Structural elucidation of two novel degradants of lurasidone and their formation mechanisms under free radical‐mediated oxidative and photolytic conditions via liquid chromatography‐photodiode array/ultraviolet‐tandem mass spectrometry and one‐dimensional/two‐dimensional nuclear magnetic resonance spectroscopy

Abstract

Lurasidone is an antipsychotic drug clinically used for the treatment of schizophrenia and bipolar disorder. During a mechanism‐based forced degradation study of lurasidone, two novel degradation products were observed under free radical‐mediated oxidative (via AIBN) and solution photolytic conditions. The structures of the two novel degradants were identified through an approach combining HPLC, LC‐MSn (n = 1, 2), preparative HPLC purification and NMR spectroscopy. The degradant formed under the free radical‐mediated condition is an oxidative degradant with half of the piperazine ring cleaved to form two formamides; a mechanism is proposed for the formation of the novel N,N′‐diformyl degradant, which should be readily applicable to other drugs that contain a piperazine moiety that is widely present in drug molecules. The degradant observed under the solution photolytic condition is identified as the photo‐induced isomer of lurasidone with the benzisothiazole ring altered into a benzothiazole ring.

Microbial degradation products of lurasidone and their significance in postmortem toxicology

“…The 509 compound is proposed to be lurasidone‐sulfoxide (LURA‐SO) based on a mass difference from LURA consistent with the mass of an oxygen atom (15.9949 Da, δ = 0.5 mDa), along with the m/z 99.0917 and m/z 358.2489 product ions in common with an oxidative degradation product reported by Kumar Talluri et al 24 A degradant with an observed m/z [M + H] + of 551.2687 was not detected in acetylated extracts, which would be expected were the 509 compound instead a hydroxylated product 25 …”

“…With the exception of the 509 and 523 degradation products thought to be lurasidone-sulfoxide and an N,N 0 -diformyl degradant, respectively, the lurasidone degradation products observed in the blood experiments have not been reported previously in studies that assessed lurasidone stability against acid, alkali, oxidation, 25 photolysis and heat 24 done degradation and to mitigate scenarios where lurasidone may not be detected due to complete degradation. That is, in the event that lurasidone is not detected, its degradation product may serve as a marker to indicate antemortem lurasidone administration.…”

“…Agilent Technologies MassHunter™ Workstation Qualitative Analysis (version B.07.00 Service Pack 2) software was used to screen for potential degradation products based on the mass defect of LURA (calculated m/z [M + H] + = 493.2631, therefore mass defect = 0.2631 Da) with a tolerance of ±100 mDa. Data were also interrogated using the mass defects of LURA degradation products reported previously in the literature 24,25 . A collision energy of 40 eV was used.…”

“…The 509 compound is proposed to be lurasidone-sulfoxide (LURA-SO) based on a mass difference from LURA consistent with the mass of an oxygen atom (15.9949 Da, δ = 0.5 mDa), along with the m/z 99.0917 and m/z 358.2489 product ions in common with an oxidative degradation product reported by Kumar Talluri et al 24 detected in acetylated extracts, which would be expected were the 509 compound instead a hydroxylated product. 25 The 523 degradation product is proposed to be the oxidative N,N 0 -diformyl degradant of lurasidone reported by Wang et al 25 based on the acceptable mass accuracy for the [M + H] + ion of this compound (δ = 2.5 ppm) as well as the shared product ion of m/z 467.2475 detected and proposed by Wang et al to correspond to a didesformyl ion. 25 If this is the case, the 495 and 467 degradation products are likely N-formyl and N,N 0 -didesformyl degradation products of lurasidone given their mass differences from the 523 degradant corresponding to a loss of CO and C 2 O 2 , respectively (calculated mass 509.258 precursor ion decreased in response as the experiment progressed until it was undetectable at the end of the experiment (Figure 5f).…”

“…25 The 523 degradation product is proposed to be the oxidative N,N 0 -diformyl degradant of lurasidone reported by Wang et al 25 based on the acceptable mass accuracy for the [M + H] + ion of this compound (δ = 2.5 ppm) as well as the shared product ion of m/z 467.2475 detected and proposed by Wang et al to correspond to a didesformyl ion. 25 If this is the case, the 495 and 467 degradation products are likely N-formyl and N,N 0 -didesformyl degradation products of lurasidone given their mass differences from the 523 degradant corresponding to a loss of CO and C 2 O 2 , respectively (calculated mass 509.258 precursor ion decreased in response as the experiment progressed until it was undetectable at the end of the experiment (Figure 5f). In the 7-day experiment, in most specimens stored at 37 C LURA-SO relative responses did not significantly increase (Figure 6).…”