvastatin sodium, atorvastatin potassium, atorvastatin magnesium and atorvastatin ammonium. 
   
   
       3 . The process according to  claim 1  further comprising one or more isolation steps. 
   
   
       4 . The process according to  claim 3  wherein the isolation step is selected from the group consisting of preparative normal phase chromatography and reverse phase chromatography. 
   
   
       5 . The process according to  claim 4  wherein the preparative normal phase chromatography comprises using silica gel or silica-based bonded phases functionalized with a group selected from aminopropyl, cyanopropyl, diol and nitrophenyl. 
   
   
       6 . The process according to  claim 5  wherein the preparative normal phase chromatography comprises using a mobile phase comprising a mixture of an alcohol selected from the group consisting of methanol, ethanol, propanol and acetonitrile and a non-polar solvent selected from the group consisting of hexane, dichloromethane, methylcyclohexane, and any combination thereof. 
   
   
       7 . The process according to  claim 4  wherein in the preparative reverse phase chromatography comprises using octadecylsylan or octylsilan bonded on silica gel. 
   
   
       8 . The process according to  claim 7  wherein the preparative reverse phase chromatography comprises using a mobile phase comprising a mixture of water with an organic or inorganic buffer and one or more organic modifiers selected from the group consisting of alcohols and acetonitrile.