某医药中间体合成工艺的热危险性研究
摘要
工厂在新工艺投产前有必要对工艺进行热风险评估,以保证安全生产。
本文对某医药中间体的合成工艺进行了的热风险评估。主要通过实验室全自动反应量热仪(RCle)测试了每一步的热力学数据,同时利用差示扫描量热仪(DSC)以及AKTS高等动力学软件研究了产物的二次分解特性,从而对反应的热危险性进行评估分级。首先进行实验室小试,初步了解反应的放热特征；再采用RCle研究每一步的放热特性计算得出反应失控条件下的绝热温升(ΔTad)、反应所能达到的最高温度(MTSR)等参数；用DSC对反应产物进行扫描量热,得到产物高温下的热分解情况,用AKTS软件进行动力学模拟,根据模拟结果计算得到诱导期为24h所对应的温度TD24等参数；最后结合这些数据,根据热失控危险等级分类标准进行热失控危险等级划分。
结果表明：在由3个反应构成的合成工艺中,反应2的放热量最小,几乎不放热,反应3的放热量最大,引起的绝热温升也最高,反应1居中；反应3在投料初始阶段放比较剧烈,值得注意；3个反应的热风险等级分别为三级、一级、三级,均可以接受,只需采取适当的措施就可以使合成工艺的热风险处于受控状态内。
The runway reaction often leads to combustion and explosion accidents in chemical factory. It is necessary to carry out the systems analysis, testing, evaluation and investigation on the direction of security control before a new process production.
In this paper, Reaction Calorimeter (RC1e), Differential Scanning Calorimeter(DSC) and Advanced Kinetics and Technology Solutions (AKTS) were used to study the thermal risk of the synthesis of a pharmaceutical intermediate. First of all, the cp of some raw materials was tested by DSC. Then some experiments were carried out with RC1e to study the exothermic character of each step. Some parameters such as adiabatic temperature increase (ΔTad), maximum temperature of synthetic reaction(MTSR) were obtained. After that DSC was used to study the thermal decomposition of each product, and some apparent parameters, such as onset temperature, heat release were obtained. On the base of DSC data, the kinetics parameters and TD24 were got with AKTS simulation. Finally combining the datum from RC1e, DSC and AKTS, the thermal risk class of each reaction is studied.
The results showed that the second reaction has the minimum heat release, and the third reaction has the maximum heat release. The risk class of thermal runaway reaction of first reaction is class 3, the risk class of thermal runaway reaction of the second reaction is class 1, and the risk class of thermal runway reaction of the third reaction is class 3. The thermal risks of three reactions are all acceptable and appropriate measures should be taken to ensure the reaction under control.
本文对某医药中间体的合成工艺进行了的热风险评估。主要通过实验室全自动反应量热仪(RCle)测试了每一步的热力学数据,同时利用差示扫描量热仪(DSC)以及AKTS高等动力学软件研究了产物的二次分解特性,从而对反应的热危险性进行评估分级。首先进行实验室小试,初步了解反应的放热特征；再采用RCle研究每一步的放热特性计算得出反应失控条件下的绝热温升(ΔTad)、反应所能达到的最高温度(MTSR)等参数；用DSC对反应产物进行扫描量热,得到产物高温下的热分解情况,用AKTS软件进行动力学模拟,根据模拟结果计算得到诱导期为24h所对应的温度TD24等参数；最后结合这些数据,根据热失控危险等级分类标准进行热失控危险等级划分。
结果表明：在由3个反应构成的合成工艺中,反应2的放热量最小,几乎不放热,反应3的放热量最大,引起的绝热温升也最高,反应1居中；反应3在投料初始阶段放比较剧烈,值得注意；3个反应的热风险等级分别为三级、一级、三级,均可以接受,只需采取适当的措施就可以使合成工艺的热风险处于受控状态内。
The runway reaction often leads to combustion and explosion accidents in chemical factory. It is necessary to carry out the systems analysis, testing, evaluation and investigation on the direction of security control before a new process production.
In this paper, Reaction Calorimeter (RC1e), Differential Scanning Calorimeter(DSC) and Advanced Kinetics and Technology Solutions (AKTS) were used to study the thermal risk of the synthesis of a pharmaceutical intermediate. First of all, the cp of some raw materials was tested by DSC. Then some experiments were carried out with RC1e to study the exothermic character of each step. Some parameters such as adiabatic temperature increase (ΔTad), maximum temperature of synthetic reaction(MTSR) were obtained. After that DSC was used to study the thermal decomposition of each product, and some apparent parameters, such as onset temperature, heat release were obtained. On the base of DSC data, the kinetics parameters and TD24 were got with AKTS simulation. Finally combining the datum from RC1e, DSC and AKTS, the thermal risk class of each reaction is studied.
