原料药1-甲基海因的质量研究及稳定性考察
|
摘要
目的:本文对原料药1-甲基海因进行了较为完善的质量研究,着重对1-甲基海因的有关物质和含量测定方法及其限度以及稳定性考察进行了系统的研究。
方法:本文对1-甲基海因质量控制方法建立了其鉴别、杂质检查、有关物质及含量测定等项目的测定方法,首次用高效液相色谱仪DAD检测器确定了有关物质的测定方法,选择用agela venusil MP C18柱,(5um,250mm×4.6mm),流动相为0.2%磷酸水溶液;检测波长:200nm;在鉴定有关物质2-(1-甲基脲基)乙酸结构中,采用了元素分析、EI-MS、1H-NMR、1C-NMR、IR等现代光谱技术综合分析,最终确定为2-(1-甲基脲基)乙酸。
结果:所建立的有关物质检查方法具有良好的专属性,1-甲基海因的浓度在0.10～0.60ug范围内,峰面积与其浓度呈良好线性关系(r=0.9997),检测限为2ng(S/N=3),精密度试验RSD=0.12%,重复性试验RSD为0.67%。本文还建立了用非水溶液中和法测定1-甲基海因含量的方法。同时为1-甲基海因原料药初步制订了药品质量标准,并进行了1-甲基海因稳定性的影响因素试验和加速试验,结果表明1-甲基海因对光、湿、热稳定。
结论:本文为制订1-甲基海因原料药质量标准以及贮藏条件和有效期提供了依据,同时为制剂的研发和生产工艺标准的设计提供了参考,不仅填补了国内外在1-甲基海因质量控制研究领域的空白,并且为1-甲基海因开发成为国家一类新药及其更广阔的应用奠定了基础。
Purpose: This article on raw materials of l-Methylhydantoin for better quality,focus on the relative substance of l-Methylhydantoin and determination method and its limits and stability research on the system.
Method:In this thesis, the quality control in-depth study about l-Methylhydantoin is established for chemical identification,checking impurities, the relative substance and substance determination etc.For the first time,HPLC-DAD detector is used to identify and determine the relative substance, with the usage of agela venusil MP C18 column(5um,250mm×4.6mm), the mobile phase was 0.2% phosphate solution, 200nm as detective wavelength. In the identification of the relative substance of 2– (1 - methyl - urea - based) acetic acid structure, use element analysis, EI-MS, 1H-NMR, 1C-NMR, IR and so on analysis of modern spectrum technologies and final set at 2– (1 - methyl - urea - based) acetic acid.
Result:The established method has a good specification,linearity and precision within the range of 0.10- 0.60ug (r=0.9997),the limit of detection is 2ng(S/N=3). The analysis percision RSD was 0.12%,The repeatabiliy Precision RSD was 0.67%. It also established acid-base method using non-aqueous . At the same time the quality criteria for the l-Methylhydantoin was developed as well as the stability test and accelerated test of l-Methylhydantoin; the results show that l-Methylhydantoin stabilizes in front of the light, moisture, thermal.
Conclusion:This thesis provides a quality standards basis for making l-Methylhydantoin Raw Materials, storage conditions and validity, at the same time, lays a foundation for the research and development of preparation and the design of production technology standards. Not only does it fill the blank of the research field of the quality control of l-Methylhydantoin at home and abroad, but also paves the way for making l-Methylhydantoin a nation-class medicine and its wider application.
方法:本文对1-甲基海因质量控制方法建立了其鉴别、杂质检查、有关物质及含量测定等项目的测定方法,首次用高效液相色谱仪DAD检测器确定了有关物质的测定方法,选择用agela venusil MP C18柱,(5um,250mm×4.6mm),流动相为0.2%磷酸水溶液;检测波长:200nm;在鉴定有关物质2-(1-甲基脲基)乙酸结构中,采用了元素分析、EI-MS、1H-NMR、1C-NMR、IR等现代光谱技术综合分析,最终确定为2-(1-甲基脲基)乙酸。
结果:所建立的有关物质检查方法具有良好的专属性,1-甲基海因的浓度在0.10～0.60ug范围内,峰面积与其浓度呈良好线性关系(r=0.9997),检测限为2ng(S/N=3),精密度试验RSD=0.12%,重复性试验RSD为0.67%。本文还建立了用非水溶液中和法测定1-甲基海因含量的方法。同时为1-甲基海因原料药初步制订了药品质量标准,并进行了1-甲基海因稳定性的影响因素试验和加速试验,结果表明1-甲基海因对光、湿、热稳定。
结论:本文为制订1-甲基海因原料药质量标准以及贮藏条件和有效期提供了依据,同时为制剂的研发和生产工艺标准的设计提供了参考,不仅填补了国内外在1-甲基海因质量控制研究领域的空白,并且为1-甲基海因开发成为国家一类新药及其更广阔的应用奠定了基础。
Purpose: This article on raw materials of l-Methylhydantoin for better quality,focus on the relative substance of l-Methylhydantoin and determination method and its limits and stability research on the system.
