Assessment of Lurasidone Hydrochloride and Its Impurities for Neuronal and Cardiac Toxicities Using Integrated Toxicological Approaches

Lurasidone hydrochloride (LH) has over 98 other impurities produced during its manufacturing and storage process. LH had two crucial impurities that were reported cytotoxic and genotoxic in nature: 4‐chloro‐1,2‐benzisothiazole (Impurity 1) and 3‐(1‐piperazinyl)‐1,2‐benzisothiazole (Impurity 2). When the impurity threshold is exceeded due to chronic administration, evaluation of the toxicity of critical organs become crucial. A variety of endpoints were evaluated to assess the neurotoxicity of LH along with both impurities. The parameters related to neurotoxicity includes assessment of neurobehavioral abnormalities, evaluation of acetylcholinesterase and oxidative stress level by super oxide dismutase and malondialdehyde. Acetylcholinesterase is the most desirable targets affected by both impurities, according to AI‐based toxicity prediction tools and docking scores. Cytotoxic nature of LH's and its impurities were discovered at 80‐, 160‐, and 320‐μM concentrations through in vitro study with PC12 and H9C2 cell lines. In zebrafish study, at 0.2 μg/L of Impurity 2, there was an increase in mirror biting and time spent at the bottom of the tank, but there was no discernible decline in memory or learning during the T‐maze assay. Impurity 1 and Impurity 2 demonstrated inhibition of AchE at the molecular level, which raises acetylcholine levels and causes excitotoxicity. Oxidative damage in neuronal cells is indicated by a lower amount of superoxide dismutase and a higher level of malondialdehyde. Cardiac histological damages like exhibiting myofilament fiber rupture and dissolution observed to decide toxicity induced damage. At 0.2‐μg/L dose, the Impurity 2 has shown potential neurotoxicity as well cardiotoxicity in zebrafish study.