使用液相色谱与轨道阱质谱联用技术鉴定伊潘立酮的应激降解产物。
Identification of stress degradation products of iloperidone using liquid chromatography coupled with an Orbitrap mass spectrometer.
作者信息
Pandeti Sukanya, Rout Tofan Kumar, Tadigoppula Narender, Thota Jagadeshwar Reddy
机构信息
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
Division of Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow, India.
出版信息
Rapid Commun Mass Spectrom. 2017 Aug 30;31(16):1324-1332. doi: 10.1002/rcm.7907.
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.
原理
伊潘立酮（ILOP）是一种用于治疗精神分裂症及相关精神障碍的非典型抗精神病药物。按照国际人用药品注册技术协调会（ICH）指南对ILOP药物进行了全面的应力测试，以了解其降解情况。药物中降解产物的存在不仅会影响药物质量，还会影响药物制剂的安全性和有效性。因此，开发一种高效的分析方法对于分离、鉴定和表征ILOP所有可能的降解产物非常有用。
方法
对ILOP施加各种应力条件，如酸性、碱性、中性水解、氧化、光解和热条件；并使用液相色谱-光电二极管阵列-高分辨质谱（LC-PDA-HRMS）和串联质谱（MS/MS）研究所得的降解产物。在Acquity UPLC® BEH C18柱（2.1×100mm，1.7μm）上，以七氟丁酸（0.1% HFBA）和乙腈的梯度洗脱作为流动相，开发了一种高效且简单的超高效液相色谱（UHPLC）方法。
结果
发现ILOP在酸性和碱性水解以及氧化应激条件下降解，而在中性水解、热和光解条件下稳定。通过液相色谱/串联质谱（LC/MS/MS）在正离子模式下进行精确质量测量，共鉴定和表征了七种降解产物（DP1至DP7）。酸性和碱性条件下的水解降解分别产生了两种降解产物（DP1和DP2）和四种降解产物（DP4至DP7），而DP3是在氧化条件下形成的。计算机辅助毒性预测显示DP4、DP6和DP7的概率值较高，这表明这些降解产物具有使DNA发生突变的潜力。
结论
发现ILOP在水解和氧化条件下不稳定。通过适当的机制对降解产物的结构进行了合理说明。所提出的方法可有效地用于ILOP及其降解产物的测定和检测。
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