Method:In this thesis, the quality control in-depth study about l-Methylhydantoin is established for chemical identification,checking impurities, the relative substance and substance determination etc.For the first time,HPLC-DAD detector is used to identify and determine the relative substance, with the usage of agela venusil MP C18 column(5um,250mm×4.6mm), the mobile phase was 0.2% phosphate solution, 200nm as detective wavelength. In the identification of the relative substance of 2– (1 - methyl - urea - based) acetic acid structure, use element analysis, EI-MS, 1H-NMR, 1C-NMR, IR and so on analysis of modern spectrum technologies and final set at 2– (1 - methyl - urea - based) acetic acid.
Result:The established method has a good specification,linearity and precision within the range of 0.10- 0.60ug (r=0.9997),the limit of detection is 2ng(S/N=3). The analysis percision RSD was 0.12%,The repeatabiliy Precision RSD was 0.67%. It also established acid-base method using non-aqueous . At the same time the quality criteria for the l-Methylhydantoin was developed as well as the stability test and accelerated test of l-Methylhydantoin; the results show that l-Methylhydantoin stabilizes in front of the light, moisture, thermal.
Conclusion:This thesis provides a quality standards basis for making l-Methylhydantoin Raw Materials, storage conditions and validity, at the same time, lays a foundation for the research and development of preparation and the design of production technology standards. Not only does it fill the blank of the research field of the quality control of l-Methylhydantoin at home and abroad, but also paves the way for making l-Methylhydantoin a nation-class medicine and its wider application.
引文
[1]蒋煜.化学药物质量研究和质量标准制订的一般原则和内容, Chinese Journal of New Drugs 2009,18(12)
[2]化学药物杂质研究的技术指导原则,[s]GPH3-1,2005,3
[3]雨风,潘安.止咳药市场呈现三大特点[N].医药导报/2006.9.20(C19).
[4]王志寒. 1-甲基海因合成路线的筛选及其止咳活性研究[D].长春:吉林大学,2009
[5]王永生. 1-甲基海因在制备止咳平喘去痰的药物中的应用[P].中国:200510017262.X,2006.8.9
[6]Reynolds SM, Mackenzie AJ. The pharmacology of cough [J].TRENDS in PharmacologicalSciences, 2004, 25: 325-8.
[7]BarnesPJ.The problem of cough and development of novel antitus-sives[J]. Pulmonary Pharmacology& Therapeutics, 2007, 20(4):416-22.
[8]孔维清,江璇,徐鹏.新型镇咳药的研究进展[J]安徽医药2009 Sep;13(9)
[9]张楠.海因及5,5-二甲基海因的合成及活性筛选研究[D].长春:吉林大学,2009
[10]陈冠荣.化工百科全书.北京:化学工业出版社,第18卷,1990,769-783.
[11]周宁琳,夏小仙,刘心立.海因类化合物的研究(Ⅰ)[J].热固性树脂.1998,(3):13215.
[12]张天宝,岳木生,黄小波等.二氯二甲基乙内酰脲复方消毒剂性能的实验室观察[ J].中国消毒学杂志, 1997, 14(4):204-207.
[13]陈强,李清禄.复方溴氯海因消毒剂的性能[J].福建农林大学学报(自然科学版), 2003, 32(2): 227-229.
[14]王志寒. 1-甲基海因合成路线的筛选及其止咳活性研究[D].长春:吉林大学,2009
[15]李清禄,林新华.复方二氯海因消毒剂的制备与性能[J].福建医科大学学报, 2001, (35)2: 176-179.
[16]张胜利,许祖勋,黄锦霞等. N,N-二卤代二甲基乙内酰脲的合成及杀菌性能研究[ J].湖北大学学报(自然科学版),2002, 75(1): 63-65.