The results showed that the second reaction has the minimum heat release, and the third reaction has the maximum heat release. The risk class of thermal runaway reaction of first reaction is class 3, the risk class of thermal runaway reaction of the second reaction is class 1, and the risk class of thermal runway reaction of the third reaction is class 3. The thermal risks of three reactions are all acceptable and appropriate measures should be taken to ensure the reaction under control.
引文
[1]周忠元,田维金,邹德敏.化工安全技术[M].北京：化学工业出版社,2000
[2]崔克清,张礼敬,陶刚.化工安全设计[M].北京：化学工业出版社,2004
[3]崔克清,陶刚.化工工艺及安全[M].北京：化学工业出版社,2004
[4]刘荣海,陈网桦,胡毅亭.安全原理与危险化学品测评技术[M].北京：化学工业出版社,2004
[5]Francis Stoessel[瑞士].化工工艺的热安全-风险评估与工艺设计[M].陈网桦,彭金华,陈利平译.北京：科学出版社,2009
[6]Jingqili.失控反应http://bbs1.organicchem.com/?action-viewthread-tid-96125
[7]Theodor Grewer. Thermal hazards of chemical reactions.1st ed[J]. The Netherlands:Elservier Science B. V.,1993:365-380
[8]陈网桦,陈利平,李春光等.苯和甲苯硝化及磺化反应热危险性分级研究[J].中国安全科学,2010,20(5)：67-74
[9]Ruedi W. Gygax. Chemical Reaction Engineering for Safety[J]. Chemical Engineering Science,1988,43(8):1759-1771
[10]Ralph N. Landau, Donna G. Blackmond. Scale up heat transfer based on reaction calorimetry [J]. Chemical Engineering Progress,1994,91:4343-4348
[11]Ralph N. Landau, Robert S. Cutro. Assess risk due to desired chemistry [J]. Chemical Engineering Progress,1993,89(4):66-71
[12]P. Hugo, J. Steinbach, F. Stoessel. Calculation of the maximum temperature in stirred tank reactors in case of a breakdown of cooling [J]. Chemical Engineering Science,1988(8):2147-2152
[13]John Barton, Richard Rogers. Chemical Reaction Hazards [M].Institution of Chemical Engineers,1993
[14]Grewer T. Thermal Hazards of Chemical Reaction [M]. Elsevier.1994
[15]Alos M A, et al. A new method for assessing the thermal stability of semi batch processes based on Lyapunov exponents [J].Chemical Engineering Science,1996, 51(11):3089-3094
[16]Zaldivar J M, Molga E, Alos M A, Hernandez H. Aromatic nitration by mixed ac id, fast liquid-liquid reaction regime [J]. Chemical Engineering and Progressing,1996,35(2):91-105
[17]Zaldivar J M, Barcons C, Hernandez H, eta 1. Modeling and optimization of semi-batch toluene mono nitration with mixed acid from performance and safety view points [J]. Cheical Engineering Science,1992,47(9-11):2517-2522
[18]Zaldivar JM, Molga E, Alos M A, Hernandez H. Aromatic nitration by mixed ac id. Slow liquid-liquid reaction regime [J]. Chemical Engineering and Progressing,1995,34(6):543-559
[19]Flavio Augusto DAngelo, Lena Brunet, Patrick Cognet, et al. Modeling and constraint optimization of an aromatic nitration in liquid-liquid medium[J]. Chemical Engineering Journal 2003,91(1):75-84
[20]Eduard Serra, Thermal hazard. Assessment and macro kinetics analysis of toluene mono nitration in a batch reactor [J]. Journal of Loss Prevention Industries,2001,9(5):309-316
[21]Francis Stoessel. What is your thermal risk [J].Chemical Engineering Progress, 1993,90:67-75
[22]Francis Stoessel. Thermal Safety of Chemical processes [M]. The Federal Republic of Germany:Wiley-VCH,2008:61-73
[23]王晓峰,陈网桦,薛艳.甲苯一段半间歇硝化工艺的反应失控研究[J].火工品,2007(3)：18-22
[24]王晓峰.甲苯一段硝化的工艺优化和过程安全性研究[D].南京：南京理工大学,2005
[25]吴燕.硝酸铵及其溶液的热安全性研究[D].南京：南京理工大学[硕士论文],2005.
[26]陈利平,陈网桦,李春光,等.混酸中甲苯半间歇硝化过程的危险性研究[J].中国安全科学学报,2007,17(12)：102-106.
