Process for preparing forms of atorvastatin calcium substantially free of impurities
AssigneeTeva Pharmaceutical Industries Ltd.
InventorNina Finkelstein
Life of this patent
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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.
Claims106
Isolated atorvastatin epoxy dihydroxy (AED), having the formula:
A method for determining the level of AED in atorvastatin calcium comprising
- (b) measuring by HPLC the area under a peak corresponding to AED in a reference standard comprising a known amount of AED;
- (c) measuring by HPLC the area under a peak corresponding to AED in a sample comprising atorvastatin calcium and AED;
- (d) determining the amount of AED in the sample by comparing the area of step (a) to the area of step (b).
An HPLC method for assaying atorvastatin calcium 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 standard or 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 standard or sample with a UV detector.
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.
A method for reducing the level of AED in atorvastatin calcium sample by dissolving a selected form of atorvastatin calcium in an organic solvent, water or mixtures thereof, and crystallizing to obtain atorvastatin calcium having a reduced level of AED.
The method of claim 58, wherein the polar organic solvent is a mixture of C1-4 alcohol and an ether.
Dependencies are inferred from the claim text.