Background. Indomethacin is considered a potent nonsteroidal anti-inflammatory drug that could be combined with Paracetamol to have superior and synergist activity to manage pain and inflammation. To reduce the gastric side effect, they could be combined with Famotidine. Methodology. A codrug of Indomethacin and Paracetamol was synthesized and combined in solution with Famotidine. The quantification of the pharmaceutically active ingredients is pivotal in the development of pharmaceutical formulations. Therefore, a novel reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated according to the International Council for Harmonization (ICH) Q2R1 guidelines. A reverse phase C18 column with a mobile phase acetonitrile: sodium acetate buffer 60 : 40 at a flow rate of 1.4 mL/min and pH 5 was utilized. Results. The developed method showed good separation of the four tested drugs with a linear range of 0.01–0.1 mg/mL (R² > 0.99). The LODs for FAM, PAR, IND, and codrug were 3.076 × 10⁻⁹, 3.868 × 10⁻¹⁰, 1.066 × 10⁻⁹, and 4.402 × 10⁻⁹ mg/mL respectively. While the LOQs were 9.322 × 10⁻⁹, 1.172 × 10⁻¹⁰, 3.232 × 10⁻⁹, and 1.334 × 10⁻⁸ mg/mL, respectively. Furthermore, the method was precise, accurate, selective, and robust with values of relative standard deviation (RSD) less than 2%. Moreover, the developed method was applied to study the in vitro hydrolysis and conversion of codrug into Indomethacin and Paracetamol. Conclusion. The codrug of Indomethacin and Paracetamol was successfully synthesized for the first time. Moreover, the developed analytical method, to our knowledge, is the first of its kind to simultaneously quantify four solutions containing the following active ingredients of codrug, Indomethacin, Paracetamol, and Famotidine mixture with added pharmaceutical inactive ingredients in one HPLC run.

中文翻译：

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与吲哚美辛、扑热息痛和法莫替丁组合的合成复合药物的 RP-HPLC 方法开发和验证。


背景。吲哚美辛被认为是一种有效的非甾体抗炎药，可以与扑热息痛联合使用，具有卓越的协同活性来控制疼痛和炎症。为减少胃副作用，可与法莫替丁合用。方法论。合成了吲哚美辛和扑热息痛的复合药物，并与法莫替丁在溶液中混合。药物活性成分的定量对于药物制剂的开发至关重要。因此，根据国际协调委员会 (ICH) Q2R1 指南，开发并验证了一种新型反相高效液相色谱 (RP-HPLC) 方法。使用具有流动相乙腈:乙酸钠缓冲液60:40、流速1.4mL/min和pH 5的反相C18柱。结果。所开发的方法显示四种测试药物的分离良好，线性范围为 0.01–0.1 mg/mL ( R ² > 0.99)。 FAM、PAR、IND 和共药的 LOD 分别为 3.076 × 10 ^-9 、3.868 × 10 ^-10 、1.066 × 10 ^-9和 4.402 × 10 ^-9 mg/mL。 LOQ 分别为 9.322 × 10 ^-9 、1.172 × 10 ^-10 、3.232 × 10 ^-9和 1.334 × 10 ^-8 mg/mL。此外，该方法精密、准确、选择性强、稳健，相对标准偏差 (RSD) 值小于 2%。此外，所开发的方法还用于研究复合药物体外水解和转化为吲哚美辛和扑热息痛。结论。 首次成功合成吲哚美辛和扑热息痛的复药。此外，据我们所知，所开发的分析方法是同类中第一个在一次 HPLC 运行中同时定量含有以下共药活性成分、吲哚美辛、扑热息痛和法莫替丁混合物以及添加的药物非活性成分的四种溶液的方法。