改进用于测定阿托伐他汀钙盐药物对映体纯度的现行欧洲药典对映体选择性高效液相色谱法

Francesca Romana Mammone, Daniele Sadutto, Giulia D’Ettorre, A. Mosca, R. Cirilli
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摘要

阿托伐他汀(ATV)是一种成熟的降血脂药物。ATV 有两个立体中心,在四种可能的立体异构体中,只有 (3R,5R) 形式可用于治疗。欧洲药典》(EP)第 2022 号专著中的 ATV 钙盐描述了一种基于 150 毫米 × 4.6 毫米 Chiralpak AD-H 色谱柱的正相高效液相色谱法(HPLC),用于测定药物和工作标准样品中对映体的纯度。这种方法的主要问题是分析时间长、溶剂消耗量大。在此,我们开发了一种替代色谱方案,使用 Chiralpak AD-3 色谱柱(250 mm × 4.6 mm),以 3 μm 硅胶颗粒代替 Chiralpak AD-H 手性固定相的 5 μm 硅胶颗粒,并使用相同的多糖选择剂--直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)。以正己烷-乙醇-甲酸 90:10:0.1 (v/v/v) 混合液为流动相,流速和柱温分别设定为 1.0 mL min-1 和 35 °C,在 35 分钟内同时实现了立体选择性分离,未观察到对映体杂质峰与其他 ATV 杂质峰之间有任何重叠。与 HPLC EP 条件相比,洗脱所有潜在相关物质的分析时间更短,所需的流动相体积也大大减少。该方法的线性范围为 4.4 μg mL-1 至 1000 μg mL-1(R2 > 0.999)。当浓度为 4.4 μg mL-1 时,即测试溶液(5.8 mg mL-1,以 ATV 游离酸计)的 0.075%,信噪比为 20。
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Improving the Current European Pharmacopoeia Enantio-Selective HPLC Method for the Determination of Enantiomeric Purity in Atorvastatin Calcium Salt Drug Substance
Atorvastatin (ATV) is a well-established lipid-lowering agent. ATV has two stereogenic centers, and of the four possible stereoisomers, only the (3R,5R) form is used therapeutically. The European Pharmacopoeia (EP) monograph 2022 for ATV calcium salt describes a normal-phase high-performance liquid chromatography (HPLC) method for the determination of enantiomeric purity in both drug substance and working standard samples, based on a 150 mm × 4.6 mm Chiralpak AD-H column. The main problems with this method are the very long analysis time and the high solvent consumption. Here, an alternative chromatographic protocol was developed using the Chiralpak AD-3 column (250 mm × 4.6 mm) packed with 3 μm silica particles instead of the 5 μm silica particles of the Chiralpak AD-H chiral stationary phase and characterized by the same polysaccharide selector, amylose-tris(3,5-dimethylphenylcarbamate). Using a mobile phase consisting of a mixture of n-hexane-ethanol-formic acid 90:10:0.1 (v/v/v) as the mobile phase and setting the flow rate and column temperature to 1.0 mL min−1 and 35 °C, respectively, a simultaneous stereo-selective separation was achieved within 35 min without observing any overlap between the enantiomeric impurity peak and peaks related to other ATV impurities. Compared to HPLC EP conditions, the analysis time to elute all the potentially related substances was faster and significantly less mobile phase volume was required. The linearity of the method has been demonstrated in the range of 4.4 μg mL−1 to 1000 μg mL−1 (R2 > 0.999). At a concentration of 4.4 μg mL−1, which is 0.075% of the test solution (5.8 mg mL−1, as ATV free acid), the signal-to-noise ratio was found to be 20.
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