Laboratory of Analytical Chemistry, CIRM, Department of Pharmacy, University of Liège, Avenue de l'Hôpital 1, B36, B-4000 Liège, Belgium.
J Chromatogr A. 2011 Aug 5;1218(31):5205-15. doi: 10.1016/j.chroma.2011.05.102. Epub 2011 Jun 12.
An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE-ICA-DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE-ICA-DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE-ICA-DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the determination of three antimalarial compounds in a pharmaceutical formulation was optimized to demonstrate both the efficiency and flexibility of the methodology proposed in the present study.
基于实验设计（DoE）、独立成分分析（ICA）和设计空间（DS）的创新方法学已在之前的工作中开发出来，并已通过 19 种抗疟药物混合物进行了测试。这种全局 LC 方法开发方法（即 DoE-ICA-DS）用于优化 19 种抗疟药物的分离，以获得筛选方法。DoE-ICA-DS 方法完全符合当前质量源于设计的趋势。DoE 用于定义实验集，以模拟每个峰的起始、顶点和结束时的保留时间。此外，ICA 用于数值分离共洗脱峰并估计其无偏保留时间。梯度时间、温度和 pH 被选为完全析因设计的因素。这些保留时间通过逐步多元线性回归进行建模。最近引入的关键质量属性，即分离标准（S），也被用于评估分离质量，而不是使用分辨率。此外，还从色谱角度研究了所得数学模型，以了解和研究每个化合物的色谱行为。发现数学模型与预期的色谱理论预测的色谱行为之间具有良好的适应性。最后，聚焦于质量管理风险管理，通过蒙特卡罗模拟，从模型化响应到质量标准传播预测误差来计算 DS。DoE-ICA-DS 允许遇到最佳操作条件，以在打击假药的框架内获得 19 种考虑的抗疟药物的稳健筛选方法。此外，并且仅基于相同的数据集，优化了用于确定药物制剂中三种抗疟化合物的专用方法，以证明本研究中提出的方法的效率和灵活性。
