柱前衍生化HPLC法测定4-氯-3-(三氟甲基)苯异氰酸酯中CTF-苯胺和CTF-脲
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摘要
目的:建立柱前衍生化HPLC法测定抗癌药物原料4-氯-3-(三氟甲基)苯异氰酸酯中的杂质CTF-苯胺[4-氯-3-(三氟甲基)苯胺]和CTF-脲{1,3-双[4-氯-3-(三氟甲基)苯基]脲}。方法:采用Symmetry C18色谱柱(4.6 mm×150 mm,3.5μm),以0.01 mol·L~(-1)磷酸二氢钾溶液(用2 mol·L~(-1)氢氧化钾溶液调p H至6.5)(A)-乙腈(B)为流动相,梯度洗脱(0~10 min,60%A→40%A;10~20 min,40%A→30%A;20~30 min,30%A→25%A),流速1.0 m L·min~(-1),检测波长260 nm,柱温35℃。结果:CTF-苯胺、CTF-脲质量浓度分别在1.87~46.80和4.15~103.76μg·m L~(-1)范围内呈良好的线性关系,线性关系系数r值均大于0.999 6;平均回收率(n=9)分别为98.7%、98.0%,RSD分别为1.43%、2.36%;定量限分别为0.187μg·m L~(-1)(相当于0.04%)、0.208μg·m L~(-1)(相当于0.04%)。试验测得3批4-氯-3-(三氟甲基)苯异氰酸酯中含CTF-苯胺0.21%、0.22%、0.25%,含CTF-脲1.68%、1.81%、1.24%。结论:经方法学验证,该方法适用于4-氯-3-(三氟甲基)苯异氰酸酯中CTF-苯胺和CTF-脲的测定。
Objective: To establish an HPLC method after pre-column derivatization for the determination of CTF-aminobenzene [4-chloro-3-(trifluoromethyl)-benzenamine] and CTF-urea {1,3-bis(4-chloro-3-(trifluoromethyl)phenyl)urea} in a raw material of anti-cancer drug 4-chloro-3-(trifluoromethyl)phenyl isocyanate.Methods: A Symmetry C18 column(4.6 mm×150 mm,3.5 μm) was adopted.The mobile phase consisted of 0.01 mol·L-1 KH2PO4(adjusting p H to 6.5 with 2 mol·L-1 KOH)(A)-acetonitrile(B) with linear gradient elution(0-10 min,60%A → 40%A;10-20 min,40%A → 30%A;20-30 min,30%A → 25%A).The flow rate was 1.0 m L·min-1 and the detection wavelength was 260 nm.The column temperature was 35 ℃.Results: CTF-aminobenzene and CTF-urea exhibited good linearity in the ranges of 1.87-46.80 μg·m L-1 and 4.15-103.76 μg·m L-1(r>0.999 6) respectively; the average recoveries(n=9) were 98.7% and 98.0%, and RSDs were 1.43% and 2.36%; the limits of quantity were 0.187 μg·m L-1(equal to 0.04%) and 0.208 μg·m L-1(equal to 0.04%).The determination results of three batchs of samples were 0.21%, 0.22%, 0.25%(CTF-aminobenzene) and 1.68%, 1.81%, 1.24%(CTF-urea),respeclively.Conclusion: The established method is proved to be suitable for the determination of CTF-aminobenzene and CTF-urea in 4-chloro-3-(trifluoromethyl) phenyl isocyanate.
Objective: To establish an HPLC method after pre-column derivatization for the determination of CTF-aminobenzene [4-chloro-3-(trifluoromethyl)-benzenamine] and CTF-urea {1,3-bis(4-chloro-3-(trifluoromethyl)phenyl)urea} in a raw material of anti-cancer drug 4-chloro-3-(trifluoromethyl)phenyl isocyanate.Methods: A Symmetry C18 column(4.6 mm×150 mm,3.5 μm) was adopted.The mobile phase consisted of 0.01 mol·L-1 KH2PO4(adjusting p H to 6.5 with 2 mol·L-1 KOH)(A)-acetonitrile(B) with linear gradient elution(0-10 min,60%A → 40%A;10-20 min,40%A → 30%A;20-30 min,30%A → 25%A).The flow rate was 1.0 m L·min-1 and the detection wavelength was 260 nm.The column temperature was 35 ℃.Results: CTF-aminobenzene and CTF-urea exhibited good linearity in the ranges of 1.87-46.80 μg·m L-1 and 4.15-103.76 μg·m L-1(r>0.999 6) respectively; the average recoveries(n=9) were 98.7% and 98.0%, and RSDs were 1.43% and 2.36%; the limits of quantity were 0.187 μg·m L-1(equal to 0.04%) and 0.208 μg·m L-1(equal to 0.04%).The determination results of three batchs of samples were 0.21%, 0.22%, 0.25%(CTF-aminobenzene) and 1.68%, 1.81%, 1.24%(CTF-urea),respeclively.Conclusion: The established method is proved to be suitable for the determination of CTF-aminobenzene and CTF-urea in 4-chloro-3-(trifluoromethyl) phenyl isocyanate.
