期刊名称:药物分析杂志 主管单位:中国科学技术协会 主办单位:中国药学会承办:中国食品药品检定研究院 主编:金少鸿 地址:北京天坛西里2号 邮政编码:100050 电话:010-67012819,67058427 电子邮箱:ywfx@nifdc.org.cn 国际标准刊号:ISSN 0254-1793 国内统一刊号:CN 11-2224/R 邮发代号:2-237
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盐酸头孢他美酯分散片有关物质的色谱-质谱结构鉴定
Separation and identification of related substances in cefetamet pivoxil hydrochloride dispersible tablets by LC-MS method
分类号:R917
出版年·卷·期(页码):2017,37 (3):451-460
DOI:
10.16155/j.0254-1793.2017.01.01
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目的:采用液相色谱-飞行时间质谱法对盐酸头孢他美酯分散片中有关物质进行结构鉴定。方法:采用HPLC 梯度洗脱方法对有关物质进行测定,色谱柱为C18(4.6 mm×250 mm,5 μm),流动相A 为0.005 mol·L-1 四丁基氢氧化铵溶液(用磷酸调节pH 至4.5),流动相B 为乙腈,梯度洗脱,流速1.0 mL·min-1,检测波长为232 nm;采用液相色谱-飞行时间质谱技术对未知杂质进行鉴定,色谱柱为C18(2.1 mm×100mm,2.7 μm),流动相A 为10 mmol·L-1 醋酸铵溶液,流动相B 为甲醇-乙腈(50:50),梯度洗脱,流速0.2mL·min-1,采用正离子扫描(ESI+)方式,在m/z 100~1 200 范围内进行质谱扫描。结果:头孢他美酯与其有关物质能较好地分离,检测出10 个有关物质,Ⅰ:(6R,7R)-3-苯乙烯基-7-[(Z)-2-(2-特戊酰氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-甲酸新戊酰氧甲酯;Ⅱ:(6R,7R)-3-甲基-7-[(Z)-2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-羧酸;Ⅲ:(6R,7R)-3-甲基-7-[(Z)-2-(2-特戊酰氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-羧酸;Ⅳ:(6R,7R)-3-甲基-7-[(Z)-2-(2-羟甲基氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-甲酸新戊酰氧甲酯;Ⅴ:(6R,7S)-3-甲基-7-[(Z)-2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-甲酸新戊酰氧甲酯;Ⅵ:(6R,7R)-3-甲基-7-[(Z)-2-[2-(2-甲氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-甲酸新戊酰氧甲酯;Ⅶ:(6R,7R)-3-甲基-7-[(Z)-2-[2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-甲酸新戊酰氧甲酯;Ⅷ:(6R,7R)-3-甲基-7-[(Z)-2-(2-特戊酰氨基-4-噻唑基)-2-(甲氧亚氨基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-稀-2-甲酸新戊酰氧甲酯;Ⅸ、Ⅹ:((6S,7S)-3-甲基-7-((Z)-2-(甲氧基亚氨基)-2-(2-((((4-((Z)-1-(甲氧基亚氨基)-2–(6R,7R)-3-甲基-8-氧代-2-(((新戊酰氧基)甲氧基)羰基)-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-7-基)氨基)-2-氧代乙基)-2-噻唑基)氨基)甲基)氨基)-4-噻唑基)乙酰氨基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸,它们都具有头孢菌素的基本母核7-氨基去乙酰氧基头孢烷酸(7-ADCA),其中有关物质Ⅰ、Ⅲ、Ⅵ尚未见文献报道。结论:色谱-质谱联用技术能有效地鉴定盐酸头孢他美酯分散片中有关物质,为其生产工艺和质量控制提供参考依据。
-----英文摘要:---------------------------------------------------------------------------------------
Objective: Separation and identification of the related substances in cefetamet pivoxil hydrochloride by high performance liquid chromatography coupled with time-of-flight mass spectrometry(HPLC-TOF/MS). Methods: To establish an HPLC-gradient elution method for the determination of related substances in cefetamet pivoxil hydrochloride dispersible tablets,use a C18(4.6 mm×250 mm,5 μm)column,with the mobile phase A of 0.005 mol·L-1 tetrabutyl ammonium hydroxide solution(adjusted with phosphoric acid to a pH of 4.5)and the mobile phase B of acetonitrile by gradient elution programme,and with a flow rate of 1.0 mL·min-1,at the detection wavelength of 232 nm;An HPLC-TOF/MS system(C18,2.1 mm×100 mm,2.7 μm)was performed by gradient elution programme with the mobile phase A of 10 mmol·L-1 ammonium acetate and the mobile phase B of methanolacetonitrile(50:50)at a flow rate of 0.2 mL·min-1. The analysis was run with electric spray interface under the positive ion mode within the mass range of m/z 100-1 200. Results: Each pair of adjacent peaks due to cefetamet pivoxil and individual impurities can be well separated by using established HPLC-gradient elution method. Ten related substances of cefetamet pivoxil hydrochloride containing with cephalosporin mother nucleus(7-ADCA)were detected,three of them had been reported previously. Ⅰ:(pivaloyloxy)methyl(6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-3-methyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; Ⅱ:(6R,7R)-7-((Z)-2-(methoxyimino)-2-(2-pivalamidothiazol-4-yl)acetamido)-8-oxo-3-((Z)-styryl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;Ⅲ:(6R,7R)-7-((Z)-2-(methoxyimino)-2-(2-pivalamidothiazol-4-yl)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;Ⅳ:(6R,7R)-7-((Z)-2-(2-((hydroxymethyl)amino) thiazol-4-yl)-2-(methoxyimino)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;Ⅴ:(6R,7S)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;Ⅵ:(6R,7R)-7-((Z)-2-(methoxyimino)-2-(2-((Z)-2-(methoxyimino)-2-(2-(methylamino)thiazol-4-yl)acetamido)thiazol-4-yl)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;Ⅶ:(6R,7R)-7-((Z)-2-(2-((E)-2-(2-aminothiazol-5-yl)-2-(methoxyimino)acetamido)thiazol-4-yl)-2-(methoxyimino) acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; Ⅷ:(6R,7R)-7-((Z)-2-(methoxyimino)-2-(2-pivalamidothiazol-4-yl)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylate; Ⅸ and Ⅹ:(6S,7S)-7-((Z)-2-(methoxyimino)-2-(2-((((4-((Z)-1-(methoxyimino)-2-(((6R,7R)-3-methyl-8-oxo-2-(((pivaloyloxy)methoxy)carbonyl)-5-thia-1-azabicyclo [4.2.0]oct-2-en-7-yl)amino)-2-oxoethyl)thiazol-2-yl)amino)methyl)amino)thiazol-4-yl)acetamido) -3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;Conclusion: The hyphenated LC-MS method is useful for the identification of related substances in cefetamet pivoxil hydrochloride dispersible tablets. The results obtained are referential experiences for the optimization of manufacturing process and quality control.
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