头孢曲松钠结晶过程研究
|
摘要
头孢曲松钠（Ceftriaxone Sodium）是第三代头孢菌素中具有长效作用的抗生素。随着头孢曲松钠在国内抗感染药物市场上地位的提高，对于其质量提出了更高的要求。采用溶析结晶工艺，对头孢曲松钠进行精制分离，可以明显的提高其质量。因此，本文对头孢曲松钠在水—丙酮体系中的溶析结晶过程进行了较为系统的研究，其中包括结晶热力学、结晶动力学、结晶工艺过程三个方面。
利用失重法测定了不同温度下，头孢曲松钠在水—丙酮体系中的溶解度,用λh方程回归了上述溶解度数据，回归出的计算值和实验值相比较，吻合较好。利用激光法，测定了不同温度下头孢曲松钠在水—丙酮体系中的超溶解度，从而获得了头孢曲松钠在水—丙酮体系中的介稳区数据。并采用DSC测量了头孢曲松钠的脱水温度、熔化分解温度和熔化热。以上基础数据为结晶器的设计提供了操作依据。
结晶动力学数据是结晶器设计的重要参数。本文通过对头孢曲松钠的结晶工艺分析，对粒数衡算模型进行简化，对于具有聚结和破碎的头孢曲松钠的溶析结晶过程，采用生死函数法建立的聚结－破碎粒数衡算模型，采用间歇动态法中的矩量变换法，对动力学进行研究。在此基础上对实验数据按最小二乘法进行多元线性回归得到了头孢曲松钠结晶的动力学方程参数，为过程模拟和工艺放大提供了可靠的实验依据和理论基础。
在热力学、动力学研究的基础上，依据收率、粒度分布和电镜照片等指标，结合一定的对比实验，对结晶工艺过程中的溶析剂、晶种的加入、溶析剂的加入速率、搅拌速率以及结晶温度、养晶时间等进行了优化，得到了较佳的工艺条件。
Ceftriaxone Sodium is the tertiary cephalosporin antibiotics. The quality of Ceftriaxone Sodium needs to be improved because the role of Ceftriaxone Sodium is important in the resisting infection market. Ceftriaxone Sodium is refined through solventing-out crystallization processes in order to improve its quality. Therefore, the solventing-out crysallization of Ceftriaxone Sodium was studied systematically both in experiment and theory, including crystallization thermodynamics, crystallization kinetics and crystallization process.
The crystallization thermodynamics of Ceftriaxone Sodium were studied.The λh equation of solubility of Ceftriaxone Sodium had been founded on experiment data.and the solubility of Ceftriaxone Sodium in acetone-water solvent in different temperature were measured by using gravimetric method. The metastable zone for crystallization of Ceftriaxone Sodium in acetone-water solvent in different temperature was studied by laser method. The dehydrate temperature, decomposition temperature were measured by the instrument named DSC204.
Crystallization kinetics are the basic for crystallization behavior and crystallizer design.Estimating kinetics parameters is essentially important in the study on industrial crystallization process. The kinetics of Ceftriaxone Sodium were studied in batch MSMPR crystallizer. The nucleation and growth rate equation of Ceftriaxone Sodium have been determined by simulation the crystallization processes model which is a simplified population model including Birth and Death function.With the moment transformation method and the least square method for the multivariate linear regression, the kinetic parameters under the experimental conditions were obtained. Based on the the above study and experiment data, the optimum process and the operation schedule have been obtained.
