Abstract
Simple, sensitive and accurate stability indicating analytical method for dronedarone has been developed and validated using RP-HPLC technique. Developed method is used to evaluate the assay and related substances of dronedarone drug substance and tablets (Multaq?). The drug substance was subjected to the stress conditions such as hydrolysis (acid and base), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH) pre- scribed stress conditions to show the stability-indicating the nature of the method. Significant degradation was observed during acid and base hydrolysis, and peroxide degradation. The major degredants were identified by LC-MS, FTIR and 1H NMR spectral analysis. The chromatographic conditions were optimized using an impurity-spiked solution and the samples generated from forced degradation studies. In the developed HPLC method, the resolution between dronedar- one, process-related impurities, (namely Imp-1, Imp-2, Imp-3, Imp-4, Imp-5, Imp-6, Imp-7, Imp-8, Imp-9, Imp-10 and Imp-11) and degradation products were found to be greater than 1.5. The eleven potential process related impurities were separated on an Ascentis? Express C18 column (4.6 × 10 cm i.d., particle size 2.7 μm) at a flow rate of 1.2 mL.min-1. The LC method employed a linear gradient elution and the detection wavelength at 220 nm. The chroma- tographic behavior of all the impurities was examined under variable compositions of different solvents, temperatures and pH values.
Highlights
Dronedarone, a benzofuran derivative, N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-benz ofuran-5-yl}methanesulfonamide, is a potent drug mainly used for the indication of cardiac arrhythmias [1]
The drug substance was subjected to the stress conditions such as hydrolysis, oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating the nature of the method
The data on degradation studies revealed that the degradation products were well separated from the dronedarone and known related substances, peak purity data of dronedarone hydrochloride indicated that the compound is spectrally pure
Summary
Dronedarone, a benzofuran derivative, N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-benz ofuran-5-yl}methanesulfonamide, is a potent drug mainly used for the indication of cardiac arrhythmias [1]. It has been developed by Sanofi Aventis to overcome iodineassociated adverse effects of the commonly used antiarrhythmic drug, amiodarone, with which it is structurally related [2]. During the chemical process development of bulk drug, several impurities aroused from precursors, side products formed in the reaction and impurities related to the reagents used may be present at low levels [5,6] Separation of all these impurities including degradation impurities in a single analytical HPLC method is a challenging job.
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