Abstract
A rapid, reversed-phase liquid chromatographic method was developed for the quantitative determination of Atorvastatin calcium, its related substances (12 impurities), and degradation impurities in bulk drugs. The chromatographic separation was achieved on a Zorbax Bonus-RP column by employing a gradient elution with water–acetonitrile–trifluoroacetic acid as the mobile phase in a shorter run time of 25 min. The flow rate was 1.0 mL/min and the detection wavelength was 245 nm. The drug substance was subjected to stress studies such as hydrolysis, oxidation, photolysis, and thermal degradation, and considerable degradation was observed in acidic hydrolysis, oxidative, thermal, and photolytic stress conditions. The formed degradation products were reported and were well-resolved from the Atorvastatin and its related substances. The stressed samples were quantified against a qualified reference standard and the mass balance was found to be close to 99.5% (w/w) when the response of the degradant was considered to be equal to the analyte (i.e. Atorvastatin), which demonstrates the stability-indicating capability of the method. The method was validated in agreement with ICH requirements. The method developed here was single and shorter (25 min method for the determination of all 12 related impurities of Atorvastatin and its degradation products), with clearly better resolution and higher sensitivity than the European (85 min method for the determination of six impurities) and United States pharmacopeia (115 min and 55 min, two different methods for the determination of six related substances).
Highlights
Atorvastatin calcium, chemically (3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt (2:1), is an inhibitor of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
Imp-A, Imp-B, ImpC, Imp-D, Imp-F, Imp-G, Imp-H, Imp-I, Imp-J, Imp-K, Imp-L, and Imp-M (Imp-E was 3S, 5S enantiomer of Atorvastatin, so it was not captured in this method and the Imp-D will undergo a transformation equilibrium with its cyclic hemiketal form, which is nothing but the Imp-L) are the potential impurities of the Atorvastatin calcium drug substance
It was observed that Atorvastatin calcium and its 12 potential impurities were well-separated with a resolution greater than two
Summary
Atorvastatin calcium, chemically (3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt (2:1), is an inhibitor of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. To the best of our knowledge, no single rapid stability-indicating LC method was reported for the determination of Atorvastatin calcium, its 12 potential impurities, and degradants in the bulk drugs and in pharmaceutical dosage forms. The pharmacopeia methods were much longer in run time: the European pharmacopeia method was 85 min for the determination of only six impurities, and the United States pharmacopeia mentions two different methods in 115 min and 55 min for the determination of the six related substances
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