Characterization and in‐silico toxicity prediction of the oxidative degradation products of Pimozide.

The investigation's objective was to access the stability of the drug substance Pimozide under the stress conditions specified in the International Conference on Harmonization Q1A(R2) guideline and to separate, identify, and characterize the degradation products by using liquid chromatography‐tandem mass spectrometry studies without isolating them from the reaction mixture. It was observed that the drug was susceptible to oxidative degradation (15% hydrogen peroxide, 48 h, room temperature) forming four novel degradation products while being stable under hydrolytic, Photolytic, and thermal conditions. The separation of the drug and the degradation products was achieved with good resolution on a Phenomenex C18 column (150 mm × 4.6 mm, 5 µm) using gradient elution. The fragmentation pattern constructed from the liquid chromatography‐quadrupole‐time of flight mass spectrometry data was used for structural characterization of the degradation products. Lastly, the in‐silico absorption, distribution, metabolism, excretion, and toxicity properties prediction was performed by using in‐silico tools like the pKCSM webserver, ToxTree, and OSIRIS property explorer. The primary screening through the pKCSM webserver exposed the hepatoxic and the mutagenic potential of Pimozide, 1‐(1‐(4‐(4‐fluorophenyl)‐4‐phenylbutyl) piperidin‐4‐yl)‐1,3‐dihydro‐2H‐benzo[d]imidazol‐2‐one (degradation product 3) and 1‐(4,4‐bis(4‐fluorophenyl)butyl)‐4‐(2‐oxo‐2,3‐dihydro‐1H‐benzo[d]imidazol‐1‐yl)piperidine 1‐oxide (degradation product 5) whereas, 1‐(1‐(4,4‐diphenylbutyl) piperidin‐4‐yl)‐2,3‐dihydro‐1H‐benzo[d]imidazol‐2‐ol (degradation product 1) was predicted to only possess mutagenic potential. Secondary screening for mutagenicity was done by using ToxTree and OSIRIS property explorer. [ABSTRACT FROM AUTHOR]