[17]赵春兰,石磊,宋晖,等.溴氯二甲基乙内酰脲复方消毒剂杀灭微生物效果与腐蚀性实验观察[J].中国消毒学杂志,1999, 16(4): 205-208.
[18]陈荣凤,薛广波.二溴二甲基乙内酰脲消毒剂机理的实验室研究[J].南方护理学报, 2002, 9(5): 69-71.
[19]谢刚.溴氯海因对几种病原真菌的室内毒力试验及田间药害试验[J].湖南农业大学学报(自然科学版)2010,6(11)
[20]LaunayM, Potin D, MailletM. Jeannine B,et al.Hydantoincompounds useful as anti-inflammatory agents [ P ]. FR:US2002143035, 2002-10-03.
[21]Ienaga, K, Nakamura, K. HydantoinDerivatives[J].Chem Ab-str, 104: 109642c 1985.
[22]Sun Q, Kyle D J. Ary.l substituted hydantoin compounds andtheiruse as sodium channelblockers[P]. US: WO2004010950,2004-02-05.
[23]刘继敏,赵勇.溴氯海因杀灭微生物效果与稳定性的试验观察[J].中国消毒学杂志, 2001, 18(4): 218-222.
[24]张天宝,岳木生,黄晓波等.二氯二甲基乙内酰脲复方消毒剂性能的实验室观察[ J].中国消毒学杂志, 1997, 14(4):204-207.
[25]陈荣凤,薛广波,顾春英.卤代二甲基乙内酰脲消毒杀菌剂研究进展[J].上海预防医学杂志, 1999, 11(11): 503-505.
[26]胡艾希.五元杂环类化妆品防腐剂的合成[J].日用化学工业, 1995(6): 322-325.
[27]吴健敏,李自力,蒋冬福,等.二氯海因抗菌活性的测试[J].广西畜牧兽医, 1996, 12(1): 13-14.
[28]李焰,陈祖兴,黄锦霞,等.新型二溴二甲基海因复合保鲜剂的研制[J].精细化工, 2001, 18(5): 307-309.
[29]GilbertK, HobbsDW, VeberD F,et al.Hydantoin and suc-cinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists[P]. US:WO9414438, 1994-07-07.
[30]Goodnow R, AlanG, KangL. Hydantoin-containing glucokinase activators[P]. CH: CN1427838, 2003-07-02.
[31]MikamiH, Ienage K. Hydantoin or imidazolidinetrione derivatives for the prevention or treatment of renal failure[P]. JP:EP0412940, 1991-02-13.
[32]OkamotoK, IshiiA, OkukadoN,etal.Preparation of (S)-hy-dantoin derivative and its use for treatment of renal failure[J].Chem Abstr, 140: 339327 2004.
[33]OkamotoK, IshiiA, OkukadoN,etal.Preparation of(R)-hy-dantoin derivative and its use for treatment of renal failure[J].Chem Abstr, 140: 339328 2004.
[34]IenageK, MikamiH, NishibataR. Use ofa hydantoin derivativein a pharmaceutical composition against hypoalbuminaemia[P].JP: EP1243261, 2002-09-25.
[35]KuronoM, UnnoR, KimuraH,etal.Hydantoin derivatives for treating complications of diabetes and circulatory diseases[P].JP:EP0418834, 1991-03-27.
[36]叶榕,含二氯二甲基海因复方消毒剂性能的试验观察, [J].中国消毒学杂志,2002,19(2)73-77
[37]张天宝,二氯二甲基乙内酰脲复方消毒剂性能的实验室观察,[J].中国消毒学杂志,1997,14(4)204-207
[38]陈越英,二溴海因对嗜肺军团菌杀灭效果及其影响因素的实验研究[J].中国消毒学杂志,2009,26(2):121-125
[39]姜霞,二溴海因对水中微生物杀灭效果及影响因素研究[J].河北医药,2009,31(6)736-737
[40]陈越英,二溴海因对水中细菌杀灭效果观察[J].中国消毒学杂志,2006,23(5)429-431
[41]白雪媛,杨桠楠,王永生.海因类化合物的药理作用进展[J]中成药2006Vol.28 No.10
[42]崔玉杰,溴氯海因消毒片杀菌性能与腐蚀性的试验研究,[J].中国消毒学杂志,2005,22(1)18-21
[43]姜霞,溴氯海因消毒粉剂杀灭微生物效果与腐蚀性的试验观察, [J].中国消毒学杂志,2006,23(2)152-154
[44]崔玉杰,溴氯海因现场消毒效果应用研究,[J].医学动物防制,2009, 25(4)258-259
[45]Miyoda Yoshiaki,Saito Makoto,Shibuya Akira.Nishimura Norito Method for Producing 1-Alkylhydantoin[P].Japan:20032171367,2003-06-30.
