模拟移动床分离胆固醇和24-去氢胆固醇的研究
摘要
模拟移动床色谱技术(SMB)作为一种先进分离技术在精细化工、制药和生化领域取得了巨大发展,目前正处于从尖端技术向成熟工艺流程转型阶段,并有朝着分离-反应一体化方向发展的趋势。
胆固醇是脊椎动物细胞的重要组成部分,具有形成胆酸、构成细胞膜、合成激素等重要生理功能,广泛应用于化妆品、乳化剂、医药等领域。24-去氢胆固醇是胆固醇生物合成途径中的直接前体,与胆固醇相比因为支链带双键,所以在许多具有重要生理活性的甾醇合成中更有优势。
本文是对羊毛酯中胆固醇和24-去氢胆固醇的模拟移动床分离研究。通过固定床分离胆固醇和24-去氢胆固醇,分别测定了单根色谱柱的死时间,计算得到色谱柱的总空隙率为0.68,测定了低浓度下胆固醇和24-去氢胆固醇在甲醇中的吸附平衡常数为10.02和7.86;然后基于微分传质方程的通用多组分速率模型,在Matlab~(?)境下根据有限元正交配置法编制程序求得数值解,继而进行模拟移动床的过程仿真。再参照模拟移动床的计算结果,在实际模拟移动床分离过程中以纯度、生产率和溶剂消耗量为指标,考察了模拟移动床的切换时间、进料流量和进料浓度等因素对分离过程的影响,确定SMB的实验最佳操作条件为:柱温35℃,切换时间为9min,四区流量Q_1为6.5ml/min,Q_2为4.4ml/min,Q_3为4.65ml/min,Q_4为3.0ml/min,进料总浓度2.5mg/ml,经过8周期后,成功地分离了胆固醇和24-去氢胆固醇,相对纯度达到100%和98.5%。
Introduced by Broughton and Gerhold in the early 1960s,the Simulated Moving Bed (SMB) appeared predominantly in large scale separations in the petrochemical industry without any attention from fine chemical industry.This changed 15 years ago, when SMB was introduced as a novel technique to separate racemates in early drug development.The role of SMB in pharmaceutical industry has changed dramatically since then.Although SMB is now on its way from an emerging technology to a classical unit operation,the greatest task for the future will be to show that SMB technology is not a sophisticated,technically demanding and unreliable method for separating racemates,but an easy to master tool that can be applied both in early development and in scale-up production.
This paper took cholesterol and desmosterol,valuable resources of intermediate for steroids,as study object.The adsorption equilibrium constants of desmosterol and cholesterol were determined as 7.86 and 10.02,respectively,by separating of cholesterol and desmosterol with fixed-bed chromatography.The porosity of chromatograhy columns was 0.68.With these parameters,the region leading to complete separation predicted by triangle theory was able to be drawed out for the choosing of the initiative operating variables.
A general multicomponents rate model based on differential mass balance equations is adopted for simulating SMB.According to the outlined numerical solution,results of the simulation program in MATLAB~((?)) are shown.
Separation of desmosterol from cholesterol by SMB was simulated.The effects of flow rate in section 2(Q_2) and 3(Q_3),switching time,feed flow rate and feed concentration were studied on the operating performance parameters as purity, recovery,productivity and desorbent consumption.And Operating conditions leading to more than 90%purity in both outlet streams had been identified,together with those achieving optimal performance.Comparison between the results of simulations and the experimentation indicates that the present model describes very well the dynamic behavior of the systems under study.
A simple optimization procedure was runned for the choosing the optimal SMB operatingg conditions.Under temperature column of 35℃,switch time 9min,with flow rate of Q_1=6.5ml/min,Q_2=4.4ml/min for,Q_3=4.65ml/min,Q_4=3.0ml/min, cholesterol and desmosterol are separated completely.
