Stable and Bio-equivalent Formulation of HMG-CoA reductase inhibitor: Atorvastatin Calcium

Background: The present study aims to develop stable and bioequivalent non-infringing generic formulation of highly bio-variable Atorvastatin calcium (ATV) using amorphous API. Atorvastatin undergoes two major degradation pathways: lactonization and oxidation; that affects its pharmaceutical efficacy and henceforth the useful shelflife of the product. Method: In order to prevent oxidation, oil soluble anti-oxidants are incorporated in formulation, for blocking the oxidation of ATV by breaking the free radical chain reaction at chain propagation step. For achieving anticipated bioavailability and bioequivalence; Atorvastatin should be immediately released form tablet granules less than 5 minutes with micro-environmental pH more than pKa+1 of Atorvastatin acid. Accordingly, combination of compatible disintegrants with alkalizers is desirable for rapid disintegration of the tablet granules within an alkaline micro-environmental pH to prevent lactonization in stomach by direct exposure to acidic pH. Once ATV completely released from granules; the nonionic surfactant Tween® 80 (Polysorbate 80) helps for quick “micellar solubilization” of poorly water soluble ATV at the site of absorption. Accelerated stability study results of optimized formulation revealed that there were no significant changes in impurity profile of final formulations with 1% of Meglumine (organic alkalizer) and 1% Magnesium Oxide (inorganic alkalizer) as a combination. Conclusion: A randomized, two-treatment, four-period, two-sequence, single dose, two-way replicate crossover bioequivalence study was carried out in 24 healthy human volunteers. Biostatistics of bioequivalence study clearly inveterate that optimization of the Tween® 80 (Polysorbate 80) concentration leads towards desired Cmax and AUC of test formulation meeting the Bioequivalence criteria with respect to commercial reference formulation Lipitor®.