Abstract
Quality by Design (QbD) is a systematic approach that takes predefined objectives and emphasizes process understanding and control. Analytical QbD (AQbD) is widely used when it comes to the development and optimization of analytical methods. Since impurities and contaminants may be present in the pharmaceutical product, current regulatory guidelines recommend monitoring these substances. Thus, the aim of this work was to develop and validate a fast and sensitive stability indicating method by high-performance liquid chromatography (HPLC) for the simultaneous determination of apixaban and three synthesis impurities using AQbD approach. Experiments were designed and assessed on MODDE® 11 (Umetrics, Sweden) software and carried out in a Shimadzu® LC-20A Prominence HPLC–DAD at 220 nm. Design of experiments was applied to achieve the optimum conditions through response surface methodology with four quantitative critical method parameters (CMPs): column temperature, flow rate, mobile phase pH and organic percentage. Besides, the chromatographic column was the fifth CMP taken as a qualitative variable. The HPLC method was established using an Inertsil® CN-3 column at the temperature of 30 °C. The mobile phase consisted of methanol and water (50.2:49.8) at a flow rate of 1.015 mL/min with no pH adjustment. In order to confirm method selectivity excipients mixture was evaluated, as well as hydrolytic, photolytic, thermolytic, and oxidative conditions. The method was also validated for sensitivity (LOQ 0.5 μg/mL, LOD 0.01–0.05 μg/mL for impurities), linearity (concentration range 1–35 μg/mL for APX and 0.5–10 μg/mL for impurities, r > 0.999), precision (RSD ≤ 10%) and accuracy between levels (RSD < 3.0 for APX and < 4.0% for impurities). The application of AQbD led to a well-understood and validated analytical method that provided assured separation of APX and all significant impurities, turning it into a powerful decision-making tool for the analytical methodologies development.
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