胆固醇是脊椎动物细胞的重要组成部分,具有形成胆酸、构成细胞膜、合成激素等重要生理功能,广泛应用于化妆品、乳化剂、医药等领域。24-去氢胆固醇是胆固醇生物合成途径中的直接前体,与胆固醇相比因为支链带双键,所以在许多具有重要生理活性的甾醇合成中更有优势。
本文是对羊毛酯中胆固醇和24-去氢胆固醇的模拟移动床分离研究。通过固定床分离胆固醇和24-去氢胆固醇,分别测定了单根色谱柱的死时间,计算得到色谱柱的总空隙率为0.68,测定了低浓度下胆固醇和24-去氢胆固醇在甲醇中的吸附平衡常数为10.02和7.86;然后基于微分传质方程的通用多组分速率模型,在Matlab~(?)境下根据有限元正交配置法编制程序求得数值解,继而进行模拟移动床的过程仿真。再参照模拟移动床的计算结果,在实际模拟移动床分离过程中以纯度、生产率和溶剂消耗量为指标,考察了模拟移动床的切换时间、进料流量和进料浓度等因素对分离过程的影响,确定SMB的实验最佳操作条件为:柱温35℃,切换时间为9min,四区流量Q_1为6.5ml/min,Q_2为4.4ml/min,Q_3为4.65ml/min,Q_4为3.0ml/min,进料总浓度2.5mg/ml,经过8周期后,成功地分离了胆固醇和24-去氢胆固醇,相对纯度达到100%和98.5%。
Introduced by Broughton and Gerhold in the early 1960s,the Simulated Moving Bed (SMB) appeared predominantly in large scale separations in the petrochemical industry without any attention from fine chemical industry.This changed 15 years ago, when SMB was introduced as a novel technique to separate racemates in early drug development.The role of SMB in pharmaceutical industry has changed dramatically since then.Although SMB is now on its way from an emerging technology to a classical unit operation,the greatest task for the future will be to show that SMB technology is not a sophisticated,technically demanding and unreliable method for separating racemates,but an easy to master tool that can be applied both in early development and in scale-up production.
This paper took cholesterol and desmosterol,valuable resources of intermediate for steroids,as study object.The adsorption equilibrium constants of desmosterol and cholesterol were determined as 7.86 and 10.02,respectively,by separating of cholesterol and desmosterol with fixed-bed chromatography.The porosity of chromatograhy columns was 0.68.With these parameters,the region leading to complete separation predicted by triangle theory was able to be drawed out for the choosing of the initiative operating variables.
A general multicomponents rate model based on differential mass balance equations is adopted for simulating SMB.According to the outlined numerical solution,results of the simulation program in MATLAB~((?)) are shown.
Separation of desmosterol from cholesterol by SMB was simulated.The effects of flow rate in section 2(Q_2) and 3(Q_3),switching time,feed flow rate and feed concentration were studied on the operating performance parameters as purity, recovery,productivity and desorbent consumption.And Operating conditions leading to more than 90%purity in both outlet streams had been identified,together with those achieving optimal performance.Comparison between the results of simulations and the experimentation indicates that the present model describes very well the dynamic behavior of the systems under study.
A simple optimization procedure was runned for the choosing the optimal SMB operatingg conditions.Under temperature column of 35℃,switch time 9min,with flow rate of Q_1=6.5ml/min,Q_2=4.4ml/min for,Q_3=4.65ml/min,Q_4=3.0ml/min, cholesterol and desmosterol are separated completely.
引文
[1]陈远飞,胆固醇.生物学通报,1992(4).11-12
[2]谭兰兰,羊毛脂皂化及其胆甾醇提取的工艺研究.四川大学硕士学位论文,2002年5月
[3]陈小利,林苗,胡杰等,进一步开发羊毛脂.化学世界,2000,(1):8-12
[4]刘莉莉,羊毛脂及其衍生物.四川日化,1994,(1):52-54
[5]B.Sion,G.Grizard,D.Boucher.Quantitative analysis of desmosterol,cholesterol and cholesterol sulfate in semen by high-performance liquid chromatography.Journal of Chromatography A,935,2001,259-265
[6]Don.S.Lin,William E.Connor Don P.Wolf,Martha Neuringer,David L.Hachey.Unique lipids of primate spermatozoa:desmosterol and docosahexaenoic acid.Journal of Lipid Research Vol 34,491-499
[7]伊海雄 编译,一种指示药物控制野生生物节育效果的生物标记物:24-去氢胆固醇,世界农药第二十五卷第四期 200325-28
[8]William E.Connor,Don s.Lin,Martha Neuringer.Biochemical Markers for Puberty in the Monkey Testis:Desmosterol and Docosahexaenoic Acid Journal of Clinical Endocrinology and Metabolism Vol.82,No.6 1911-1916
[9]宁正祥主编,食品成分分析手册[M].北京:中国轻工业出版社,1998,174-177
[10]宋国艾,杨根源等,化妆品原料技术规格[M].北京:中国轻工业出版社,2000:930
[11]Feliks Modrzejiwski,Maria Kwiatkowska.Ann.Acad.Med.Lodz.1971,(12):373-377
[12]中华人民共和国国家标准汇编,GB/T,9695,24-1990,北京:中国标准出版社,1992
[13]中国光学学会光谱专业委员会,AOAC(美国公职分析家协会)分析方法手册.北京:中国光学学会光谱专业委员会,1986:931-932,938
[14]周同惠,国际标准常规分析方法大全[M].北京:科学出版社,1998:849,857-859
[15]黄岛平,陈建红等,HPLC紫外检测器测定出口月饼中的胆固醇.光谱实验室,2001,18(4):499-501
[16]Elizabeth Hansbury and Terence J.Scallen.Resolution of desmosterol,cholesterol,and other sterol intermediates by reverse-phase highpressure liquid chromatography.Journal of Lipid Research,Vol 19,1978
[17]B.Sion,G.Grizard,D.Boucher.Quantitative analysis of desmosterol,cholesterol and cholesterol sulfate in semen by high-performance liquid chromatography.Journal of Chromatography A,935,2001,259-265
[18]Gale,Douglas J.;Logan,Raymond I.;Rivett,Donald E.Detection of desmosterol in the internal lipids of wool fibers.Textile Research Journal,1987,57(9),539-42.
