基于质量源于设计的多产品药物分析的 UHPLC 方法。
UHPLC method for multiproduct pharmaceutical analysis by Quality-by-Design.
机构信息
ChemBioPharm Team, ARNA Laboratory, INSERM U1212, CNRS UMR 5320, Bordeaux University, France.
ChemBioPharm Team, ARNA Laboratory, INSERM U1212, CNRS UMR 5320, Bordeaux University, France.
出版信息
J Pharm Biomed Anal. 2018 Jan 30;148:361-368. doi: 10.1016/j.jpba.2017.10.014. Epub 2017 Oct 16.
An innovative Analytical Quality-by-Design (AQbD) methodology was followed to develop a specific and robust UHPLC method for the simultaneous separation of 16 active pharmaceutical ingredients (APIs). In the context of pharmaceutical repositioning, these molecules have been selected as good candidates for buccal per mucous (BPM) administration route. Given the structural and physico-chemical diversity of compounds, an innovative development strategy based on QbD was applied. The main advantage of QbD is to ensure the robustness of the method. During a first scouting phase, the C18 chromatographic column was selected. Throughout the study, acetonitrile and ethanol based-mobile phases were investigated and compared. Ethanol was chosen as an alternative to acetonitrile due to its green properties coming from its lower toxicity and sourcing from renewable sources. Screening designs were performed to identify critical process parameters (CPPs). In ethanol media, temperature turned out to be a critical factor on peak retention and separation. Response surface methodology was then carried out to optimize CPPs and define the experimental domain of the method where complete separation between all peaks was obtained. Because changes in the elution order of the compounds occurred when modifying the experimental conditions, time differences between peaks were chosen as critical quality attributes, and an original data treatment was developed. It consisted in a systematic modelling of the time intervals between all possible pairs of peaks over the whole 3D experimental domain. Finally, a desirability analysis based on the smallest predicted time interval between peaks enabled to find optimal conditions only with ethanol based-mobile phases. Optimal conditions using ethanol, a Xbridge BEH Shield RP18 column and a 500 mL starting isocratic step, were determined by maximizing the desirability value and corresponded to a gradient slope of 2.57 %/min, a pH of 4.85, and a temperature of 33.7°C. A baseline separation of the 16 APIs was achieved with resolutions superior to 2.4 and the robustness of the method was experimentally validated.
采用创新的分析质量源于设计（AQbD）方法，开发了一种同时分离 16 种活性药物成分（APIs）的特定、稳健的 UHPLC 方法。在药物再定位的背景下，这些分子被选为颊黏膜给药（BPM）途径的良好候选药物。鉴于化合物的结构和物理化学多样性，采用了基于 QbD 的创新开发策略。QbD 的主要优势在于确保方法的稳健性。在初步探索阶段，选择了 C18 色谱柱。在整个研究过程中，研究了并比较了基于乙腈和乙醇的流动相。由于乙醇具有较低的毒性和源自可再生资源的绿色特性，因此选择乙醇替代乙腈。进行了筛选设计以确定关键工艺参数（CPPs）。在乙醇介质中，温度成为影响峰保留和分离的关键因素。然后进行响应面法优化 CPPs 并定义方法的实验域，在该实验域中可以获得所有峰的完全分离。由于改变实验条件会导致化合物的洗脱顺序发生变化，因此选择峰之间的时间差异作为关键质量属性，并开发了一种原始的数据处理方法。该方法包括在整个 3D 实验域中对所有可能的峰对之间的时间间隔进行系统建模。最后，基于峰之间最小预测时间间隔的可接受性分析，仅使用基于乙醇的流动相即可找到最佳条件。使用乙醇、Xbridge BEH Shield RP18 柱和 500mL 起始等度步骤，通过最大化可接受性值确定最佳条件，对应于 2.57%/min 的梯度斜率、pH 值为 4.85 和 33.7°C 的温度。实现了 16 种 API 的基线分离，分辨率高于 2.4，并且方法的稳健性通过实验验证。
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