Drug Substance Analytical Development Division, Egis Pharmaceuticals Plc., Keresztúri út 30-38, H-1106 Budapest, Hungary.
Waters Corporation, CMU-Rue Michel Servet 1, 1211 Geneva 4, Switzerland.
Molecules. 2021 Jun 8;26(12):3505. doi: 10.3390/molecules26123505.
In-process control (IPC) is an important task during chemical syntheses in pharmaceutical industry. Despite the fact that each chemical reaction is unique, the most common analytical technique used for IPC analysis is high performance liquid chromatography (HPLC). Today, the so-called "Quality by Design" (QbD) principle is often being applied rather than "Trial and Error" approach for HPLC method development. The QbD approach requires only for a very few experimental measurements to find the appropriate stationary phase and optimal chromatographic conditions such as the composition of mobile phase, gradient steepness or time (tG), temperature (), and mobile phase pH. In this study, the applicability of a multifactorial liquid chromatographic optimization software was studied in an extended knowledge space. Using state-of-the-art ultra-high performance liquid chromatography (UHPLC), the analysis time can significantly be shortened. By using UHPLC, it is possible to analyse the composition of the reaction mixture within few minutes. In this work, a mixture of route of synthesis of apixaban was analysed on short narrow bore column (50 × 2.1 mm, packed with sub-2 µm particles) resulting in short analysis time. The aim of the study was to cover a relatively narrow range of method parameters (tG, , pH) in order to find a robust working point (zone). The results of the virtual (modeled) robustness testing were systematically compared to experimental measurements and Design of Experiments (DoE) based predictions.
过程控制（IPC）是制药行业化学合成中的一项重要任务。尽管每个化学反应都是独特的，但用于 IPC 分析的最常见分析技术是高效液相色谱（HPLC）。如今，通常应用所谓的“质量源于设计”（QbD）原则，而不是“试错”方法来开发 HPLC 方法。QbD 方法仅需要进行很少的实验测量即可找到合适的固定相和最佳色谱条件，例如流动相的组成、梯度陡度或时间（tG）、温度（）和流动相 pH。在这项研究中，在扩展的知识空间中研究了多因素液相色谱优化软件的适用性。使用最先进的超高效液相色谱（UHPLC），可以显著缩短分析时间。通过使用 UHPLC，可以在几分钟内分析反应混合物的组成。在这项工作中，分析了 apixaban 合成途径的混合物在短窄孔柱（50×2.1mm，填充亚 2µm 颗粒）上的情况，从而缩短了分析时间。该研究的目的是覆盖相对较窄的方法参数范围（tG、、pH），以找到稳健的工作点（区域）。虚拟（建模）稳健性测试的结果与实验测量和基于实验设计（DoE）的预测进行了系统比较。