[46]LaunayMichele,PotinDominique,MailletMagali Jeannie Blandi,et al.Hydantoin Compo- unds Useful as Anti-inflammatory Agents [P]. France : US2002143035, 2002– 10-03.
[47]Ienaga Kazuharu,Mikami Hiroki,Nishibata Ryoji.Use of a Hydantoin Derivative in a Pharmaceutical Composition Against Hypoalbuminaemia[P]. Japan: EP124326 1,2002-09-25.
[48]Endou Hitoshi,Ienaga Kazuharu.Pharmaceutical Composition Containing a Hydantoin Derivative and Use of Said Derivative[P].Japan: EP0780125, 1997-06-25.
[2]化学药物杂质研究的技术指导原则,[s]GPH3-1,2005,3
[3]雨风,潘安.止咳药市场呈现三大特点[N].医药导报/2006.9.20(C19).
[4]王志寒. 1-甲基海因合成路线的筛选及其止咳活性研究[D].长春:吉林大学,2009
[5]王永生. 1-甲基海因在制备止咳平喘去痰的药物中的应用[P].中国:200510017262.X,2006.8.9
[6]Reynolds SM, Mackenzie AJ. The pharmacology of cough [J].TRENDS in PharmacologicalSciences, 2004, 25: 325-8.
[7]BarnesPJ.The problem of cough and development of novel antitus-sives[J]. Pulmonary Pharmacology& Therapeutics, 2007, 20(4):416-22.
[8]孔维清,江璇,徐鹏.新型镇咳药的研究进展[J]安徽医药2009 Sep;13(9)
[9]张楠.海因及5,5-二甲基海因的合成及活性筛选研究[D].长春:吉林大学,2009
[10]陈冠荣.化工百科全书.北京:化学工业出版社,第18卷,1990,769-783.
[11]周宁琳,夏小仙,刘心立.海因类化合物的研究(Ⅰ)[J].热固性树脂.1998,(3):13215.
[12]张天宝,岳木生,黄小波等.二氯二甲基乙内酰脲复方消毒剂性能的实验室观察[ J].中国消毒学杂志, 1997, 14(4):204-207.
[13]陈强,李清禄.复方溴氯海因消毒剂的性能[J].福建农林大学学报(自然科学版), 2003, 32(2): 227-229.
[14]王志寒. 1-甲基海因合成路线的筛选及其止咳活性研究[D].长春:吉林大学,2009
[15]李清禄,林新华.复方二氯海因消毒剂的制备与性能[J].福建医科大学学报, 2001, (35)2: 176-179.
[16]张胜利,许祖勋,黄锦霞等. N,N-二卤代二甲基乙内酰脲的合成及杀菌性能研究[ J].湖北大学学报(自然科学版),2002, 75(1): 63-65.
[17]赵春兰,石磊,宋晖,等.溴氯二甲基乙内酰脲复方消毒剂杀灭微生物效果与腐蚀性实验观察[J].中国消毒学杂志,1999, 16(4): 205-208.
[18]陈荣凤,薛广波.二溴二甲基乙内酰脲消毒剂机理的实验室研究[J].南方护理学报, 2002, 9(5): 69-71.
[19]谢刚.溴氯海因对几种病原真菌的室内毒力试验及田间药害试验[J].湖南农业大学学报(自然科学版)2010,6(11)
[20]LaunayM, Potin D, MailletM. Jeannine B,et al.Hydantoincompounds useful as anti-inflammatory agents [ P ]. FR:US2002143035, 2002-10-03.
[21]Ienaga, K, Nakamura, K. HydantoinDerivatives[J].Chem Ab-str, 104: 109642c 1985.
[22]Sun Q, Kyle D J. Ary.l substituted hydantoin compounds andtheiruse as sodium channelblockers[P]. US: WO2004010950,2004-02-05.
