Identification of stress degradation products of iloperidone using liquid chromatography coupled with an Orbitrap mass spectrometer.

RATIONALE Iloperidone (ILOP) is an atypical antipsychotic drug used for the treatment of schizophrenia and related psychotic disorders. Comprehensive stress testing of the ILOP drug was carried out as per ICH guidelines to understand its degradation profile. The presence of degradation products in a drug affects not only the quality, but also the safety and efficacy of drug formulation. Thus, it is essential to develop an efficient analytical method which can be useful for the separation, identification and characterization of all possible degradation products of ILOP. METHODS ILOP was subjected to various stress conditions such as acidic, basic, neutral hydrolysis, oxidation, photolysis and thermal conditions; and the resulting degradation products were investigated using LC-PDA-HRMS and MS/MS. An efficient and simple ultra-high-performance liquid chromatography (UHPLC) method has been developed on Acquity UPLC® BEH C18 column (2.1 × 100mm, 1.7 μm) using a gradient elution of heptafluorobutyric acid (0.1% HFBA) and acetonitrile as mobile phase. RESULTS ILOP was found to degrade under acidic and basic hydrolysis and oxidative stress conditions, whereas it was stable under neutral hydrolysis, thermal and photolytic conditions. A total of seven degradation products (DP1 to DP7) were identified and characterized by LC/MS/MS in positive ion mode with accurate mass measurements. The hydrolytic degradation under acidic and basic conditions produced two DPs (DP1 and DP2) and four DPs (DP4 to DP7), respectively, whereas DP3 was formed under oxidative conditions. In silico toxicity predictions showed higher probability values for DP4, DP6 and DP7, which indicates these DPs have the potential to mutate DNA. CONCLUSIONS ILOP was found to be labile under hydrolytic and oxidative conditions. The structures of the degradation products were rationalized by appropriate mechanisms. The proposed method can be effectively used for the determination and detection of ILOP and its degradation products.