An Automated and Precise Approach for the Determination of Azide Residue in Angiotensin II Receptor Blockers Using In Situ Matrix Elimination Ion Chromatography with Switching Strategy

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.