引文
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[13]李进.新型口服多激酶抑制剂瑞戈非尼治疗癌症的研究进展[J].临床肿瘤学杂志,2014,19(5):385LI J.Research progress on new oral multikinase inhibitor regorafenib in the treatment of cancer[J].Chin Clin Oncol,2014,19(5):385
[14]张学忠.2,6-二氟苯甲酰基异氰酸酯的HPLC分析[J].现代农药,2004,3(1):20ZHANG XZ.HPLC analysis of 2,6-difluorobenzoyl isocyanate[J].Mod Agrochem,2004,3(1):20
[15]姚洁,戴云生,王公应.苯异氰酸酯的高效液相色谱分析[C]//全国生物医药色谱学术交流会论文集,2006YAO J,DAI YS,WANG GY.HPLC analysis of phenyl isocyanate[C]//Proceedings of the National Symposium on Biomedical Chromatography and Related Technologies,2006
[16]陈鉴东,陈见阳,张林海,等.柱前衍生-HPLC-FLD法测定对甲苯磺酸拉帕替尼中的基因毒性杂质[J].药物分析杂志,2015,35(9):1640CHEN JD,CHEN JY,ZHANG LH,ZHANG Y,et al.Determination of genotoxic impurity in lapatinib ditosylate by HPLC-FLD after pre-column derivatization[J].Chin J Pharm Anal,2015,35(9):1640
[2]李巍巍,王建英,邵梦璐.索拉非尼的合成研究[J].广东化工,2014,41(10):110LI WW,WANG JY,SHAO ML.The research progress on sorafenib synthesis[J].Guangdong Chem Ind J,2014,41(10):110
[3]陈欢生,梁俊,陈宇.对甲苯磺酸索拉非尼的合成[J].中国药物化学杂志,2013,23(4):289CHEN HS,LIANG J,CHEN Y.Synthesis of sorafenib tosylate[J].Chin J Med Chem,2013,23(4):289
[4]黄霞.索拉非尼靶向治疗晚期肝细胞癌的临床分析[J].保健医学研究与实践,2015,12(4):43HUANG X.The clinical analysis of targeted therapy of sorafenib on advanced hepatocellular carcinoma[J].Health Med Res Pract,2015,12(4):43
[5]刘健颖,唐伟方,陆涛.索拉非尼研究进展[J].海峡药学,2010,22(4):9LIU JY,TANG WF,LU T.Recent progress on sorafenib[J].Strait Pharml J,2010,22(4):9
[6]龚新雷,秦叔逵.索拉非尼治疗国人晚期肝细胞癌的临床研究进展[J].临床肿瘤学杂志,2015,20(2):175GONG XL,QIN SK.Research progress on treatment of sorafenib for Chinese patients with advanced hepatocellular carcinoma[J].Chin Clin Oncol,2015,20(2):175
[7]张英,张洪,彭锐.索拉非尼纳米混悬剂的稳定性研究[J].中国医药导报,2015,12(15):120ZHANG Y,ZHANG H,PENG Y.Stability study on sorafenib nanosuspension[J].China Med Her,2015,12(15):120
[8]吴晓刚,陈宁,毛柯,等.甲苯磺酸索拉非尼片的制备及体外溶出行为考察[J].药学与临床研究,2015,23(2):144WU XG,CHEN N,MAO K,et al.Study on prescription technology and dissolution behavior of sorafenib tosylate tablets[J].Pharm Clin Res,2015,23(2):144
[9]刘亚方,李小刚,李洪玉,等.索拉非尼的合成研究[J].精细化工中间体,2012,42(5):36LIU YF,LI XG,LI HY,et al.Study on the synthesis of sorafenib[J].Fine Chem Intermediate,2015,42(5):36
[10]苏鹏,袁晨欢,王德才,等.瑞戈非尼的合成工艺改进的研究[J].药学与临床研究,2015,23(4):368SU P,YUAN CH,WANG DC,et al.Improvement of the synthesis process on regorafenib[J].Pharm Clin Res,2015,23(4):368
[11]王明森,刘正平,侯良玉,等.小分子抑制剂瑞戈非尼的药理和临床概述[J].药学研究,2015,34(10):617WANG MS,LIU ZP,HOU LY,et al,The progress on pharmacological and clinical research of small molecule inhibitors regorafenib[J].J Pharm Res,2015,34(10):617
[12]刘正平,刘军田,王明森,等.瑞戈非尼固体分散体的制备及体外溶出度考察[J].药学研究,2015,34(9):524LIU ZP,LIU JT,WANG MS,et al,Prepartion and dissolution of regorafenib solid dispersion in vitro[J].J Pharm Res,2015,34(9):524
[13]李进.新型口服多激酶抑制剂瑞戈非尼治疗癌症的研究进展[J].临床肿瘤学杂志,2014,19(5):385LI J.Research progress on new oral multikinase inhibitor regorafenib in the treatment of cancer[J].Chin Clin Oncol,2014,19(5):385
[14]张学忠.2,6-二氟苯甲酰基异氰酸酯的HPLC分析[J].现代农药,2004,3(1):20ZHANG XZ.HPLC analysis of 2,6-difluorobenzoyl isocyanate[J].Mod Agrochem,2004,3(1):20
[15]姚洁,戴云生,王公应.苯异氰酸酯的高效液相色谱分析[C]//全国生物医药色谱学术交流会论文集,2006YAO J,DAI YS,WANG GY.HPLC analysis of phenyl isocyanate[C]//Proceedings of the National Symposium on Biomedical Chromatography and Related Technologies,2006
[16]陈鉴东,陈见阳,张林海,等.柱前衍生-HPLC-FLD法测定对甲苯磺酸拉帕替尼中的基因毒性杂质[J].药物分析杂志,2015,35(9):1640CHEN JD,CHEN JY,ZHANG LH,ZHANG Y,et al.Determination of genotoxic impurity in lapatinib ditosylate by HPLC-FLD after pre-column derivatization[J].Chin J Pharm Anal,2015,35(9):1640
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