Fluvastatin sodium crystal forms XIV, LXXIII, LXXIX, LXXX and LXXXVII, processes for preparing them, compositions containing them and methods of using them

Abstract

Provided are polymorphic forms of fluvastatin sodium and processes for their preparation.

1 . A crystalline form of fluvastatin sodium (Form LXXXVII) characterized by a PXRD pattern with peaks at 3.5, 12.5, 17.7. 19.7. 21.4±0.2 degrees two-theta. 
     
     
         2 . The crystalline form of  claim 2  further characterized by peaks at 7.1, 10.7, 18.3, 19.1, 25.5±0.2 degrees two-theta. 
     
     
         3 . The crystalline form of  claim 3  wherein the crystalline form is characterized by a PXRD pattern substantially as depicted in  FIG. 8 . 
     
     
         4 . A process for preparing the crystalline fluvastatin sodium form of  claim 1  comprising:
 a) hydrolyzing a lower alkyl ester of fluvastatin with a sodium base catalyst in a mixture of water and methanol,   b) evaporating methanol from the mixture,   c) contacting the water with a water-immiscible extraction solvent,   d) evaporating the water to leave a residue,   e) contacting the residue with acetonitrile, and   f) recovering the crystalline fluvastatin sodium.   
     
     
         5 . A process for preparing the crystalline fluvastatin sodium form of  claim 1  comprising:
 a) hydrolyzing a lower alkyl ester of fluvastatin with a sodium base catalyst in a mixture of water and methanol,   b) evaporating methanol from the mixture,   c) contacting the mixture with acetonitrile, and   d) recovering the crystalline fluvastatin sodium.   
     
     
         6 . A process for preparing crystalline fluvastatin (Form LXXXVII) characterized by a PXRD pattern with peaks at 3.5, 12.5, 17.7, 19.7, 21.4±0.2 degrees two-theta and other peaks at 7.1, 10.7, 18.3, 19.1, 25.5±0.2 degrees two-theta comprising heating a mixture of fluvastatin diol tert-butyl ester, methanol, NaOH and water to obtain a solution, evaporating the methanol from the solution while maintaining at least about 1 mL of water per gram of tert-butyl ester, adding acetonitrile and optionally water, wherein a solution exists after such addition, and recovering fluvastatin Form LXXXVII as a precipitate. 
     
     
         7 . The process of  claim 6 , wherein drying is carried out at a pressure below about 100 mmHg and a temperature of about 30° C. to about 60° C. 
     
     
         8 . The process of  claim 6 , wherein the temperature is about 40° C. 
     
     
         9 . The process of  claim 6 , wherein the temperature is about 50° C. 
     
     
         10 . The fluvastatin sodium prepared by the process of  claim 6 . 
     
     
         11 . A pharmaceutical composition comprising an effective amount of a fluvastatin sodium form selected Form (LXXXVII), having a PXRD pattern with peaks at 3.5, 12.5, 17.7, 19.7, 21.4±0.2 degrees two-theta, and mixtures thereof and a pharmaceutically acceptable excipietn. 
     
     
         12 . A pharmaceutical dosage form prepared from the pharmaceutical composition of  claim 11 . 
     
     
         13 . A method of treating a patient suffering from hypercholesterolemia or hyperlipidemia comprising the step of administering to the patient an effective amount of the pharmaceutical composition of  claim 11 .