Lou Chaoyan, Pan Shaojie, Yu Xiaolin, Zhang Kaidi, Zhang Kai, Zhu Yan
College of Quality and Standardization, China Jiliang University, Hangzhou 310018, China.
Ningbo Key Laboratory of Agricultural Germplasm Resources Mining and Environmental Regulation, College of Science and Technology, Ningbo University, Ningbo 315300, China.
Int J Mol Sci. 2025 May 20;26(10):4895. doi: 10.3390/ijms26104895.
Angiotensin II receptor blockers (ARBs), a critical class of second-generation antihypertensive drugs, require azide intermediates for constructing their biphenyl tetrazole pharmacophore. This synthetic reaction introduces hypertoxicity risks, as residual azides can induce fatal damage even at trace concentrations. The pharmacopoeias of most countries have highlighted the urgency for improved detection paradigms of the control of azides in ARBs. Current ion chromatography (IC) methods face analytical challenges due to matrix interference from organic solvents and incompatibility with hydrophobic ARB ingredients. Herein, an in situ matrix elimination ion chromatography methodology was established for the sensitive detection of trace azides in angiotensin II receptor blocker pharmaceuticals. The switching strategy used in the proposed methodology eliminates organic interference and avoids the incompatibility issue with ARB ingredients. Under the optimal conditions, the proposed method exhibited satisfactory linearity in the range of 2.0-200.0 ng/mL, with a correlation coefficient of 0.9996. Validation studies demonstrated a detection limit (LOD, S/N = 3) of 0.57 ng/mL and a quantification limit (LOQ, S/N = 10) of 1.89 ng/mL, surpassing the sensitivity requirements in pharmacopeias. Method robustness was confirmed, with recovery rates from 92.8 to 108.7% using spiked ARBs real samples, and the intra-day and inter-day RSDs were less than 9.7%. The proposed approach establishes a reliable, precise, and sensitive alternative for monitoring azide impurities in ARBs, and such a framework can overcome limitations such as solubility issues, contributing to a universal applicability to diverse hydrophobic drugs.
血管紧张素 II 受体阻滞剂（ARBs）是一类关键的第二代抗高血压药物，构建其联苯四唑药效基团需要叠氮化物中间体。这种合成反应带来了高毒性风险，因为即使是痕量浓度的残留叠氮化物也可能导致致命损害。大多数国家的药典都强调了改进 ARBs 中叠氮化物控制检测方法的紧迫性。目前的离子色谱（IC）方法面临分析挑战，因为有机溶剂会产生基质干扰，且与疏水性 ARB 成分不兼容。在此，建立了一种原位基质消除离子色谱方法，用于灵敏检测血管紧张素 II 受体阻滞剂药物中的痕量叠氮化物。所提出方法中使用的切换策略消除了有机干扰，并避免了与 ARB 成分的不兼容问题。在最佳条件下，所提出的方法在 2.0 - 200.0 ng/mL 范围内表现出令人满意的线性，相关系数为 0.9996。验证研究表明，检测限（LOD，S/N = 3）为 0.57 ng/mL，定量限（LOQ，S/N = 10）为 1.89 ng/mL，超过了药典中的灵敏度要求。方法的稳健性得到了证实，加标的 ARBs 实际样品回收率为 92.8%至 108.7%，日内和日间相对标准偏差均小于 9.7%。所提出的方法为监测 ARBs 中的叠氮化物杂质建立了一种可靠、精确且灵敏的替代方法，这样的框架可以克服诸如溶解性问题等局限性，有助于广泛适用于各种疏水性药物。
