Study on forced degradation behaviour of dofetilide by LC-PDA and Q-TOF/MS/MS: Mechanistic explanations of hydrolytic, oxidative and photocatalytic rearrangement of degradation products.

A solution and solid state forced decomposition study was carried on dofetilide under diverse stress conditions of hydrolysis, oxidation, photolysis and thermal as per International Council for Harmonisation guidelines (ICH) Q1A(R2) to understand its degradation behaviour. A total of eight degradation products (DPs) were identified and separated on reversed phase kromasil 100 C8 column (4.6 mm x 250 mm x5 μm) using gradient elution with ammonium acetate (10 mM, pH 6.2) and acetonitrile as mobile phase. The detection wavelength was selected as 230 nm. The high performance liquid chromatography (HPLC) study found that the drug was susceptible to hydrolytic stress condition, but it was highly unstable to photolytic and oxidative conditions. The solid drug was stable in thermal and photolytic conditions. Initially comprehensive mass fragmentation pattern of the drug was accomplished with the LC/ESI/QTOF/MS/MS studies in positive ionization mode. The same was followed for all the eight degradation products to characterise their structure. The DP4 was N-oxide and the structure was confirmed by LC/APCI/QTOF/MS/MS in positive ionization mode. The complete mass fragmentation pattern of the drug and its DPs were established which in turn helped the characterisation of their structures. The mechanistic pathway for the formation of all the DPs was explained.