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

作　　者：李丹凤 颜其双 邓鸣 朱健萍 

机构地区：[1]广西壮族自治区食品药品检验所,南宁530021

出　　处：《药物分析杂志》2017年第3期451-460,共10页Chinese Journal of Pharmaceutical Analysis

摘　　要：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C_(18)(4.6 mm×250 mm,5μm),流动相A为0.005 mol·L^(-1)四丁基氢氧化铵溶液(用磷酸调节p H至4.5),流动相B为乙腈,梯度洗脱,流速1.0mL·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C_(18)(2.1 mm×100 mm,2.7μm),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�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 C_（18）（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 p H of 4.5）and the mobile phase B of acetonitrile by gradient elution programme,and with a flow rate of 1.0mL·min（-1）,at the detection wavelength of 232 nm;An HPLC-TOF/MS system（C_（18）,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 methanol-acetonitrile（50∶50）at a flow rate of 0.2mL·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-（met

关 键 词：盐酸头孢他美酯 头孢菌素 分散片 有关物质 飞行时间质谱 杂质裂解途径 结构鉴定 

分 类 号：R917[医药卫生—药物分析学]