Comparative Stability Evaluation of Marketed Paracetamol IV Formulations in India

Abstract

Paracetamol is a well-established drug widely used around the world for analgesic and antipyretic purposes in oral solid dosage forms. While paracetamol is stable in solid dosage form, intravenous formulations have significant stability related issues, as the drug is susceptible to hydrolysis and oxidation in aqueous media. Formation of hydrolytic product can be well controlled by adjusting the pH of formulation. However, control of oxidation of the drug during manufacturing and packaging is a challenge, as it requires sophisticated operational controls to remove dissolved oxygen and/or addition of compatible anti-oxidant. Seven commercially available paracetamol intravenous formulations from the Indian market were evaluated for their oxidative degradation potential. The study was performed in two tiers: i) to compare formation of oxidative products in selected stress degradation conditions; and ii) to determine presence of cysteine, an anti-oxidant excipient. Firstly, all formulations were subjected to thermal stress condition at 80oC for 7 days and oxidative stress condition with 2,2' -azobis (2-amidino-propane) dihydrochloride (AAPH) at 40oC for 48 hours. Of the seven formulations tested, one formulation (PerfalganTM, Manufactured by BMS) showed absence of oxidative products after both stress conditions. For tier II studies, a sensitive HILIC-MS/MS method was developed on API 4000 (AB Sciex) for the determination of cysteine presence. Only PerfalganTM showed presence of cysteine. Thus, PerfalganTM can be expected to have better stability compared to other marketed formulations. Overall, it is concluded that presence of an anti-oxidant in intravenous formulation could give additional advantage over stability of paracetamol. Key words: HILIC, LC-MS, Oxidative stress, Paracetamol, stability.