[19]Jyh-Horng Sheu,Shiang-Yuh Huang,Chang-Yih.Duh Cytotoxic Oxygenated Desmosterols of the Red Alga Galaxaura marginata Journal of Nature Products.1996,59,23-26
[20]M.Thomas Njimi,George Charles,Cameroun,Method for preparing Desmosterol.US Patent 3803184A1,1974
[21]Staat Kamerum,Verfahren zur Herstellung von Desmosterol.DE Patent 2236930A1,1973
[22]Nobuo,Ikekawa,Masuo Morisaki,Process for the preparation of 25-hydroxy-cholesterol and esters thereof.US Patent 3846455,1974
[23]Ikekawa,Nobuo;Morisaki,Masuo;Lightbourn,Julieta R.Preparation of 25-hydroxycholesterol and esters thereof.US Patent 3868396,1975
[24]方煜宇,模拟移动床连续离交分离L_缬氨酸,南京工业大学硕士学位论文.(2005.6)
[25]Donald.B.Broughton,Clarence.G.Gerhold,Continuous sorption process employing fixed bed of sorbent and moving inlets and outlets.US Patent 2985589.(May 23,1961).
[26]UOP.LLC,Understanding the SorbexTM Process.http://www.uop.com/aromatics/3060.html/.2006
[27]FDA's Policy Statement on the Development of New Stereoisomeric Drugs (Stereoisomeric Drug Policy) Fed.Regist.(1992) 57 FR22249.
[28]S.R.Pen-in,R.M.Nicoud,Charpter10,The Use of SMB for the Manufacture of Enantiopure Drug Substances:From Principle to cGMP Compliance.G.Subramanian,Chiral Separation Techniques:A Practical Approach,Second edition,Wiley-VCH,(2001)
[29]Martin and Kuhn,Ztschr.elektrokem.,bd.47,no 3,(1941).
[30] R.M. Nicoud, G. Fuchs, P. Adam, M. Bailly, E. Kusters, F. Antia, R. Reuille, E. Schmid,Chirality 5, 267 (1993).
[31 ] R.M. Nicoud, M. Bailly, J.N. Kinkel, R. Devant, T. Hampe, E. Kusters, in: R.M. Nicoud (Ed.),Simulated Moving Beds -Basics and Applications, INPL, Nancy, p. 65, (1993)
[32] J. Blehaut, F. Charton, R.M. Nicoud, LC-GC Int. 9, 228 (1996).
[33] M. Negawa, F. Shoji, Journal of Chromatography. 590, 113 (1992).
[34] C.B. Ching, B.G. Lin, E.J.D. Lee, S.C. Ng, Journal of Chromatography. 634, 215 (1993)
[35] E. Kusters, G Gerber, F. Antia, Chromatographia 40, 387 (1995).
[36] E. Francotte, P. Richert, Journal of Chromatography. 769, 101 (1997).
[37] E. Francotte, presented at Analytica-Conference, Munich (1996).
[38] M. Schulte, R. Ditz, R.M. Devant, J.N. Kinkel, F. Charton, Journal of Chromatography. 769, 93 (1997).
[39] D. Seebach, M. Hoffmann, A. Sting, J.N. Kinkel, M. Schulte, E. Kusters, Journal of Chromatography. 796,299 (1998).
[40] M. Gattuso, B. McCulloch, D.W. House,W.M. Baumann, in: Proceedings of Chiral USA '95,1995.
[41] J. Strube, A. Jupke, A. Epping, H. Schmidt-Traub, M. Schulte, R.M. Devant, Chirality 11, 440(1999).
[42] D. Guest, Journal of Chromatography. 760, 159 (1997)
[43] E. Cavoy, M.F. Deltent, S. Lehouq, D. Miggiano, Laboratory-developed simulated moving bed for chiral drug separations Design of the system and separation of Tramadol enantiomers Journal of Chromatography. 769, 49 (1997).
[44] U. Voigt, R. Hempel, J.N. Kinkel, R.M. Nicoud, WO Pat.97/34018 (1997).
[45] S. Nagamatsu, K. Murazumi, S. Makino,Chiral separation of a pharmaceutical intermediate by a simulated moving bed process Journal of Chromatography. 832, 55 (1999).