[27]陈利平,蔡刘霖,彭金华,等.硝酸甲胺反应过程的安全性研究[J].中国安全科学学报,2006,16(12)：97-102.
[28]Liping CHEN, Wanghua CHEN, Ying LIU, et al Toluene mono nitration in a semi-batch reactor[J]. Central European Journal of Energetic Materials,2008, 5(2):37-47
[29]陈利平,陈网桦,李春光,等.一硝基甲苯硝化过程的热危险性[J].火炸药学报,2008,31(3)：36-40
[30]陈利平,陈网桦,彭金华,等.间歇与半间歇反应热失控危险性评估方法[J].化工学报.2008,59(12)：2963-2970
[31]陈利平.甲苯硝化反应热危险性的实验与理论研究[D].南京：南京理工大学,2009
[32]朱贤峰.甲苯磺化反应过程的热危险性分析[D].南京：南京理工大学,2008.
[33]刘婷婷.异辛醇硝化制备硝酸异辛酯合成工艺热危险性的初步研究[D].南京：南京理工大学,2010
[34]Varma A, Morbidelli M, Wu H. Parametric Sensitivity in Chemical Systems [M]. 1st ed. Cambridge:The press syndicate of the University of Cambridge,1999: 1-8
[35]Steensma Metske, Westerterp K Roel. Thermally safe operation of a semi-batch reactor for liquid-liquid reactions[J]. Slow reactions. Industrial and Engineering Chemistry Research,1990,29:1259-1270
[36]Woezik B A A van, Westerterp K R. Runaway behavior and thermally safe operation of multiple liquid-liquid reactions in the semi-batch reactor. The nitric acid oxidation of 2-octannol[J]. Chemical Engineering and Processing,2002,41: 59-77
[37]Gygax R. Scale up principles for assessing thermal runaway risks[J]. Chemical Engineering Progress,1990, February:53-60
[38]王彝,黄文君,黄飞,等.硫酸羟胺的热分解动力学研究[J].中国安全生产科学技术,2011,7(4)：40-45
[39]石宁,谢传欣,于丽明,等.双氧水分解危险性的定量研究[J].大氮肥,2010,33(1)：53-55
[40]Bertrand Roduit, Patrick Folly, Alexandre Sarbach. Estimation of time to maximum rate under adiabatic conditions (TMRad) using kinetic parameters derived from DSC-investigation of thermal behavior of 3-methyl-4-nitrophenol[J]. 化学推进剂与高分子材料,2011,9(1):84-96
[41]楚士晋.炸药热分析[M].北京：科学出版社,1994
[2]崔克清,张礼敬,陶刚.化工安全设计[M].北京：化学工业出版社,2004
[3]崔克清,陶刚.化工工艺及安全[M].北京：化学工业出版社,2004
[4]刘荣海,陈网桦,胡毅亭.安全原理与危险化学品测评技术[M].北京：化学工业出版社,2004
[5]Francis Stoessel[瑞士].化工工艺的热安全-风险评估与工艺设计[M].陈网桦,彭金华,陈利平译.北京：科学出版社,2009
[6]Jingqili.失控反应http://bbs1.organicchem.com/?action-viewthread-tid-96125
[7]Theodor Grewer. Thermal hazards of chemical reactions.1st ed[J]. The Netherlands:Elservier Science B. V.,1993:365-380
[8]陈网桦,陈利平,李春光等.苯和甲苯硝化及磺化反应热危险性分级研究[J].中国安全科学,2010,20(5)：67-74
[9]Ruedi W. Gygax. Chemical Reaction Engineering for Safety[J]. Chemical Engineering Science,1988,43(8):1759-1771
[10]Ralph N. Landau, Donna G. Blackmond. Scale up heat transfer based on reaction calorimetry [J]. Chemical Engineering Progress,1994,91:4343-4348
[11]Ralph N. Landau, Robert S. Cutro. Assess risk due to desired chemistry [J]. Chemical Engineering Progress,1993,89(4):66-71
[12]P. Hugo, J. Steinbach, F. Stoessel. Calculation of the maximum temperature in stirred tank reactors in case of a breakdown of cooling [J]. Chemical Engineering Science,1988(8):2147-2152
[13]John Barton, Richard Rogers. Chemical Reaction Hazards [M].Institution of Chemical Engineers,1993
[14]Grewer T. Thermal Hazards of Chemical Reaction [M]. Elsevier.1994
[15]Alos M A, et al. A new method for assessing the thermal stability of semi batch processes based on Lyapunov exponents [J].Chemical Engineering Science,1996, 51(11):3089-3094
