Abstract
BackgroundThe aim of the present work was to determine potential toxicity of degradation products of febantel generated under different stress conditions mentioned in guideline Q1A (R2) laid down by International Council for Harmonization (ICH). The stability behavior of febantel was studied by subjecting it to hydrolytic, oxidative, photolytic and thermal forced degradation conditions.ResultsFive degradation products (DPs) were observed which were resolved using high-performance liquid chromatography (HPLC) and characterized by LC-MS/MS using positive mode of electrospray ionization. The chromatographic separation was carried out on Hypersil® BDS C18 (150 × 4.6 mm, 5 μm) column. Optimum resolution was obtained using ammonium formate buffer (10 mM, pH 3.5) and acetonitrile programmed in gradient elution mode at 281.0 nm using photodiode array detector.ConclusionThe drug was found susceptible to degradation under all the stress conditions except thermal and oxidative stress. Five major unknown degradation products DP–I, DP–II, DP–III, DP–IV, and DP–V generated under photolytic, alkali, and acidic stress condition were identified and characterized by LC-MS/MS. The drug and identified degradation products were screened for prediction of in-silico toxicity using software viz. Swiss ADME, OSIRIS Property Explorer and Pro Tox II which indicated overall no toxicological concerns.Graphical abstract
Highlights
The aim of the present work was to determine potential toxicity of degradation products of febantel generated under different stress conditions mentioned in guideline Q1A (R2) laid down by International Council for Harmonization (ICH)
Development and optimization of stability indicating assay method (SIAM) Optimum resolution separation was obtained by using mixture of acetonitrile (A) and 10 mM ammonium
Degradation behavior Drug was found to degrade generating total five degradation products. They were labelled as Degradation products (DP)–I, DP–II, DP– III, DP–IV, and DP–V in accordance with the elution order appeared in the chromatogram
Summary
The aim of the present work was to determine potential toxicity of degradation products of febantel generated under different stress conditions mentioned in guideline Q1A (R2) laid down by International Council for Harmonization (ICH). The stability behavior of febantel was studied by subjecting it to hydrolytic, oxidative, photolytic and thermal forced degradation conditions. Febantel is a broad spectrum veterinary anthelmintic. It is chemically designated as 2′-(2,3-bis(methoxycarbonyl)guanidino)-5′-phenylthio-2-methoxyacetanilide, and is active against wide range of gastrointestinal parasites in ruminants. It belongs to chemical class of benzimidazole (Fig. 1). It is official in Indian Pharmacopoeia [1] and European Pharmacopoeia [2]. Febantel is a prodrug; after oral administration, it gets transformed into active metabolite fenbendazole by hydrolytic removal of methoxy acetyl group and subsequent cyclization; febantel is called as probenzimidazole [4, 5]
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