利用失重法测定了不同温度下，头孢曲松钠在水—丙酮体系中的溶解度,用λh方程回归了上述溶解度数据，回归出的计算值和实验值相比较，吻合较好。利用激光法，测定了不同温度下头孢曲松钠在水—丙酮体系中的超溶解度，从而获得了头孢曲松钠在水—丙酮体系中的介稳区数据。并采用DSC测量了头孢曲松钠的脱水温度、熔化分解温度和熔化热。以上基础数据为结晶器的设计提供了操作依据。
结晶动力学数据是结晶器设计的重要参数。本文通过对头孢曲松钠的结晶工艺分析，对粒数衡算模型进行简化，对于具有聚结和破碎的头孢曲松钠的溶析结晶过程，采用生死函数法建立的聚结－破碎粒数衡算模型，采用间歇动态法中的矩量变换法，对动力学进行研究。在此基础上对实验数据按最小二乘法进行多元线性回归得到了头孢曲松钠结晶的动力学方程参数，为过程模拟和工艺放大提供了可靠的实验依据和理论基础。
在热力学、动力学研究的基础上，依据收率、粒度分布和电镜照片等指标，结合一定的对比实验，对结晶工艺过程中的溶析剂、晶种的加入、溶析剂的加入速率、搅拌速率以及结晶温度、养晶时间等进行了优化，得到了较佳的工艺条件。
Ceftriaxone Sodium is the tertiary cephalosporin antibiotics. The quality of Ceftriaxone Sodium needs to be improved because the role of Ceftriaxone Sodium is important in the resisting infection market. Ceftriaxone Sodium is refined through solventing-out crystallization processes in order to improve its quality. Therefore, the solventing-out crysallization of Ceftriaxone Sodium was studied systematically both in experiment and theory, including crystallization thermodynamics, crystallization kinetics and crystallization process.
The crystallization thermodynamics of Ceftriaxone Sodium were studied.The λh equation of solubility of Ceftriaxone Sodium had been founded on experiment data.and the solubility of Ceftriaxone Sodium in acetone-water solvent in different temperature were measured by using gravimetric method. The metastable zone for crystallization of Ceftriaxone Sodium in acetone-water solvent in different temperature was studied by laser method. The dehydrate temperature, decomposition temperature were measured by the instrument named DSC204.
Crystallization kinetics are the basic for crystallization behavior and crystallizer design.Estimating kinetics parameters is essentially important in the study on industrial crystallization process. The kinetics of Ceftriaxone Sodium were studied in batch MSMPR crystallizer. The nucleation and growth rate equation of Ceftriaxone Sodium have been determined by simulation the crystallization processes model which is a simplified population model including Birth and Death function.With the moment transformation method and the least square method for the multivariate linear regression, the kinetic parameters under the experimental conditions were obtained. Based on the the above study and experiment data, the optimum process and the operation schedule have been obtained.
引文
[1]王静康,化学工程手册(结晶),北京:化学工业出版社,1996
[2]丁绪淮,谈 遒,工业结晶,北京:化学工业出版社,1985
[3]Mullin J W, Crystallization 2nd Ed, London: butterworths, 1993
[4]国家药典委员会,中华人民共和国药典2000年版,北京：化学工业出版社，2000
[5]Authority of the United States Pharmacopoeia Convention, The United States Pharmacopoeia, US: Pharmacopoeia convention, Inc. Twin brook parkway, Rockville,MD,20852,2000
[6]涂林,余方键,国产注射用头孢曲松钠的质量现状,中国药事,2002, 16(1):45～46
[7]Monguzzi，Riccardo,Improved process for the preparation of Ceftriaxone, EP:0399094,1990-11-28
[8]赵茜,高大维等,红霉素溶析结晶过程中原溶剂对其晶习及纯度的影响研,中国抗生素杂志,1999,24（6）:410～414
[9]李绍芬,反应工程,北京:化学工业出版社,1989
[10]杨冰,实用最优化方法及计算机程序,哈尔滨：哈尔滨船工程学院出版社，1994
[11]张克从等,晶体生长,北京:科学出版社,1981
[12]Jinng H H, Maccabe W L,Solubitity of MgSO4·7H2O,Ind.Eng.Chem 1985, 15:54～56
[13]谈遒，冯仁君,有机物系结晶介稳区的研究[硕士学位论文]，天津：天津大学化工系，1989
[14]朱自强,姚善泾,金彰礼 编著,流体相平衡原理及其应用,浙江: 浙江大学出版社,1990