[23]刘继敏,赵勇.溴氯海因杀灭微生物效果与稳定性的试验观察[J].中国消毒学杂志, 2001, 18(4): 218-222.
[24]张天宝,岳木生,黄晓波等.二氯二甲基乙内酰脲复方消毒剂性能的实验室观察[ J].中国消毒学杂志, 1997, 14(4):204-207.
[25]陈荣凤,薛广波,顾春英.卤代二甲基乙内酰脲消毒杀菌剂研究进展[J].上海预防医学杂志, 1999, 11(11): 503-505.
[26]胡艾希.五元杂环类化妆品防腐剂的合成[J].日用化学工业, 1995(6): 322-325.
[27]吴健敏,李自力,蒋冬福,等.二氯海因抗菌活性的测试[J].广西畜牧兽医, 1996, 12(1): 13-14.
[28]李焰,陈祖兴,黄锦霞,等.新型二溴二甲基海因复合保鲜剂的研制[J].精细化工, 2001, 18(5): 307-309.
[29]GilbertK, HobbsDW, VeberD F,et al.Hydantoin and suc-cinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists[P]. US:WO9414438, 1994-07-07.
[30]Goodnow R, AlanG, KangL. Hydantoin-containing glucokinase activators[P]. CH: CN1427838, 2003-07-02.
[31]MikamiH, Ienage K. Hydantoin or imidazolidinetrione derivatives for the prevention or treatment of renal failure[P]. JP:EP0412940, 1991-02-13.
[32]OkamotoK, IshiiA, OkukadoN,etal.Preparation of (S)-hy-dantoin derivative and its use for treatment of renal failure[J].Chem Abstr, 140: 339327 2004.
[33]OkamotoK, IshiiA, OkukadoN,etal.Preparation of(R)-hy-dantoin derivative and its use for treatment of renal failure[J].Chem Abstr, 140: 339328 2004.
[34]IenageK, MikamiH, NishibataR. Use ofa hydantoin derivativein a pharmaceutical composition against hypoalbuminaemia[P].JP: EP1243261, 2002-09-25.
[35]KuronoM, UnnoR, KimuraH,etal.Hydantoin derivatives for treating complications of diabetes and circulatory diseases[P].JP:EP0418834, 1991-03-27.
[36]叶榕,含二氯二甲基海因复方消毒剂性能的试验观察, [J].中国消毒学杂志,2002,19(2)73-77
[37]张天宝,二氯二甲基乙内酰脲复方消毒剂性能的实验室观察,[J].中国消毒学杂志,1997,14(4)204-207
[38]陈越英,二溴海因对嗜肺军团菌杀灭效果及其影响因素的实验研究[J].中国消毒学杂志,2009,26(2):121-125
[39]姜霞,二溴海因对水中微生物杀灭效果及影响因素研究[J].河北医药,2009,31(6)736-737
[40]陈越英,二溴海因对水中细菌杀灭效果观察[J].中国消毒学杂志,2006,23(5)429-431
[41]白雪媛,杨桠楠,王永生.海因类化合物的药理作用进展[J]中成药2006Vol.28 No.10
[42]崔玉杰,溴氯海因消毒片杀菌性能与腐蚀性的试验研究,[J].中国消毒学杂志,2005,22(1)18-21
[43]姜霞,溴氯海因消毒粉剂杀灭微生物效果与腐蚀性的试验观察, [J].中国消毒学杂志,2006,23(2)152-154
[44]崔玉杰,溴氯海因现场消毒效果应用研究,[J].医学动物防制,2009, 25(4)258-259
[45]Miyoda Yoshiaki,Saito Makoto,Shibuya Akira.Nishimura Norito Method for Producing 1-Alkylhydantoin[P].Japan:20032171367,2003-06-30.
[46]LaunayMichele,PotinDominique,MailletMagali Jeannie Blandi,et al.Hydantoin Compo- unds Useful as Anti-inflammatory Agents [P]. France : US2002143035, 2002– 10-03.
[47]Ienaga Kazuharu,Mikami Hiroki,Nishibata Ryoji.Use of a Hydantoin Derivative in a Pharmaceutical Composition Against Hypoalbuminaemia[P]. Japan: EP124326 1,2002-09-25.
[48]Endou Hitoshi,Ienaga Kazuharu.Pharmaceutical Composition Containing a Hydantoin Derivative and Use of Said Derivative[P].Japan: EP0780125, 1997-06-25.