In vitro degradation of ziprasidone in human whole blood

A systematic study was performed into the degradation of ziprasidone in simulated postmortem blood. Fifteen potential degradation products not previously reported in the literature were observed. Four resulted from degradation in human blood, whereas the remaining products resulted from reaction with solvents: four from alkaline degradation, four from reaction with acetaldehyde, and three from reaction with acetone. To identify possible degradation products, a liquid chromatograph‐diode array detector (LC‐DAD) and liquid chromatograph quadrupole‐time‐of‐flight mass spectrometer (LC‐QTOF‐MS) operating in auto‐MS/MS mode were used. It was indicated from red‐shifted UV–Vis spectra, accurate mass data, mass fragmentation data, and a deuteration experiment that the site of ziprasidone degradation, in the in vitro blood experiments, was the methylene carbon of the oxindole moiety. The major in vitro blood degradation products were proposed to be E/Z isomers of 3‐ethylidene‐ziprasidone. Further, another in vitro degradation product in microbially inoculated blood specimens was proposed to be 3‐ethyl‐ziprasidone. 3‐Ethylidene‐ziprasidone was hypothesized to form from the reaction of ziprasidone with acetaldehyde derived from the ethanol used to spike ziprasidone into the in vitro blood experiments. Data from two postmortem investigations were available for retrospective reanalysis. Attempts were made to detect degradation products of ziprasidone, but none were found. LC‐QTOF‐MS analyses of ziprasidone degradation in prior in vitro blood experiments, and a deuteration experiment reported herein, revealed ziprasidone degradation in blood likely occurs at the methylene carbon of the oxindole moiety. In this environment, reactions with carbonyl species, such as acetaldehyde, may yield aldol condensation products that could then hydrogenate in postmortem specimens due to microbial activity. Future work is warranted to investigate the stability of other drugs containing oxindole moieties to ensure postmortem toxicology screening methods are appropriate.