Page 64 - 202007

ABSTRACT OBJECTIVE： To establish the method for simultaneous determination of four known related substances
（olmesartan，olmesartan ester dimer，olmesartan ester alkene，benzothiadiazine impurity，called impurity A，B，C，D for short）in
Olmesartan medoxomil hydrochlorothiazide tablets. METHODS：HPLC-principal component self-control with correction factor
were adopted. The determination was performed on YMC-Triart C8 column with mobile phase A consisted of acetonitrile- 0.015 mol/L
potassium dihydrogen phosphate solution（pH adjusted to 2.8 with phosphoric acid）（70 ∶ 30，V/V），mobile phase B consisted of
acetonitrile-0.015 mol/L potassium dihydrogen phosphate solution（pH adjusted to 2.8 with phosphoric acid）（15 ∶ 85，V/V）at the
flow rate of 0.8 mL/min（gradient elution）. The detection wavelength was set at 265 nm，and column temperature was 25 ℃. The
temperature of injector was 4 ℃；the injection volume was 10 μL. RESULTS：The correction factors of impurity A，B，C，D were
1.42，1.17，0.89，0.92，respectively. The linear range of olmesartan medoxomil，hydrochlorothiazide and impurity A，B，C，D
were 0.252 7-7.580 0，1.152 1-4.562 9，0.244 0-18.299 0，0.244 7-3.670 8，0.265 2-3.978 3 and 0.149 9-4.497 3 μg/mL（r≥
0.999 7），respectively. The limits of detection were 0.084 2，0.050 7，0.081 3，0.081 6，0.088 4，0.050 0 μg/mL，respectively.
The quantitative limits were 0.252 7，0.152 1，0.244 0，0.244 7，0.265 2 and 0.149 9 μ g/mL，respectively. The results of
intermediate precision，stability（24 h）and repeatability tests all met the relevant requirements. The average recovery rates were
104.00％-108.04％，102.00％-104.94％，100.99％-106.89％，92.00％-95.18％，102.00％-105.06％，103.90％-107.00％（n＝3），
respectively. The contents of impurity A，B and D in 3 batches of Olmesartan medoxomil hydrochlorothiazide tablets were
0.90％ -1.00％ ，0-0.11％ ，0.16％ -0.24％ ，respectively. The impurity C and other impurities were not detected. There is no
significant difference between the results measured by the established method and by the external standard method.
CONCLUSIONS：The method has been proved to be highly sensitive and reproducible. It can be used to simultaneously determine
four known substances in Olmesartan medoxomil hydrochlorothiazide tablets.
KEYWORDS Olmesartan medoxomil hydrochlorothiazide tablets；Related substances；HPLC；Principal component self-control
with correct factor

奥美沙坦酯氢氯噻嗪片作为治疗高血压的二线药 及。加校正因子的主成分自身对照法，是以主成分作为
物，于 2010 年在我国获批上市 ，主要活性成分为奥美 对照的内标法，结合建立方法时测定的相对校正因子，
[1]
沙坦酯和氢氯噻嗪。奥美沙坦酯在胃肠道水解成活性 能够准确测定已知有关物质的含量，可弥补现有研究的
成分奥美沙坦后发挥降压的作用 [2-3] ；氢氯噻嗪通过增加 不足。因此，本研究拟建立HPLC-加校正因子的主成分
[4]
钠、钾、氯离子与水的排泄，从而减小血容量 ，增强奥美 自身对照法对奥美沙坦酯氢氯噻嗪片中4种已知有关物
沙坦酯的降压效果。在奥美沙坦酯氢氯噻嗪片的现行 质进行检测，提高该药品分析方法的灵敏度、可靠性，以
标准中（简称“标准”）明确提及，需对该制剂中4种已知 期能更为科学、有效地控制该复方制剂中的有关物质含
有关物质奥美沙坦（简称“杂质A”）、奥美沙坦酯二聚体 量，进一步加强该药品的质量控制。4 种已知有关物质
（简称“杂质 B”）、奥美沙坦酯烯（简称“杂质 C”）和苯并 的结构式详见图1。
[5]
噻二嗪杂质A（简称“杂质D”）进行控制 。其中，杂质A
是奥美沙坦酯合成过程中的中间体残留，也可因奥美沙
坦酯的酯键稳定性差而降解产生；杂质B与杂质C均为
奥美沙坦酯的潜在降解杂质；杂质D是氢氯噻嗪的合成
中间体，同时也是氢氯噻嗪不稳定的降解产物，其含量 杂质A 杂质B
高低会影响药品的稳定性和不良反应 [6-8] 。
现行标准是采用高效液相色谱（HPLC）法测定该药
[5]
中的有关物质，但该法灵敏度与分离度相对较差 。笔
者查阅相关文献后发现，目前关于该复方制剂临床疗效 杂质C 杂质D
的文献报道较多，但对其有关物质含量测定方法的文献 图1 4种已知有关物质的结构式
报道较少，且其测定方法仍存在不足。比如，赵建峰 虽 Fig 1 Structure diagrams of 4 known related sub-
[1]
然建立了该复方制剂的有关物质分析方法，但仅讨论了 stances
2 种有关物质，也并未对有关物质的定量方法进行方法 1 材料
学验证，且采用外标法定量，成本较高。又如，常慧等 [9] 1.1 仪器
虽采用超临界色谱与质谱联用法测定了该复方制剂中6 XS204DU 型万分之一电子天平、XS205DU 型十万
种有关物质的含量，但所需仪器设备要求较高，难以普 分之一电子天平、XP56 型百万分之一电子天平、FE-28

·826 · China Pharmacy 2020 Vol. 31 No. 7 中国药房 2020年第31卷第7期