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Abstract <p>Organic impurity tests are primarily employed for identification and accurate quantification, serving as critical indicators for assessing the quality of medicines and detecting potential substandard or adulterated products. In the given research work, we endorse a sensitive RP-HPLC technique for simultaneous impurities quantification of brimonidine tartrate and timolol maleate present in available drug product. A simultaneous chromatographic separation was performed on Waters X select CSH Phenyl Hexyl, 150&#xa0;mm × 4.6&#xa0;mm, 3.5&#xa0;µm column while using gradient flowing phase comprised of octane-1-sulfonic acid sodium salt buffer pH 3.0, methanol and acetonitrile. With the photodiode array, detection was set at 248&#xa0;nm for brimonidine tartrate, 295&#xa0;nm for timolol maleate and their related impurities. In this developed method, injection repeatability for organic impurity analysis was 3.0 % for brimonidine and 0.7 % for timolol, demonstrating reliable precision. A resolution greater than 3.0 was achieved between both the drugs and their related impurities. Linearity was established over 0.2–3.0&#xa0;μg/mL for brimonidine and 0.5–7.5&#xa0;μg/mL for timolol, with correlation coefficients of <i>r</i><sup>2</sup> = 0.9997. Resembling linearity was marked for their impurities. The LOD and LOQ for brimonidine with impurities were 0.07 and 0.20&#xa0;μg/mL, respectively. In case of timolol, timolol impurity B and impurity G, the LOD/LOQ values were 0.17/0.50, 0.19/0.50 and 0.09/0.27&#xa0;μg/mL, respectively. Precision (∆ ≤ 5 %) and accuracy (90–110 % recovery) demonstrated the suitability of the method for related substances analysis. The stability-indicating capability of the method was demonstrated through stress testing under hydrolytic, thermal, photolytic, acid–base, and oxidative conditions, with pronounced degradation observed under photolytic, basic, and oxidative stresses. Method suitability, efficiency, and environmental impact were assessed using established green-metric tools aligned with green analytical chemistry principles, including the Analytical Eco-Scale (AES), AGREE, and the Modified Green Analytical Procedure Index (MoGAPI). Complementary Red–Green–Blue (RGB) model tools—namely the Red Analytical Performance Index (RAPI) and the Blue Applicability Grade Index (BAGI)—were also applied to provide a comprehensive evaluation of method performance and applicability. Such stability-indicating methods are essential for impurity profiling, drug stability assessment, quality control, and regulatory submissions.</p> Graphical Abstract <p></p>

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Development and validation of RP-HPLC method for simultaneous determination of brimonidine and timolol with impurity profiling and forced degradation: application of green tools—AES, AGREE, MoGAPI, RAPI, and BAGI

  • 期刊论文

  • 发表日期：

    2026年2月19日

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  • Harmeet Kaur Kohli,
  • Satish K. Ghumare,
  • Vijay A. Bagul

摘要

Abstract

Organic impurity tests are primarily employed for identification and accurate quantification, serving as critical indicators for assessing the quality of medicines and detecting potential substandard or adulterated products. In the given research work, we endorse a sensitive RP-HPLC technique for simultaneous impurities quantification of brimonidine tartrate and timolol maleate present in available drug product. A simultaneous chromatographic separation was performed on Waters X select CSH Phenyl Hexyl, 150 mm × 4.6 mm, 3.5 µm column while using gradient flowing phase comprised of octane-1-sulfonic acid sodium salt buffer pH 3.0, methanol and acetonitrile. With the photodiode array, detection was set at 248 nm for brimonidine tartrate, 295 nm for timolol maleate and their related impurities. In this developed method, injection repeatability for organic impurity analysis was 3.0 % for brimonidine and 0.7 % for timolol, demonstrating reliable precision. A resolution greater than 3.0 was achieved between both the drugs and their related impurities. Linearity was established over 0.2–3.0 μg/mL for brimonidine and 0.5–7.5 μg/mL for timolol, with correlation coefficients of r2 = 0.9997. Resembling linearity was marked for their impurities. The LOD and LOQ for brimonidine with impurities were 0.07 and 0.20 μg/mL, respectively. In case of timolol, timolol impurity B and impurity G, the LOD/LOQ values were 0.17/0.50, 0.19/0.50 and 0.09/0.27 μg/mL, respectively. Precision (∆ ≤ 5 %) and accuracy (90–110 % recovery) demonstrated the suitability of the method for related substances analysis. The stability-indicating capability of the method was demonstrated through stress testing under hydrolytic, thermal, photolytic, acid–base, and oxidative conditions, with pronounced degradation observed under photolytic, basic, and oxidative stresses. Method suitability, efficiency, and environmental impact were assessed using established green-metric tools aligned with green analytical chemistry principles, including the Analytical Eco-Scale (AES), AGREE, and the Modified Green Analytical Procedure Index (MoGAPI). Complementary Red–Green–Blue (RGB) model tools—namely the Red Analytical Performance Index (RAPI) and the Blue Applicability Grade Index (BAGI)—were also applied to provide a comprehensive evaluation of method performance and applicability. Such stability-indicating methods are essential for impurity profiling, drug stability assessment, quality control, and regulatory submissions.

Graphical Abstract