利用LC-HRMS、GC-MS、NMR和硅毒性预测方法鉴定和表征甲基磺酸硫醚酮的强制降解产物

Journal of Pharmaceutical and Biomedical Analysis Open Pub Date : 2025-08-04 DOI:10.1016/j.jpbao.2025.100085

Nehal Bhatt , Devendra Sonaje , Vijiaya Madhyanapu Golla , Rahul Khemchandani , Roshitha K. R , Arun Kumar Gupta , Gananadhamu Samanthula

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引用次数: 0

摘要

本研究详细介绍了应力条件下lumateperone的强制降解分析，以开发一种能够分离降解产物（DP-1至DP-11）的稳定性指示方法，然后使用连线分析技术对其进行鉴定和表征。在氧化、酸性、碱性和光解条件下观察到明显的降解。氧化应激产生了与DP-3、DP-4和DP-6一样的颜色强烈的醌衍生物（DP-2）。碱性水解产生n -脱烷基和羟基化产物（DP-1, DP-4, DP-5），并产生挥发性降解产物DP-7。光解胁迫生成DP-2和DP-8，而中性水解生成DP-1、DP-2、DP-4和DP-7。值得注意的是，盐酸中的酸性水解引发了二聚体降解产物（DP-9）和氯代位置异构体（DP-10和DP-11）。采用液相色谱-高分辨率质谱（LC-HRMS）分析了DP-1 ~ DP-6和DP-8 ~ DP-11的化学结构。采用气相色谱-质谱联用（GC-MS）鉴定DP-7为1-（4-氟苯基）乙醇。对主要降解产物DP-2进行了分离，并用核磁共振（NMR）对其进行了表征。一些DPs与先前报道的代谢物具有相同的结构特征，表明化学降解和代谢过程之间存在相似性。该方法按照ICH Q2（R1）进行验证，具有良好的线性(r²>；0.999)，准确度、精密度、特异性和稳健性。在硅毒性分析中，使用ADMET Predictor®标记四种dp （DP-1, DP-2， DP-5和DP-6）具有致突变警报，并预测额外的肝毒性，心脏毒性和受体介导的风险。这些发现为氟替他酮的配方和质量管理提供了支持。

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Identification and characterization of forced degradation products of lumateperone tosylate by LC-HRMS, GC-MS, NMR, and in silico toxicity prediction

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Identification and characterization of forced degradation products of lumateperone tosylate by LC-HRMS, GC-MS, NMR, and in silico toxicity prediction

This study presents a detailed forced degradation profiling of lumateperone under stress conditions to develop a stability-indicating method capable of separating degradation products (DP-1 to DP-11), followed by their identification and characterization using hyphenated analytical techniques. Significant degradation was observed under oxidative, acidic, alkaline, and photolytic conditions. Oxidative stress generated an intensely colored quinone derivative (DP-2) as a major degradation product along with DP-3, DP-4, and DP-6. Alkaline hydrolysis yielded N-dealkylated and hydroxylated species (DP-1, DP-4, DP-5) and also produced a volatile degradation product, DP-7. Photolytic stress resulted in DP-2 and DP-8, whereas neutral hydrolysis led to the formation of DP-1, DP-2, DP-4, and DP-7. Notably, acidic hydrolysis in hydrochloric acid triggered dimer degradation product (DP-9) and chlorinated positional isomers of lumateperone (DP-10 and DP-11). The chemical structures of DP-1 to DP-6 and DP-8 to DP-11 were proposed by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). DP-7 was identified as 1-(4-Fluorophenyl)ethanol using gas chromatography-mass spectrometry (GC–MS). The major degradation product, DP-2, was isolated and further characterized by nuclear magnetic resonance (NMR). A few DPs shared structural features with previously reported metabolites, suggesting a resemblance between chemical degradation and metabolic processes. The developed method was validated in accordance with ICH Q2(R1), demonstrating excellent linearity (r² > 0.999), accuracy, precision, specificity, and robustness. In silico toxicity analysis using ADMET Predictor® flagged four DPs (DP-1, DP-2, DP-5, and DP-6) with mutagenic alerts and predicted additional hepatotoxic, cardiotoxic, and receptor-mediated risks.These findings support formulation and quality management of lumateperone.

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Journal of Pharmaceutical and Biomedical Analysis Open

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