Characterization of the stress degradation products of tolvaptan by UPLC-Q-TOF-MS/MS

Abstract

Tolvaptan (TVT) is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia. TVT was subjected to forced degradation under hydrolysis, oxidation, dry heat and photolysis conditions, in accordance with the ICH guideline Q1A (R2). The degradation products (DPs) formed have been characterized through UPLC-PDA and UPLC-Q-TOF-MS/MS studies. The chromatographic separation was achieved on an Acquity UPLC HSS T3 column (100 × 2.1 mm, 1.7 μm) with a mobile phase containing a gradient mixture of solvents A (0.1% formic acid) and B (acetonitrile) at a flow rate of 0.3 ml min⁻¹ at 30 °C. The detection wavelength was set at 266 nm. The drug degraded under acid hydrolysis, base hydrolysis and oxidative conditions to form a total of 7 DPs. When methanol was used as the co-solvent during stress degradation, four additional DPs were formed which were absent when acetonitrile was used as the co-solvent. Comparison of the fragmentation pattern of the DPs with that of the drug helped in the elucidation of the structures of all the degradation products. The degradation pathway of the drug was established, which was duly justified by the mechanistic explanation. The developed UPLC method was validated as per ICH guidelines.