Development of RP UPLC-TOF/MS, stability indicating method for omeprazole and its related substances by applying two level factorial design; and identification and synthesis of non-pharmacopoeial impurities
Development of RP UPLC-TOF/MS, stability indicating method for omeprazole and its related substances by applying two level factorial design; and identification and synthesis of non-pharmacopoeial impurities
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DOI：
10.1016/j.jpba.2015.10.005
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发表时间：
2016-01-25
影响因子：
3.4
通讯作者：
Bhosale, P. N.
中科院分区：
文献类型：
--
作者：
Jadhav, Sushant Bhimrao;Kumar, C. Kiran;Bhosale, P. N.
通过实施实验设计（DoE），即二级全析因设计（2（3）+ 3个中心点= 11个实验），开发了一种新的UPLC-TOF/MS兼容的反相稳定性指示方法，用于测定药物剂型中的奥美拉唑（OMP）及其相关物质，以了解关键方法参数（CMP）及其与关键方法属性（CMA）的关系；以确保方法的稳健性。包括 OMP 相关化合物 F (13) 和 G (14) 转化产物在内的 11 种指定杂质，即杂质-I (1)、OMP 相关化合物-I (11) 和 OMP 4-氯类似物 (12)，通过单一方法在 Acquity BEHshield RP18 100 x 2.1 mm、1.7 p.m 色谱柱上实现分离，配有入口过滤器 (0.2 μm)，使用梯度洗脱和检测器波长305 nm 并根据 ICH 指南进行验证，结果准确、精确、可重复、稳健且特异。人们发现该药物在热、湿和酸性条件下会广泛降解，并在稳定性研究过程中形成未知的降解产物。使用相同的方法进行 LC-MS 分析，以鉴定稳定性研究过程中形成的最大未知杂质（非药典）的 m/z 和碎片，即杂质-I (1)、杂质-III (3)、杂质-V (5) 和杂质-VIII (9)。根据结果，提出了药物的降解途径，并详细讨论了已识别杂质（杂质-I (1)、杂质-III (3)、杂质-V (5) 和杂质-VIII (9)）的合成，以确保深入了解 OMP 及其相关杂质以及产品生命周期内的最佳性能。 2015 年由 Elsevier B.V. 出版
A new UPLC-TOF/MS compatible, reverse phase-stability indicating method was developed for determination of Omeprazole (OMP) and its related substances in pharmaceutical dosage forms by implementing Design of Experiment (DoE) i.e. two level full factorial Design (2(3) + 3 center points = 11 experiments) to understand the Critical Method Parameters (CMP) and its relation with Critical Method Attribute (CMA); to ensure robustness of the method. The separation of eleven specified impurities including conversion product of OMP related compound F (13) and G (14) i.e. Impurity-I (1), OMP related compound-I (11) and OMP 4-chloro analog (12) was achieved in a single method on Acquity BEH shield RP18 100 x 2.1 mm, 1.7 p.m column, with inlet filter (0.2 mu m) using gradient elution and detector wavelength at 305 nm and validated in accordance with ICH guidelines and found to be accurate, precise, reproducible, robust and specific. The drug was found to degrade extensively in heat, humidity and acidic conditions and forms unknown degradation products during stability studies. The same method was used for LC-MS analysis to identify m/z and fragmentation of maximum unknown impurities (Non-Pharmacopoeial) i.e. Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9) formed during stability studies. Based on the results, degradation pathway for the drug has been proposed and synthesis of identified impurities i.e. impurities (Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9)) are discussed in detail to ensure in-depth understanding of OMP and its related impurities and optimum performance during lifetime of the product. 2015 Published by Elsevier B.V.