[46] M. Schulte, R. Devant, German Pat. Appl. P 199 31 755.0 (1999).
[47] O. Reiser, Ch. Bubert, R. Beumer, P. Kreitmeier, M. Schulte, A. Meudt, German Pat. Appl.P19858 893.3(1998).
[48]G.Jordan,Diploma Thesis,Georg-Simon-Ohm FH Numberg,(1999).
[49]L.S.Pais,J.M.Loureiro,A.E.Rodrigues,Journal of Chromatogr.A 827,215(1998).
[50]林炳昌,模拟移动床技术在中药有效成分分离中的应用,精细化工,22(2),110-112(2005).
[51]D.-J.Wu,Y.Xie,Z,Ma,N.-H.L.Wang,Design of simulated moving bed chromatography for amino acid separations.Ind.Eng.Chem.Res.37,4023-4035(1998).
[52]Gottschlich N,Kasche V.J ChromatogrA.765,201(1997).
[53]Markus Juza,Orazio Di Giovanni,Giovanni Biressi,Volker Schurig,Marco Mazzotti,,Massimo Morbidelli,Continuous enantiomer separation of the volatile inhalation anesthetic enflurane with a gas chromatographic simulated moving bed unit.Journal of chromatography A.813,333-347
[54]Andreev B M,Kruglov A V,Selivanenko Y L.Sep Sci Technol.30(3),211(1995).
[55]Kruglov A V,Andreev B M,Pojidaev Y E.Sep Sci Technol.31,471(1996).
[56]Depta A,Gies T e,Johannsen W.,Separation of steroisomers in a simulated moving bed-supercritical fluid chromatography plant.Journal of chromatography A..865,175(1999).
[57]Houwing J,Billiet H A H,van der Wielen L A M.Journal of chromatography A.944,189(2002).
[58]Stefanie Abel and Markus Juza,Less Common Applications of Enantioselective HPLC Using the SMB Technology in the Pharmaceutical Industry,Chiral Separation Techniques.Third Edition.Edited by G.Subramanian,2007 WILEY-VCH
[59]P.R.Adam,M.Nicoud,M.Bailly,Ludemann-Hombourger,Process and device for separation with variable-length,US Patent 6136198,2000.
[60]Ludemman-Hombouger,R.Nicoud,M.Bailly,Sep.Sci.Technol.2000,35,1829-1862.
[61]M.Morbidelli,M.Mazzotti,presented at PREP,15th International Symposium,Exhibit Workshops on Preparative/Process Chromatography Ion Exchange,Adsorption/Desorption Processes and Related Separation Techniques,Washington DC,USA,2002,Lecture 201,53-54.
[62] Z. Zhang, M. Mazzotti, M. Morbidelli, PowerFeed operation of simulated moving bed units: changing flow-rates during the switching interval Journal of Chromatography A ,2003, 1006, 87-99.
[63] H. Schramm, M. Kaspereit, A. Kienle, A.Seidel-Morgenstern, Chem. Eng. Tech. 2002, 25 1151-1155.
[64] H. Schramm, M. Kaspereit, A. Kienle, A.Seidel-Morgenstern, Simulated moving bed process with cyclic modulation of the feed concentration Journal of Chromatography A.2003, 1006, 77-86.
[65] Florian Lode,A New Reaction-Separation Unit:The Simulated Moving Bed Reactor[J].Chimia 55(2001)883-886
[66] Mazzotti Marco, Kruglov Alexey, Neri Bernardo, Chemical Engineering Science. 51,1827-1836(1996).
[67] Frederic Charton, Roger-Marc Nicoud,Complete design of a simulated moving bed. Journal of Chromatography A, May 1995, 702, 1-2, 19 ,97-112
[68] Douglas M.Ruthven, Principles of Adsorption and Adsorption Processes. Wiley, NewYork 1984
[69] Giuseppe Storti, Marco Mazzotti, Massimo Morbidelli, Sergio Card, Robust design of binary countercurrent adsorption separation processes 1. AlChE Journal March 1993 /Vol. 39, No. 3,471-492
[70] Marco Mazzotti, Giuseppe Storti, Massimo Morbidelli, Robust design of countercurrent adsorption separation processes 2 Multicomponent systems. AIChE Journal November 1994, Vol. 40, No. 11,1825-1842
[71] Marco Mazzotti, Giuseppe Storti, Massimo Morbidelli, Robust design of countercurrent adsorption separation 3. Nonstoichiometric systems. AlChE Journal October 1996,Vol. 42, No. 10, 2784-2796
[72] Marco Mazzotti, Giuseppe Storti, Massimo Morbidelli, Robust design of countercurrent adsorption separation processes 4. Desorbent in the feed. AlChE Journal, Januray 1997, Vol. 43, No. 1, 64-72
[73] Giuseppe Storti, Marco Mazzotti, Massimo Morbidelli, Optimal operation of simulated moving bed units for nonlinear chromatographic separations. Journal of Chromatography A, 1997,769,3-24
[74] Marco Mazzotti, Equilibrium theory based design of simulated moving bed processes for a generalized Langmuir isotherm.
