Identification of <i>N</i> -debenzisothiazole-lurasidone as an enzymatic degradation product of lurasidone

Herein we report the confirmation of N-debenzisothiazole-lurasidone as a lurasidone degradation product associated with postmortem toxicology casework. Confirmation was realized by unambiguous synthesis and comparison of its LC-MS/MS properties to the lurasidone degradation product in postmortem blood using liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). The mechanism of formation of this degradant in blood is proposed to be primarily enzymatic, given it has only been previously presumptively reported in one in vitro stability study following oxidative stress conditions. It has not been reported in other in vivo pharmacokinetic and in vitro stability studies assessing lurasidone stability toward acid, alkali, oxidation, photolysis, and heat. The detection of N-debenzisothiazole-lurasidone in postmortem casework indicates that, where possible, it should be included in toxicology screening methods targeting psychoactive compounds. Until such time that a commercially available reference standard of N-debenzisothiazole-lurasidone is available, the comprehensive accurate mass and mass spectral data of N-debenzisothiazole-lurasidone that are now available enable its inclusion as a "suspect target" in high-resolution-mass-spectrometry screening methods.