柱切换-LC/MSn法快速推定注射用头孢美唑钠的杂质
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摘要
目的:对注射用头孢美唑钠中的杂质结构进行分析。方法:采用Phenomenex Gemini C_(18)(250 mm×4. 6 mm,5μm)色谱柱,以磷酸二氢铵溶液-甲醇-四氢呋喃-20%四丁基氢氧化铵(700∶280∶25∶6. 4,v/v,pH=4. 5)为流动相分离杂质;对注射用头孢美唑钠进行强制降解实验,归属杂质来源;采用柱切换-LC/MSn技术采集杂质的质谱数据,根据头孢菌素类抗生素的质谱裂解规律和降解反应机制,推定相关杂质的化学结构。结果:在制剂中共检出并推断了6种杂质的化学结构,包括3种降解杂质和3种工艺杂质,未检出聚合物类杂质。结论:采用柱切换-LC/MSn技术可快速推定注射用头孢美唑钠中相关杂质的化学结构,《中华人民共和国药典》(Ch P) 2015年版的注射用头孢美唑钠有关物质检测方法需要进一步优化和提高。
Objective: To characterize the impurity structures in cefmetazole sodium for injection. Methods:Impurities in cefmetazole sodium for injection were separated on a Phenomenex Gemini C_(18) column (250 mm ×4. 6 mm,5 μm),with ammonium dihydrogen phosphate-methanol-tetrahydrofuran-20% butyl ammonium hydroxide (700∶ 280∶ 25∶ 6. 4,v/v,pH 4. 5) as mobile phase (pH 4. 5). Stress tests were designed and performed on the cefmetazole sodium for injection to specify the impurities. By application of on-line column-switching LC/MSn method,the impurities were collected and their structures were characterized based on the mass fragmentation regularity and degradation mechanism of cephalosporin antibiotics. Results: A total of six impurities were detected and characterized in the product including three degradation products and three impurities derived from synthesis process,but no polymer impurities were detected. Conclusion: The structures of related impurities in cefmetazole sodium for injection can be rapidly identified by on-line column-switching LC/MSn method,and the related substance specification of cefmetazole sodium for injection in China Pharmacopeia (ChP) 2015 edition should be further optimized and improved.
Objective: To characterize the impurity structures in cefmetazole sodium for injection. Methods:Impurities in cefmetazole sodium for injection were separated on a Phenomenex Gemini C_(18) column (250 mm ×4. 6 mm,5 μm),with ammonium dihydrogen phosphate-methanol-tetrahydrofuran-20% butyl ammonium hydroxide (700∶ 280∶ 25∶ 6. 4,v/v,pH 4. 5) as mobile phase (pH 4. 5). Stress tests were designed and performed on the cefmetazole sodium for injection to specify the impurities. By application of on-line column-switching LC/MSn method,the impurities were collected and their structures were characterized based on the mass fragmentation regularity and degradation mechanism of cephalosporin antibiotics. Results: A total of six impurities were detected and characterized in the product including three degradation products and three impurities derived from synthesis process,but no polymer impurities were detected. Conclusion: The structures of related impurities in cefmetazole sodium for injection can be rapidly identified by on-line column-switching LC/MSn method,and the related substance specification of cefmetazole sodium for injection in China Pharmacopeia (ChP) 2015 edition should be further optimized and improved.
引文
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[23]LU L,LI J,JIN SH,et al.Combination of reversed phase liquid chromatography and zwitterion exchange-reversed phase-hydrophilic interaction mixed-mode liquid chromatography coupled with mass spectrometry for the analysis of antibiotics and their impurities[J].J Chin Pharm Sci,2014,23(2):106-117.
[24]Deshpande.Degradation ofβ-lactam antibiotics[J].Curr sci(Bangalore),2004,87(12):1684.
[25]TY AT.Comparative stability of cephalosporins in aqueous solution:kinetics and mechanisms of degradation[J].J Pharm Sci,1976,65(11):1563-1574.
[2]斯崇文,田庚善.头孢美唑临床应用的评价[J].中华内科杂志,1996,3(10):668-672.