Journal of Chromatography A,2006,1126 ,311-322
[75] Malte Kaspereit, Pavel Jandera, Michal S(?)kavrada, Andreas Seidel-Morgenstern,Impact of adsorption isotherm parameters on the performance of enantioseparation using simulated moving bed chromatography. Journal of Chromatography A, 944 (2002) 249-262
[76] Giovanni Biressi,Olivier Ludenmann-Hombourger, Marco Mazzotti, Roger-Marc Nicoud,Massimo Morbidelli.Design and optimisation of a simulated moving bed unit: role of deviations frome equilibrium theory. Journal of Chromatography A, 2000,876,3-15
[77] Douglas M.Ruthven, C.B.Ching, Counter-current and simulated counter-current adsorption seperation process,Chemical Engineering Science, 1989,44,1011-1038
[78] Z.Ma,H.-H.Wang, Standing wave analysis of SMB chromatography.linear systems. AICHE Journal,1997,43,2488-2508
[79] Yi Xie,Sungyong Mun, Jinhyun Kim, N,-H.L.Wang, Standing wave design and experimental validation of a tandem simulated moving bed process for insulin purification. Biotechnol.2002,Prog.l8,1332-1344
[80] Schmidt-Traub H, Strube J. Dynamic Simulation of Simulated-Moving-Bed Chromatographic Processes. Computers chem. Engng ,1996,20:S641
[81] Luis S.PaisJose M.Loureiro,Alirio E.Rodrigues, Modeling strategies for enantiomers seperation by SMB chromatography. AlChE Journal. 1998,44,561-569
[82] Mirjana Minceva, Luis S.PaisJose M.Loureiro,Alirio E.Rodrigues, Cyclic steady state of simulated moving bed processes for enatiomers seperation.Chemical Engineering and Processing.2003,42,93-104
[83] Cesar Lazo, Simulation of Liquid Chromatography andSimulated Moving Bed (SMB) Systems,1999
[84]Tingyue.Gu,G.-J.Tsai.,G.T.Tsa,Modeling of Nonlinear Multicomponent Chromatography.Advances in Biochemical Enginaring,Biotcchnology.1993,Vol.49
[85]厉苏州,徐玲,彭奇均,基于Matlab的SMB色谱分离过程计算机仿真研究.计算机与应用化学.2004.5,Vol.21,No.3
[86]李娟,分子筛脱蜡模拟移动床工业过程的模拟计算与分析,南京工业大学硕士学位论文.2005.1
[87]吕裕斌,模拟移动床分离天然产物的研究,浙江大学博士论文.2006.4
[88]蔡宇杰,丁彦蕊,石贵阳,张大兵,须文波,非线性模拟移动床色谱的浮点编码遗传算法优化策略,计算机与应用化学,2004,Vol 21,No.6
[89]吴献东,模拟移动床分离过程的建模与优化研究,浙江大学硕士学位论文.2006.
[90]Z.Zhang,M.Mazzotti,M.Morbidelli,Multiobjective optimization of simulated moving bed and Varicol processes using a genetic algorithm Journal of Chromatography A,989(2003) 95-108.
