Abstract Two precise and selective stability-indicating RP-LC methods have been developed and validated for simultaneous determination of metolazone in its binary mixture with losartan potassium (method 1) and spironolactone (method 2) in the presence of their degradation products. For method 1, the chromatographic separation was achieved on Kromasil C18 column, the mobile phase consisted of a mixture of 0.1% ortho-phosphoric acid in acetonitrile and 0.1% ortho-phosphoric acid in water (28:72, v/v) pumped at flow rate 2 mL/min and UV detection at 235 nm. Linearity was determined over the concentration range of 2–16µg/mL for metolazone and 40–320µg/mL for losartan potassium. For method 2, chromatographic separation of metolazone and spironolactone was achieved on a Symmetry C8 column using a mobile phase that consisted of acetonitrile, methanol, and 0.1% ortho-phosphoric in water in gradient mode pumped at a flow rate 1.5 mL/min with programed wavelength detection. Linearity was determined over the concentration range of 2–16µg/mL for metolazone and 20–160µg/mL for spironolactone. The suggested methods were proved to be highly selective, precise and accurate for simultaneous determination of the cited drugs in their combined pharmaceutical dosage form in the presence of their degradation products. The proposed methods were validated in compliance with ICH guidelines. Highlights Synchronized determination of metolazone and co-formulated drugs in presence of their degradation products. Act as a method for screening of metolazone and co-formulated drugs in quality control laboratories. Validation of suggested methods according to ICH guidelines. The pathway of degradation of metolazone under different stress conditions was proposed. Graphical Abstract

中文翻译：

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同步稳定性指示 RP-LC 方法测定美托拉宗与氯沙坦钾或螺内酯在其降解产物存在下

摘要 已开发并验证了两种精确且选择性的稳定性指示 RP-LC 方法，用于在其二元混合物中同时测定美托拉宗与氯沙坦钾（方法 1）和螺内酯（方法 2），同时测定它们的降解产物。对于方法 1，色谱分离是在 Kromasil C18 柱上实现的，流动相由乙腈中的 0.1% 正磷酸和水 (28:72, v/v) 中的 0.1% 正磷酸的混合物组成，在流速为 2 mL/min，紫外检测波长为 235 nm。在 2–16 µg/mL 的美托拉宗和 40–320 µg/mL 的氯沙坦钾浓度范围内确定了线性。对于方法 2，使用由乙腈、甲醇、和 0.1% 正磷酸水溶液在梯度模式下以 1.5 mL/min 的流速泵送，并使用程序波长检测。在 2–16 µg/mL 的美托拉宗和 20–160 µg/mL 的螺内酯浓度范围内确定了线性。所建议的方法被证明具有高度选择性、精确性和准确度，可在其降解产物存在的情况下同时测定其联合药物剂型中的引用药物。所提出的方法经验证符合 ICH 指南。亮点 在存在降解产物的情况下同步测定美托拉宗和复合制剂。作为一种在质量控制实验室中筛选美托拉宗和复合制剂的方法。根据 ICH 指南验证建议的方法。提出了不同胁迫条件下美托拉宗的降解途径。图形概要