Process for producing crystalline atorvastatin calcium

A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt comprising the steps of:

• (a) reacting a mixture of atorvastatin lactone, methanol, and methyl tert-butyl ether with sodium hydroxide to form the ring-opened sodium salt;
• (b) forming a product rich aqueous layer and an organic layer comprising methyl tert-butyl ether containing impurities;
• (c) removing the organic layer comprising methyl tert-butyl ether containing impurities;
• (d) extracting the product rich aqueous layer with methyl tert-butyl ether;
• (e) adding an extra charge of methyl tert-butyl ether to a vessel containing the product rich aqueous layer in an amount of at least 1% w/v of the contents of the vessel;
• (f) sealing the reaction vessel;
• (g) heating the contents of the sealed reaction vessel to 47° C. to 57° C. in the presence of the extra charge of methyl tert-butyl ether which saturates the crystallization matrix on heating;
• (h) adding calcium acetate hemihydrate to the sealed reaction vessel to form atorvastatin trihydrate hemi calcium salt;
• (i) providing a vacuum pan dryer having an agitator;
• and
• (j) drying the isolated product in a vacuum pan dryer whilst continuously rotating the agitator at a speed of from 0.5 rpm to 2 rpm.