[91]Schiesser WE.Computational Mathematics in Engineering and Applied Science.CRC Press,Boca Raton(1994)
[92]Bruce.A.Finlayson,Nonlinear Analysis in Chemical Engineering.McGraw-Hill,NewYork(1980)
[2]谭兰兰,羊毛脂皂化及其胆甾醇提取的工艺研究.四川大学硕士学位论文,2002年5月
[3]陈小利,林苗,胡杰等,进一步开发羊毛脂.化学世界,2000,(1):8-12
[4]刘莉莉,羊毛脂及其衍生物.四川日化,1994,(1):52-54
[5]B.Sion,G.Grizard,D.Boucher.Quantitative analysis of desmosterol,cholesterol and cholesterol sulfate in semen by high-performance liquid chromatography.Journal of Chromatography A,935,2001,259-265
[6]Don.S.Lin,William E.Connor Don P.Wolf,Martha Neuringer,David L.Hachey.Unique lipids of primate spermatozoa:desmosterol and docosahexaenoic acid.Journal of Lipid Research Vol 34,491-499
[7]伊海雄 编译,一种指示药物控制野生生物节育效果的生物标记物:24-去氢胆固醇,世界农药第二十五卷第四期 200325-28
[8]William E.Connor,Don s.Lin,Martha Neuringer.Biochemical Markers for Puberty in the Monkey Testis:Desmosterol and Docosahexaenoic Acid Journal of Clinical Endocrinology and Metabolism Vol.82,No.6 1911-1916
[9]宁正祥主编,食品成分分析手册[M].北京:中国轻工业出版社,1998,174-177
[10]宋国艾,杨根源等,化妆品原料技术规格[M].北京:中国轻工业出版社,2000:930
[11]Feliks Modrzejiwski,Maria Kwiatkowska.Ann.Acad.Med.Lodz.1971,(12):373-377
[12]中华人民共和国国家标准汇编,GB/T,9695,24-1990,北京:中国标准出版社,1992
[13]中国光学学会光谱专业委员会,AOAC(美国公职分析家协会)分析方法手册.北京:中国光学学会光谱专业委员会,1986:931-932,938
[14]周同惠,国际标准常规分析方法大全[M].北京:科学出版社,1998:849,857-859
[15]黄岛平,陈建红等,HPLC紫外检测器测定出口月饼中的胆固醇.光谱实验室,2001,18(4):499-501
[16]Elizabeth Hansbury and Terence J.Scallen.Resolution of desmosterol,cholesterol,and other sterol intermediates by reverse-phase highpressure liquid chromatography.Journal of Lipid Research,Vol 19,1978
[17]B.Sion,G.Grizard,D.Boucher.Quantitative analysis of desmosterol,cholesterol and cholesterol sulfate in semen by high-performance liquid chromatography.Journal of Chromatography A,935,2001,259-265
[18]Gale,Douglas J.;Logan,Raymond I.;Rivett,Donald E.Detection of desmosterol in the internal lipids of wool fibers.Textile Research Journal,1987,57(9),539-42.
[19]Jyh-Horng Sheu,Shiang-Yuh Huang,Chang-Yih.Duh Cytotoxic Oxygenated Desmosterols of the Red Alga Galaxaura marginata Journal of Nature Products.1996,59,23-26
[20]M.Thomas Njimi,George Charles,Cameroun,Method for preparing Desmosterol.US Patent 3803184A1,1974
[21]Staat Kamerum,Verfahren zur Herstellung von Desmosterol.DE Patent 2236930A1,1973
[22]Nobuo,Ikekawa,Masuo Morisaki,Process for the preparation of 25-hydroxy-cholesterol and esters thereof.US Patent 3846455,1974
[23]Ikekawa,Nobuo;Morisaki,Masuo;Lightbourn,Julieta R.Preparation of 25-hydroxycholesterol and esters thereof.US Patent 3868396,1975
[24]方煜宇,模拟移动床连续离交分离L_缬氨酸,南京工业大学硕士学位论文.(2005.6)
[25]Donald.B.Broughton,Clarence.G.Gerhold,Continuous sorption process employing fixed bed of sorbent and moving inlets and outlets.US Patent 2985589.(May 23,1961).
[26]UOP.LLC,Understanding the SorbexTM Process.http://www.uop.com/aromatics/3060.html/.2006
[27]FDA's Policy Statement on the Development of New Stereoisomeric Drugs (Stereoisomeric Drug Policy) Fed.Regist.(1992) 57 FR22249.
[28]S.R.Pen-in,R.M.Nicoud,Charpter10,The Use of SMB for the Manufacture of Enantiopure Drug Substances:From Principle to cGMP Compliance.G.Subramanian,Chiral Separation Techniques:A Practical Approach,Second edition,Wiley-VCH,(2001)
[29]Martin and Kuhn,Ztschr.elektrokem.,bd.47,no 3,(1941).
[30] R.M. Nicoud, G. Fuchs, P. Adam, M. Bailly, E. Kusters, F. Antia, R. Reuille, E. Schmid,Chirality 5, 267 (1993).
[31 ] R.M. Nicoud, M. Bailly, J.N. Kinkel, R. Devant, T. Hampe, E. Kusters, in: R.M. Nicoud (Ed.),Simulated Moving Beds -Basics and Applications, INPL, Nancy, p. 65, (1993)
[32] J. Blehaut, F. Charton, R.M. Nicoud, LC-GC Int. 9, 228 (1996).
[33] M. Negawa, F. Shoji, Journal of Chromatography. 590, 113 (1992).
[34] C.B. Ching, B.G. Lin, E.J.D. Lee, S.C. Ng, Journal of Chromatography. 634, 215 (1993)
[35] E. Kusters, G Gerber, F. Antia, Chromatographia 40, 387 (1995).
[36] E. Francotte, P. Richert, Journal of Chromatography. 769, 101 (1997).
[37] E. Francotte, presented at Analytica-Conference, Munich (1996).
[38] M. Schulte, R. Ditz, R.M. Devant, J.N. Kinkel, F. Charton, Journal of Chromatography. 769, 93 (1997).
