Abstract

The safety of the drug impurities and their admissible limits in the drug formulations have taken centre stage in drug regulatory affairs. Various drug regulatory bodies, like the International Conference on Harmonization and Food and Drug Administration have taken a serious view on drug impurities, and have tried to address them by issuing various guidelines. The research work presented in the manuscript addresses the above mentioned issue for the degradation products of the drug haloperidol by their toxicity profiling. Haloperidol was stressed under the International conference on harmonization specified stress conditions to assess its stability. It degraded under oxidative stress condition to form two degradation products while, being stable under other conditions viz. hydrolytic, thermal and photolytic. The drug and degradation products were separated by using high performance liquid chromatography by a method consisting of HiQ sil C18 column (250 mm×4.6 mm and 5 µm) using acetonitrile, ammonium formate (10 mM, pH adjusted to 3.7 with formic acid) and triethylamine in the ratio of 40:60:0.1 (v/v/v). The flow rate and the detection wavelength used were 1 ml/min and 246 nm, respectively. The degradation products were identified as trans-haloperidol N-oxide and cis-haloperidol N-oxide by using tandem mass spectrometry. The absorption, distribution, metabolism, excretion, toxicity and the mutagenic potential of the degradation products were studied by using in silico tools like the pKCSM webserver, Toxtree and the OSIRIS property explorer. Apart from inhibiting a few specific isoforms of the cytochrome P450 system, both the degradation products were predicted not to pose any health hazard (hepatotoxic and mutagenic potential).