[16]Zaldivar J M, Molga E, Alos M A, Hernandez H. Aromatic nitration by mixed ac id, fast liquid-liquid reaction regime [J]. Chemical Engineering and Progressing,1996,35(2):91-105
[17]Zaldivar J M, Barcons C, Hernandez H, eta 1. Modeling and optimization of semi-batch toluene mono nitration with mixed acid from performance and safety view points [J]. Cheical Engineering Science,1992,47(9-11):2517-2522
[18]Zaldivar JM, Molga E, Alos M A, Hernandez H. Aromatic nitration by mixed ac id. Slow liquid-liquid reaction regime [J]. Chemical Engineering and Progressing,1995,34(6):543-559
[19]Flavio Augusto DAngelo, Lena Brunet, Patrick Cognet, et al. Modeling and constraint optimization of an aromatic nitration in liquid-liquid medium[J]. Chemical Engineering Journal 2003,91(1):75-84
[20]Eduard Serra, Thermal hazard. Assessment and macro kinetics analysis of toluene mono nitration in a batch reactor [J]. Journal of Loss Prevention Industries,2001,9(5):309-316
[21]Francis Stoessel. What is your thermal risk [J].Chemical Engineering Progress, 1993,90:67-75
[22]Francis Stoessel. Thermal Safety of Chemical processes [M]. The Federal Republic of Germany:Wiley-VCH,2008:61-73
[23]王晓峰,陈网桦,薛艳.甲苯一段半间歇硝化工艺的反应失控研究[J].火工品,2007(3)：18-22
[24]王晓峰.甲苯一段硝化的工艺优化和过程安全性研究[D].南京：南京理工大学,2005
[25]吴燕.硝酸铵及其溶液的热安全性研究[D].南京：南京理工大学[硕士论文],2005.
[26]陈利平,陈网桦,李春光,等.混酸中甲苯半间歇硝化过程的危险性研究[J].中国安全科学学报,2007,17(12)：102-106.
[27]陈利平,蔡刘霖,彭金华,等.硝酸甲胺反应过程的安全性研究[J].中国安全科学学报,2006,16(12)：97-102.
[28]Liping CHEN, Wanghua CHEN, Ying LIU, et al Toluene mono nitration in a semi-batch reactor[J]. Central European Journal of Energetic Materials,2008, 5(2):37-47
[29]陈利平,陈网桦,李春光,等.一硝基甲苯硝化过程的热危险性[J].火炸药学报,2008,31(3)：36-40
[30]陈利平,陈网桦,彭金华,等.间歇与半间歇反应热失控危险性评估方法[J].化工学报.2008,59(12)：2963-2970
[31]陈利平.甲苯硝化反应热危险性的实验与理论研究[D].南京：南京理工大学,2009
[32]朱贤峰.甲苯磺化反应过程的热危险性分析[D].南京：南京理工大学,2008.
[33]刘婷婷.异辛醇硝化制备硝酸异辛酯合成工艺热危险性的初步研究[D].南京：南京理工大学,2010
[34]Varma A, Morbidelli M, Wu H. Parametric Sensitivity in Chemical Systems [M]. 1st ed. Cambridge:The press syndicate of the University of Cambridge,1999: 1-8
[35]Steensma Metske, Westerterp K Roel. Thermally safe operation of a semi-batch reactor for liquid-liquid reactions[J]. Slow reactions. Industrial and Engineering Chemistry Research,1990,29:1259-1270
[36]Woezik B A A van, Westerterp K R. Runaway behavior and thermally safe operation of multiple liquid-liquid reactions in the semi-batch reactor. The nitric acid oxidation of 2-octannol[J]. Chemical Engineering and Processing,2002,41: 59-77
[37]Gygax R. Scale up principles for assessing thermal runaway risks[J]. Chemical Engineering Progress,1990, February:53-60
[38]王彝,黄文君,黄飞,等.硫酸羟胺的热分解动力学研究[J].中国安全生产科学技术,2011,7(4)：40-45
[39]石宁,谢传欣,于丽明,等.双氧水分解危险性的定量研究[J].大氮肥,2010,33(1)：53-55
[40]Bertrand Roduit, Patrick Folly, Alexandre Sarbach. Estimation of time to maximum rate under adiabatic conditions (TMRad) using kinetic parameters derived from DSC-investigation of thermal behavior of 3-methyl-4-nitrophenol[J]. 化学推进剂与高分子材料,2011,9(1):84-96
[41]楚士晋.炸药热分析[M].北京：科学出版社,1994
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