[39] D. Seebach, M. Hoffmann, A. Sting, J.N. Kinkel, M. Schulte, E. Kusters, Journal of Chromatography. 796,299 (1998).
[40] M. Gattuso, B. McCulloch, D.W. House,W.M. Baumann, in: Proceedings of Chiral USA '95,1995.
[41] J. Strube, A. Jupke, A. Epping, H. Schmidt-Traub, M. Schulte, R.M. Devant, Chirality 11, 440(1999).
[42] D. Guest, Journal of Chromatography. 760, 159 (1997)
[43] E. Cavoy, M.F. Deltent, S. Lehouq, D. Miggiano, Laboratory-developed simulated moving bed for chiral drug separations Design of the system and separation of Tramadol enantiomers Journal of Chromatography. 769, 49 (1997).
[44] U. Voigt, R. Hempel, J.N. Kinkel, R.M. Nicoud, WO Pat.97/34018 (1997).
[45] S. Nagamatsu, K. Murazumi, S. Makino,Chiral separation of a pharmaceutical intermediate by a simulated moving bed process Journal of Chromatography. 832, 55 (1999).
[46] M. Schulte, R. Devant, German Pat. Appl. P 199 31 755.0 (1999).
[47] O. Reiser, Ch. Bubert, R. Beumer, P. Kreitmeier, M. Schulte, A. Meudt, German Pat. Appl.P19858 893.3(1998).
[48]G.Jordan,Diploma Thesis,Georg-Simon-Ohm FH Numberg,(1999).
[49]L.S.Pais,J.M.Loureiro,A.E.Rodrigues,Journal of Chromatogr.A 827,215(1998).
[50]林炳昌,模拟移动床技术在中药有效成分分离中的应用,精细化工,22(2),110-112(2005).
[51]D.-J.Wu,Y.Xie,Z,Ma,N.-H.L.Wang,Design of simulated moving bed chromatography for amino acid separations.Ind.Eng.Chem.Res.37,4023-4035(1998).
[52]Gottschlich N,Kasche V.J ChromatogrA.765,201(1997).
[53]Markus Juza,Orazio Di Giovanni,Giovanni Biressi,Volker Schurig,Marco Mazzotti,,Massimo Morbidelli,Continuous enantiomer separation of the volatile inhalation anesthetic enflurane with a gas chromatographic simulated moving bed unit.Journal of chromatography A.813,333-347
[54]Andreev B M,Kruglov A V,Selivanenko Y L.Sep Sci Technol.30(3),211(1995).
[55]Kruglov A V,Andreev B M,Pojidaev Y E.Sep Sci Technol.31,471(1996).
[56]Depta A,Gies T e,Johannsen W.,Separation of steroisomers in a simulated moving bed-supercritical fluid chromatography plant.Journal of chromatography A..865,175(1999).
[57]Houwing J,Billiet H A H,van der Wielen L A M.Journal of chromatography A.944,189(2002).
[58]Stefanie Abel and Markus Juza,Less Common Applications of Enantioselective HPLC Using the SMB Technology in the Pharmaceutical Industry,Chiral Separation Techniques.Third Edition.Edited by G.Subramanian,2007 WILEY-VCH
[59]P.R.Adam,M.Nicoud,M.Bailly,Ludemann-Hombourger,Process and device for separation with variable-length,US Patent 6136198,2000.
[60]Ludemman-Hombouger,R.Nicoud,M.Bailly,Sep.Sci.Technol.2000,35,1829-1862.
[61]M.Morbidelli,M.Mazzotti,presented at PREP,15th International Symposium,Exhibit Workshops on Preparative/Process Chromatography Ion Exchange,Adsorption/Desorption Processes and Related Separation Techniques,Washington DC,USA,2002,Lecture 201,53-54.
[62] Z. Zhang, M. Mazzotti, M. Morbidelli, PowerFeed operation of simulated moving bed units: changing flow-rates during the switching interval Journal of Chromatography A ,2003, 1006, 87-99.
[63] H. Schramm, M. Kaspereit, A. Kienle, A.Seidel-Morgenstern, Chem. Eng. Tech. 2002, 25 1151-1155.
[64] H. Schramm, M. Kaspereit, A. Kienle, A.Seidel-Morgenstern, Simulated moving bed process with cyclic modulation of the feed concentration Journal of Chromatography A.2003, 1006, 77-86.
[65] Florian Lode,A New Reaction-Separation Unit:The Simulated Moving Bed Reactor[J].Chimia 55(2001)883-886
[66] Mazzotti Marco, Kruglov Alexey, Neri Bernardo, Chemical Engineering Science. 51,1827-1836(1996).
