Process for preparing forms of atorvastatin calcium substantially free of impurities

Abstract

The preparation of atorvastatin calcium epoxide dihydroxy (AED) is described. AED can be used as a standard or marker in determining the amount of AED in a sample. AED can therefore be used as a tool in preparing atorvastatin calcium substantially free of AED.

1 - 23 . (canceled) 
   
   
       24 . A method for determining the level of atorvastatin epoxy dihydroxy (AED) in atorvastatin calcium comprising
 (a) measuring by HPLC the area under a peak corresponding to AED in a reference standard comprising a known amount of AED;   (b) measuring by HPLC the area under a peak corresponding to AED in a sample comprising atorvastatin calcium and AED; and   (c) determining the amount of AED in the sample by comparing the area of step (a) to the area of step (b).   
   
   
       25 . The method of  claim 24 , wherein atorvastatin calcium is either crude atorvastatin calcium or any form of atorvastatin calcium. 
   
   
       26 . The method of  claim 25 , wherein said form of atorvastatin calcium is selected from the group consisting of form I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, and amorphous. 
   
   
       27 . The method of  claim 24 , wherein the measuring by HPLC in step (a), step (b), or both, includes the following:
 (i) preparing solutions by combining the atorvastatin calcium sample of step (a), and the reference standard of step (b), with a mixture of acetonitrile:tetrahydrofuran:water in a ratio of about 60:5:35, to obtain a solution;   (ii) injecting the solutions prepared in step (i) into a 250×4.6 mm KR 100 5C-18 (or similar) column;   (iii) eluting the standard or sample that was injected in step (ii) from the column at about 50 min using a mixture of acetonitrile:tetrahydrofuran:buffer (31:9:60) and acetonitrile:buffer mix (75:25) as an eluent, and   (d) measuring the AED content in the sample with a UV detector.   
   
   
       28 . The method of  claim 27 , wherein the UV wavelength is about 254 nm. 
   
   
       29 . An HPLC method for assaying atorvastatin calcium that contains AED comprising the steps of
 (a) combining an atorvastatin calcium sample with a mixture of acetonitrile:tetrahydrofuran:water in a ratio of about 60:5:35, to obtain a solution;   (b) injecting the solution of step (a) into a 250×4.6 mm KR 100 5C-18 (or similar) column;   (c) eluting the sample from the column at about 50 min using a mixture of acetonitrile:tetrahydrofuran:buffer (31:9:60) and acetonitrile:buffer mix (75:25) as an eluent, and   (d) measuring the AED content in the sample with a UV detector by comparing with HPLC, carried out as in steps (b) and (c), of a reference standard comprising a known amount of AED.   
   
   
       30 . The method of  claim 29 , wherein the UV wavelength is about 254 nm. 
   
   
       31 . The method of  claim 29 , wherein the buffer contains an aqueous solution of NH 4 H 2 PO 4  in a concentration of about 0.05M having a pH of about 5, and ammonium hydroxide. 
   
   
       32 . The method of  claim 31 , wherein the ratio of the said aqueous solution of NH 4 H 2 PO 4  and the ammonium hydroxide is of about 1 to 4, respectively. 
   
   
       33 . The method of  claim 29 , wherein the buffer mix contains a buffer and tetrahydrofuran; wherein the buffer contains an aqueous solution of NH 4 H 2 PO 4  in a concentration of about 0.05M having a pH of about 5, and ammonium hydroxide. 
   
   
       34 . The method of  claim 33 , wherein the ratio of the said buffer and tetrahydrofuran is about 1 to 6.67, respectively. 
   
   
       35 . A process for preparing a form of atorvastatin calcium comprising less than about 0.10 w/w of AED, by HPLC comprising the steps of
 (a) obtaining one or more samples of one or more atorvastatin calcium batches;   (b) measuring the level of AED in each of the samples of (a);   (c) selecting the atorvastatin calcium batch that comprises a level of AED of less than a about 0.10 w/w by HPLC, based on the measurement or measurements conducted in step (b); and   (d) using the batch selected in step (c) to prepare said any form of atorvastatin calcium.   
   
   
       36 . The process of  claim 35 , wherein the atorvastatin calcium sample of step (a) contains less than about 0.05 w/w by HPLC of AED. 
   
   
       37 . The process of  claim 35 , wherein said any form of atorvastatin calcium is selected from the group consisting of form I, II, IV, V, VI, VII, VIII, IX, X, XI, XII, and amorphous. 
   
   
       38 . The process of  claim 35 , wherein, if the atorvastatin calcium sample in step (a) contains more than about 0.10 w/w by HPLC of AED, the sample may be purified, prior to performing step (c). 
   
   
       39 . The process of  claim 35 , wherein the atorvastatin calcium of step (a) obtained after purification, contains less than about 0.10 w/w by HPLC of AED. 
   
   
       40 . The process of  claim 39 , wherein the atorvastatin calcium of step (a) obtained after purification, contains less than about 0.05 w/w by HPLC of AED. 
   
   
       41 . The process of  claim 35 , wherein the purification is done by crystallization from an organic solvent, water, or mixtures thereof. 
   
   
       42 - 106 . (canceled)