[3]GRIFFITH DL,NOVAK E,GREENWALD CA,et al.Clinical experience with cefmetazole sodium in the United States:an overview[J].J Antimicro Chem,1989,23(Suppl D):S21.
[4]SHIMADA J,HAYASHI Y,NAKAMURA K.Cefmetazole:clinical evaluation of efficacy and safety in Japan[J].Drugs Exper Clin Res,1985,11(3):181-194.
[5]于雯,于晋建,李成建.头孢美唑所致不良反应近况文献概述[J].中国药物滥用防治杂志,2015,21(4):244-245.
[6]ICH.Q1A(R2),Stability testing of new drug substances and products,in:international conference on harmonization[R].Geneva:IFPMA,2012.
[7]EMA.Committee for medicinal products for human use(CHMP)/committee for medicinal products for veterinary use(CVMP).Guideline on setting specifications for related impurities in antibiaotics[R].Europe:EMA/CHMP/CVMP/QWP/199250/2009corr,2012.
[8]胡昌勤.化学药品杂质控制的现状与展望[J].中国科学:化学,2010,40(6):679-687.
[9]胡昌勤.化学药品杂质谱控制的现状与展望[J].中国新药杂志,2015,24(15):1727-1734.
[10]胡昌勤.药物杂质谱分析[M].北京:化学工业出版社,2015:9.
[11]国家药典委员会.中华人民共和国药典[S].2015年版.二部.北京:中国医药科技出版社,2015:281.
[12]美国药典委员会.美国药典[S].美国:美国药典委员会,2010:3007
[13]日本药典委员会.日本药典[S].XVII版.日本:日本药典委员会,2010:582.
[14]孔兴欣,沈文斌,王丽云,等.LC-MS/MS法研究头孢美唑钠中有关物质[J].中国药科大学学报,2012,43(2):170-176.
[15]刘云飞,周浩,于佳,等.UPLC/TOFMS用于头孢美唑钠系统适用性对照品的结构解析[J].化学工程师,2017,31(8):74-80.
[16]吴晓敏,王明娟,胡昌勤.采用HPLC法测定注射用头孢美唑钠中的有关物质[J].中国抗生素杂志,2011,36(12):921-925.
[17]邓晶晶,张春然,唐克慧,等.反相高效液相色谱法测定头孢美唑钠中的有关物质[J].中国新药杂志,2011,20(9):828-832.
[18]王莹莹,龚莉,王成港,等.头孢美唑钠的体外降解稳定性[J].中国新药杂志,2012,21(12):1410-1417.
[19]张春然,唐克慧.头孢美唑钠的质量与稳定性研究[J].国外医药抗生素分册,2005,26(1):5-8.
[20]NEEDHAM SR.Fast,efficient separations in drug discovery-LC-MS analysis using column switching and rapid gradients[J].Lc Gc North America,2002,18(11):1156-1157.
[21]ZANCHETTI G,FLORIS I,PICCINOTTI A,et al.Rapid and robust confirmation and quantification of 11-nor-9-tetrahydrocannabinol-9-carboxylic acid(THC-COOH)in urine by column switching LC-MS-MS analysis[J].J Mass Spectr,2012,47(1):124-130.
[22]BREINDAHL T,PETERSEN KK,ROUSING ML,et al.Quantification of fentanyl in human serum by column-switching liquid chromatography and tandem mass spectrometry[J].J Bioanal Biomed,2011,3(6):103-107.
[23]LU L,LI J,JIN SH,et al.Combination of reversed phase liquid chromatography and zwitterion exchange-reversed phase-hydrophilic interaction mixed-mode liquid chromatography coupled with mass spectrometry for the analysis of antibiotics and their impurities[J].J Chin Pharm Sci,2014,23(2):106-117.
[24]Deshpande.Degradation ofβ-lactam antibiotics[J].Curr sci(Bangalore),2004,87(12):1684.
[25]TY AT.Comparative stability of cephalosporins in aqueous solution:kinetics and mechanisms of degradation[J].J Pharm Sci,1976,65(11):1563-1574.