[67] Frederic Charton, Roger-Marc Nicoud,Complete design of a simulated moving bed. Journal of Chromatography A, May 1995, 702, 1-2, 19 ,97-112
[68] Douglas M.Ruthven, Principles of Adsorption and Adsorption Processes. Wiley, NewYork 1984
[69] Giuseppe Storti, Marco Mazzotti, Massimo Morbidelli, Sergio Card, Robust design of binary countercurrent adsorption separation processes 1. AlChE Journal March 1993 /Vol. 39, No. 3,471-492
[70] Marco Mazzotti, Giuseppe Storti, Massimo Morbidelli, Robust design of countercurrent adsorption separation processes 2 Multicomponent systems. AIChE Journal November 1994, Vol. 40, No. 11,1825-1842
[71] Marco Mazzotti, Giuseppe Storti, Massimo Morbidelli, Robust design of countercurrent adsorption separation 3. Nonstoichiometric systems. AlChE Journal October 1996,Vol. 42, No. 10, 2784-2796
[72] Marco Mazzotti, Giuseppe Storti, Massimo Morbidelli, Robust design of countercurrent adsorption separation processes 4. Desorbent in the feed. AlChE Journal, Januray 1997, Vol. 43, No. 1, 64-72
[73] Giuseppe Storti, Marco Mazzotti, Massimo Morbidelli, Optimal operation of simulated moving bed units for nonlinear chromatographic separations. Journal of Chromatography A, 1997,769,3-24
[74] Marco Mazzotti, Equilibrium theory based design of simulated moving bed processes for a generalized Langmuir isotherm.
Journal of Chromatography A,2006,1126 ,311-322
[75] Malte Kaspereit, Pavel Jandera, Michal S(?)kavrada, Andreas Seidel-Morgenstern,Impact of adsorption isotherm parameters on the performance of enantioseparation using simulated moving bed chromatography. Journal of Chromatography A, 944 (2002) 249-262
[76] Giovanni Biressi,Olivier Ludenmann-Hombourger, Marco Mazzotti, Roger-Marc Nicoud,Massimo Morbidelli.Design and optimisation of a simulated moving bed unit: role of deviations frome equilibrium theory. Journal of Chromatography A, 2000,876,3-15
[77] Douglas M.Ruthven, C.B.Ching, Counter-current and simulated counter-current adsorption seperation process,Chemical Engineering Science, 1989,44,1011-1038
[78] Z.Ma,H.-H.Wang, Standing wave analysis of SMB chromatography.linear systems. AICHE Journal,1997,43,2488-2508
[79] Yi Xie,Sungyong Mun, Jinhyun Kim, N,-H.L.Wang, Standing wave design and experimental validation of a tandem simulated moving bed process for insulin purification. Biotechnol.2002,Prog.l8,1332-1344
[80] Schmidt-Traub H, Strube J. Dynamic Simulation of Simulated-Moving-Bed Chromatographic Processes. Computers chem. Engng ,1996,20:S641
[81] Luis S.PaisJose M.Loureiro,Alirio E.Rodrigues, Modeling strategies for enantiomers seperation by SMB chromatography. AlChE Journal. 1998,44,561-569
[82] Mirjana Minceva, Luis S.PaisJose M.Loureiro,Alirio E.Rodrigues, Cyclic steady state of simulated moving bed processes for enatiomers seperation.Chemical Engineering and Processing.2003,42,93-104
[83] Cesar Lazo, Simulation of Liquid Chromatography andSimulated Moving Bed (SMB) Systems,1999
[84]Tingyue.Gu,G.-J.Tsai.,G.T.Tsa,Modeling of Nonlinear Multicomponent Chromatography.Advances in Biochemical Enginaring,Biotcchnology.1993,Vol.49
[85]厉苏州,徐玲,彭奇均,基于Matlab的SMB色谱分离过程计算机仿真研究.计算机与应用化学.2004.5,Vol.21,No.3
[86]李娟,分子筛脱蜡模拟移动床工业过程的模拟计算与分析,南京工业大学硕士学位论文.2005.1
[87]吕裕斌,模拟移动床分离天然产物的研究,浙江大学博士论文.2006.4
[88]蔡宇杰,丁彦蕊,石贵阳,张大兵,须文波,非线性模拟移动床色谱的浮点编码遗传算法优化策略,计算机与应用化学,2004,Vol 21,No.6
[89]吴献东,模拟移动床分离过程的建模与优化研究,浙江大学硕士学位论文.2006.
[90]Z.Zhang,M.Mazzotti,M.Morbidelli,Multiobjective optimization of simulated moving bed and Varicol processes using a genetic algorithm Journal of Chromatography A,989(2003) 95-108.
[91]Schiesser WE.Computational Mathematics in Engineering and Applied Science.CRC Press,Boca Raton(1994)
[92]Bruce.A.Finlayson,Nonlinear Analysis in Chemical Engineering.McGraw-Hill,NewYork(1980)