Development and Validation of a Stability-Indicating UPLC-PDA Method for Fruquintinib: LC-QTOF-MS/MS-Based Structural Characterization of Degradation Products and In Silico ADMET Prediction

IF 1.8 3区化学 Q4 BIOCHEMICAL RESEARCH METHODS

Rapid Communications in Mass Spectrometry Pub Date : 2026-10-06 DOI:10.1002/rcm.70191

Shuvam Nayak, Vishal D. Labhade, Bhakti Umesh Hirlekar, Shashank Tewari, Sachin Dattram Pawar

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引用次数: 0

Abstract

Rationale

Fruquintinib (FRQ) is a recently approved drug for the treatment of metastatic colorectal cancer. To date, only a limited number of studies have investigated the stability-indicating analysis of FRQ. Understanding its degradation pathways is essential for ensuring drug quality and safety, for regulatory compliance and for providing valuable insights into pharmaceutical development and quality control.

Methods

FRQ was subjected to acid, base, oxidative, neutral, thermal, and photolytic stress as per ICH Q1A(R2). A stability-indicating UPLC-PDA method was developed on a Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) with gradient elution using a mobile phase of 10 mM ammonium acetate (pH 3.5) and acetonitrile. Degradants were characterized by LTQ-XL ion-trap MS and LC-QTOF-MS/MS, followed by silico ADMET prediction.

Results

The method is developed and validated in accordance with the ICH Q2(R2) guidelines. Forced degradation of FRQ under acidic, basic and oxidative stress conditions generated two common degradation products, DP-1 (m/z 207.0756) and DP-2 (m/z 221.0900), common to all three stress conditions, in addition to one degradation product specific to the oxidative pathway; FRQ was stable under neutral, thermal and photolytic conditions. The two major degradation products are identified and characterized by LC-QTOF-MS/MS. Out of two DPs, the DP-2 product has not been reported previously. ADMET prediction indicated acceptable pharmacokinetic properties but flagged potential drug–drug interaction risk.

Conclusions

The developed UPLC-PDA method provides a robust stability-indicating method for FRQ and enables comprehensive characterization of its degradation products. The discovery of the novel degradation product DP-2 expands current knowledge of FRQ degradation chemistry, whereas the combined analytical and in silico findings support pharmaceutical quality assessment, regulatory evaluation, and future safety investigations.

查看原文本刊更多论文

fruquininib稳定性指示UPLC-PDA方法的建立与验证：LC-QTOF-MS/MS-Based降解产物的结构表征和硅ADMET预测。

理由：fruquininib （FRQ）是最近批准用于治疗转移性结直肠癌的药物。迄今为止，只有有限数量的研究调查了FRQ的稳定性分析。了解其降解途径对于确保药物质量和安全、遵守法规以及为药物开发和质量控制提供有价值的见解至关重要。方法：FRQ按照ICH Q1A（R2）进行酸、碱、氧化、中性、热和光解应激。采用Waters BEH C18色谱柱（2.1 × 50 mm, 1.7 μm），以10 mm醋酸铵（pH 3.5）和乙腈为流动相，梯度洗脱，建立了稳定性指示UPLC-PDA方法。采用LTQ-XL离子阱质谱和lc - qtof质谱/质谱对降解物进行了表征，然后进行了硅ADMET预测。结果：该方法按照ICH Q2（R2）指南开发和验证。酸性、碱性和氧化应激条件下FRQ的强制降解产生了两种常见的降解产物DP-1 （m/z 207.0756）和DP-2 (m/z 221.0900)，这两种降解产物在三种应激条件下都是常见的，此外还有一种氧化途径特有的降解产物；在中性、热和光解条件下FRQ是稳定的。采用LC-QTOF-MS/MS对两种主要降解产物进行了鉴定和表征。在两个DPs中，DP-2产品以前没有报道过。ADMET预测显示了可接受的药代动力学特性，但标记了潜在的药物-药物相互作用风险。结论：所建立的UPLC-PDA方法为FRQ提供了一种鲁棒的稳定性指示方法，能够对其降解产物进行全面表征。新的降解产物DP-2的发现扩展了FRQ降解化学的现有知识，而分析和计算机研究的结合结果支持药品质量评估、监管评估和未来的安全性调查。

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.