AN IMPROVED PROCESS FOR THE PREPARATION OF STABLE AMORPHOUS ATORVASTATIN HEMI CALCIUM AND THEIR SALTS THEREOF

摘要

The present invention describes the preparation of highly pure (i.e. filling in ICH quality parameters with respect to related substances) stable amorphous Atorvastatin calcium salt comprising (a) hydrolysis of 1,3-dioxane ring of (4R-Cis)-1,1-dimethylethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1lH-pyrrol-1-yl]ethyl]-2,2- dimethyl-1,3-dioxane-4-acetate having formula I, (b) in situ hydrolysis of t-butyl group to form Atorvastatin sodium salt solution (c) addition of a single or a mixture of two or more antioxidants and optionally an amine (d) addition of Atorvastatin sodium salt solution to an aqueous solution of calcium acetate or calcium chloride (e) optionally seeding with amorphous atorvastatin calcium (f) filtration and washing of obtained cake using different solvents mixtures in presence of antioxidants (g) dissolving above cake in a solvent or a mixture of two or more organic solvents followed by crystallization of product using an antisolvent.