Impurity Profiling and Mechanistic Investigation of the Photochemical Degradation of Tetrandrine

IF 1.7 3区化学 Q4 BIOCHEMICAL RESEARCH METHODS

Rapid Communications in Mass Spectrometry Pub Date : 2025-07-01 DOI:10.1002/rcm.10102

Jinmei Tan, Feng Wang, Ruihan Zheng, Weiran Yang, Jinlong Chen

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引用次数: 0

Abstract

Rationale

Tetrandrine is a bisbenzylisoquinoline alkaloid with diverse pharmacological activities and faces critical pharmaceutical challenges due to its inherent photolability under environmental stressors. Despite its therapeutic potential, systematic investigations into its photodegradation mechanisms and impurity profiling remain conspicuously absent, posing risks to drug quality control and regulatory compliance.

Methods

Structural elucidation of degradation products (DPs) was achieved through advanced analytical techniques, including high-resolution mass spectrometry (HRMS), 1D/2D nuclear magnetic resonance (NMR) spectroscopy, and comparative fragmentation analysis. Key degradation drivers—including light intensity, atmospheric composition, aqueous content, and pH extremes—were quantitatively assessed through designed single-variable experiments.

Results

Seven photodegradants (DP-1 to DP-7) were structurally characterized, including two quaternary ammonium enantiomers (DP-2 and DP-3) from N-oxidation, a benzophenone derivative (DP-4) via benzylic C–H oxidation, and macrocyclic cleavage products (DP-1 and DP-7) through oxidative C–C bond scission. Degradation exhibited irradiance threshold behavior (> 10 mW cm⁻² for 80% conversion) and oxygen dependency (R² = 0.98). Alkaline conditions (0.1 M NaOH) induced complete degradation within 0.5 h through ·OH-mediated radical chain reactions, while aqueous media (40% H₂O) accelerated hydrolysis.

Conclusions

This study provides the first mechanistic atlas of tetrandrine's photodegradation, identifying three dominant pathways: oxidative skeletal modification, oxidative ring-opening, and radical-mediated C–N cleavage. This study establishes a robust framework for the impurity analysis of natural product-derived drugs and provides actionable guidelines for stabilizing tetrandrine during manufacturing and storage.

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粉防己碱光化学降解的杂质谱及机理研究

粉防己碱是一种具有多种药理活性的双苄基异喹啉生物碱，由于其在环境胁迫下固有的光致性，在制药方面面临着严峻的挑战。尽管其具有治疗潜力，但对其光降解机制和杂质分析的系统研究仍然明显缺乏，这给药物质量控制和法规遵从性带来了风险。方法采用高分辨率质谱（HRMS）、一维/二维核磁共振（NMR）光谱和碎片化对比分析等先进分析技术对降解产物（DPs）进行结构解析。主要的降解驱动因素——包括光强度、大气成分、水含量和pH值极值——通过设计的单变量实验进行定量评估。结果对7种光降解物（DP-1 ~ DP-7）进行了结构表征，包括n -氧化生成的2个季铵对映体（DP-2和DP-3）、苯基C-H氧化生成的二苯甲酮衍生物（DP-4）和氧化C-C键裂解生成的大环裂解产物（DP-1和DP-7）。降解表现出辐照度阈值行为（> 10 mW cm−2，转化率为80%）和氧依赖性（R2 = 0.98）。碱性条件（0.1 M NaOH）通过·oh介导的自由基链反应在0.5 h内完全降解，而水介质（40% H2O）加速了水解。本研究提供了粉防己碱光降解的第一个机制图谱，确定了三种主要途径：氧化骨架修饰、氧化环打开和自由基介导的C-N切割。本研究为天然产物衍生药物的杂质分析建立了一个健全的框架，并为在生产和储存过程中稳定粉防己碱提供了可操作的指导方针。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Rapid Communications in Mass Spectrometry 化学-分析化学

CiteScore

4.10

自引率

5.00%

发文量

219

审稿时长

2.6 months

期刊介绍： Rapid Communications in Mass Spectrometry is a journal whose aim is the rapid publication of original research results and ideas on all aspects of the science of gas-phase ions; it covers all the associated scientific disciplines. There is no formal limit on paper length ("rapid" is not synonymous with "brief"), but papers should be of a length that is commensurate with the importance and complexity of the results being reported. Contributions may be theoretical or practical in nature; they may deal with methods, techniques and applications, or with the interpretation of results; they may cover any area in science that depends directly on measurements made upon gaseous ions or that is associated with such measurements.