Abstract
The aim of the present study was to optimize a chromatographic method for the analysis of atorvastatin (acid and lactone forms), ortho- and para-hydroxyatorvastatin by using an experimental design approach. Optimization experiments were conducted through a process of screening and optimization. The purpose of a screening design is to identify the factors that have significant effects on the selected chromatographic responses, and for this purpose a full 23 factorial design was used. The location of the true optimum was established by applying Derringer’s desirability function, which provides simultaneously optimization of all seven responses. The ranges of the independent variables used for the optimization were content of acetonitrile in mobile phase (60–70%), temperature of column (30–40 °C) and flow rate (0.8–1.2 mL min−1). The influences of these independent variables were evaluated for the output responses: retention time of first peak (p-hydroxyatorvastatin) and of last peak (atorvastatin, lactone form), symmetries of all four peaks and relative retention time of p-hydroxyatorvastatin. The primary goal of this investigation was establishing a new simple and sensitive method that could be used in analysis of biological samples. The method was validated and successfully applied for determination of atorvastatin (acid and lactone forms) and its metabolites in plasma.
Highlights
Atorvastatin, (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-yl-pyrrol-1-yl]3,5-dihydroxyheptanoic acid, is a member of the drug class known as statins which are used for lowering blood cholesterol
Atorvastatin is administered as the calcium salt of its active acid form
Since the RP-HPLC method is based on using a polar mobile phase, a complete description of the ionization profile of atorvastatin and its metabolites have been used for the evaluation of retention behavior and solubility
Summary
Atorvastatin, (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-yl-pyrrol-1-yl]3,5-dihydroxyheptanoic acid (abbreviated as ATO), is a member of the drug class known as statins which are used for lowering blood cholesterol. HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body. Atorvastatin is administered as the calcium salt of its active acid form. The primary proposed mechanism of atorvastatin metabolism is through cytochrome P450 3A4 hydroxylation to form active ortho- and para-hydroxylated metabolites [1]. About 70% of the total plasma HMG-CoA reductase inhibitory activity is accounted for by active metabolites (Scheme 1), adapted from [2]. Structures of atorvastatin and its metabolites and the metabolic pathways of atorvastatin [2]
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