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盐酸地巴唑原料药和片剂中有关物质的测定及最大未知杂质结构的推测
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| 篇名： | 盐酸地巴唑原料药和片剂中有关物质的测定及最大未知杂质结构的推测 |
| TITLE： | Determination of Related Substances in Dibasol Hydrochloride Raw Materials and Tablets and Structure Predic- tion of Maximum Unknown Impurity |
| 摘要： | 目的：建立测定盐酸地巴唑原料药及片剂中有关物质的方法，并对其最大未知杂质的结构进行推测。方法：采用高效液相色谱法测定盐酸地巴唑原料药及片剂中的有关物质（邻苯二胺、苯乙酸），色谱柱为KromasilC18，流动相为水-甲醇-冰醋酸-三乙胺（45∶55∶0.5∶0.5，V/V/V/V），流速为1.0mL/min，检测波长为220nm，柱温为30℃，进样量为10μL。采用超高效液相色谱-飞行时间质谱法、氢谱、碳谱推测最大未知杂质的结构，色谱柱为WatersAcquityUPLCBEHC18，流动相为水-甲醇（45∶55，V/V），流速为0.2mL/min，柱温为30℃，进样量为1μL，离子源为电喷雾离子源（ESI），扫描模式为负离子扫描模式，一级质谱扫描范围为m/z100～800，毛细管电压为3000V，离子源温度为100℃，去溶剂气体为氮气，去溶剂气体流速为600L/h，锥孔流速为50L/h。结果：邻苯二胺、苯乙酸、盐酸地巴唑检测质量浓度的线性范围为0.427～4.27μg/mL（r＝0.9989）、0.403～4.03μg/mL（r＝0.9989）、0.82～8.20μg/mL（r＝0.9999）；定量限分别为0.0427、0.1343、0.0887μg/mL，检测限分别为0.0214、0.0671、0.0443μg/mL；精密度、稳定性、重复性、耐用性试验的RSD均小于2％；邻苯二胺的加样回收率为98.31％～102.81％（RSD＝1.60％，n＝9）、苯乙酸为99.78％～102.23％（RSD＝0.70％，n＝9）。6批盐酸地巴唑原料药中均未检出邻苯二胺，苯乙酸含量为0～0.04％，最大未知杂质含量为0.05％～0.25％，未知杂质总量为0.05％～0.31％；77批盐酸地巴唑片剂中，邻苯二胺含量为0～0.11％，苯乙酸含量为0～0.03％，最大未知杂质含量为0.06％～0.51％，未知杂质总量为0.10％～0.62％。推测最大未知杂质为2-（羟苯基甲基）苯并咪唑（羟苄唑）。结论：所建方法快速、准确、专属性好，可用于测定盐酸地巴唑原料药及片剂中的有关物质。最大未知杂质可能为苯并咪唑类化合物。 |
| ABSTRACT： | OBJECTIVE：To establish a method for the determination of related substances in dibasol hydrochloride raw materials and tablets ， and to predict the maximum unknown impurity ’s structure. METHODS ： The related substances （o-phenylenediamine，phenylacetic acid ）in dibasol hydrochloride raw materials and tablets were determined by HPLC. The determination was performed on Kromasil C 18 column with mobile phase consisted of mobile phase-methanol-glacial acetic acid-triethylamine（45 ∶ 55 ∶ 0.5 ∶ 0.5，V/V/V/V）at the flow rate of 1.0 mL/min. The detection wavelength was set at 220 nm，and column temperature was 30 ℃. Sample size was 10 μL. UPLC-TOF-MS，1H-NMR and 13C-NMR were used for structure prediction. The determination was performed on Waters Acquity UPLC BEH C 18 column with mobile phase consisted of water-methanol （45∶55， V/V）at the flow rate of 0.2 mL/min. The column temperature was 30 ℃，and sample size was 1 μL. The ion source was electrospray ion source . The scanning mode was negative ion scanning mode. The first-order mass spectrum scanning range was m/z 100-800，the capillary voltage was 3 000 V，the source temperature was 100 ℃，the desolvent gas was nitrogen ，and the solvent free gas flow rate was 600 L/h. The flow rate of the conical orifice was 50 L/h. RESULTS： The linear range of o-phenylenediamine，phenylacetic acid and dibasol hydrochlo- ride were 0.427-4.27 μg/mL（r＝0.998 9），0.403-4.03 μg/mL（r＝ 0.998 9）and 0.82-8.20 μg/mL（r＝0.999 9），respec-tively. The limits of quantitation were 0.042 7，0.134 3，0.088 7 μg/mL. The limits of detection were 0.021 4，0.067 1，0.044 3 μ g/mL. RSDs of precision ，stability，reproducibility and durability tests were all less than 2％. The average recoveries were 98.31％- 99.78％-102.23％ for phenylacetic acid （RSD＝0.70％，n＝9）. No o-phenylenediamine was detected in 6 batches of dibazol hydrochloride raw materials ；the contents of phenylacetic acid · were 0-0.04％ ；the contents of maximum unknown impurity were 0.05％ -0.25％ ；total contents of unknown impurity were 0.05％-0.31％. In 77 batches of Dibasol hydrochloride tablets ，the contents of o-phenylenediamine were 0-0.11％，the contents of phenylacetic acid were 0-0.03％；the contents of maximum unknown impurity were 0.06％-0.51％；total contents of unknown impurity were 0.10％-0.62％. It was speculated that maximum unknown impurity was 2-（hydroxyphenylmethyl）benzimidazole （hydrobenzde）. CONCLUSIONS ：Established method is rapid ，accurate and specific ，and can be used for the determination of related substances in dibasol hydrochloride raw materials and tablets. The maximum unknown impurity may be benzimidazoles. |
| 期刊： | 2020年第31卷第06期 |
| 作者： | 陈宇堃，梁蔚阳 |
| AUTHORS： | CHEN Yukun ，LIANG Weiyang |
| 关键字： | 盐酸地巴唑原料药；盐酸地巴唑片剂；高效液相色谱法；有关物质；超高效液相色谱-飞行时间质谱法；杂质；结构鉴定 |
| KEYWORDS： | Dibasol hydrochloride raw materials ；Dibasol hydrochloride tablets ；HPLC；Related substance ；UPLC-TOF-MS； |
| 阅读数： | 281 次 |
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