[15]Stanley M.Walas,化工相平衡,韩世钧 等译,北京:中国石化出版社,1991
[16]Howskih, Ksiazczak A, Pietrzyk S,Solvent activity along a saturation line and solubility of hydrogen bonding solids,J Phys Chem,1980,84:975～979
[17]Ostwald,W.Z.Phys.Chem,1900,34:493～503
[18]蔡志刚,王静康,卞星青霉素钾盐蒸发结晶过程的研究,博士论文,天津：天津大学化工系
[19] British Pharmacopoeia 2000,Volume Ⅱ,1350～1353
[20] Randolph AD,Larson MA,Theroy of Particulate Processes,New York: Academic Press,1971
[21]Rao Cnrfrs,Gophalakrishnan J著,刘新生 译,固态化学的新方向-结构、合成、性质、反应性和材料设计,长春:吉林大学出版社,1990,162～166
[22] Mersmann A,et al.Sep.Technol,1992,2:85～97
[23]Mersmann A, General prediction of statistically mean growth rates of a crystal collective, Journal of Crystal Growth,1995,147,181～193
[24]Nyvlt J,Crystal Growth,1968,34:377
[25]Larson M A,et al.A.I.Ch.E.Symp,1976,68:41～47
[26]Abegg C F,Stevens J D,Larson M.A,AICHE J,1968,14:188
[27]Mydlarz J,Jones A.G,Chem.Eng.J,1993,53:125
[28]Janse A H,Proceedings of 11th Symposuim on Industrial Crystallizaion
1997,1658～1644
[29]Liang B,Hartel R W,J.Cryst.Growth,1991,108: 129
[30]David,Marchal P,Chem Eng Sci,1991,46(1):205～213
[31]David,Marchal P,Chem Eng Technal,1995,18:302～309
[32]Taodao Sugimoto,Kinetics of reaction –controlled Ostwald ripening in steady state of precipitate,Journal of Colloid and Interface Science, 1978,63:369～377
[33]陆杰,反应结晶研究（博士学位论文）,天津大学,1997
[34]范伟平,吴月,苯丙酮酸钠盐结晶过程,化工学报,1998,49(1):87～91
[35]陆杰,王静康,反应结晶过程研究,化学工业与工程,1999,16(1):58～61
[36] B Farkas,K Horvath,Z Szent-Kirrallyi,Elaboration of a test method for examination of polymorphism of active pharmaceutical ingredients, 15th ISIC,Sorrento:2002,587～592
[37]F Haselhuhn, M Kind,Pseudo-polymorphic behavior of precipitated calcium-oxalate,15th ISIC,Sorrento:2002,41～46
[38]Matynia A,Wierzboska B,Crystallization study in the ascorbic acid-isopropanol-water system,Chem Stosow,1989,33(1):113～126
[39] Tavare N S,Crystallization kinetics from transients of a MSMPR crystallizer,Can J Chem Eng,1986,64(5):752
[40]Davies MB,Austin J,Partridge D,Vitamin C(Its chemistry and biochemistry),Cambridge:The Royal Society of Chemistry,1991
[41]Bodor B，Dodony I,Crystallization of vitamin C under different experimental conditions,Hung J Ind Chem,1995,23(4):289～291
[42] Abegg CF,Stevens JD,Larson M A,Crystal Size Distribution in Continuous Crystallizers When Growth Rate is Size Dependent,AIChJ
Journal,1968,Vol(14):118～122
[43] MOSSER S,ALFASSIZ B,Separation of the KX-KXO3-KXO4(X=Cl, Br, I)system by “solventing-out” processes, Sep Sci Technol,1983,18:166
[44]Paulo A,Barata, Salting-out precipitation of potassium dehydrogenate phosphate(KDP)II.Influence of agitation intensity, Journal of Crystal Growth,1996,163:426～433
[45]B Marcant,R David, Experimental evidence for and precipitation of micromixing effects in precipitation,AIChE.1991,37:1698～1707
[46]张四维,抗生素分离精制工作中若干问题的探讨,医药工业,1988.19（3）:137.
[47]谢巾英,杜荣翠,张键,灰黄霉素的微粒结晶,抗生素,1981.6（1）:16
[48] Klug D L,Handbook of industrialcrystallization,Boston:A.S.Meyerson, Butterworth-heinemann,1993,61～79
[49]Sudha,Crystlline Solids, Advanced Drug Delivery Reviews,2001,48:3～26
[50]Rajendra K, Khankari, Pharmaceutial hydrates, Thermochimica Acta, 1995，248:61
[51]S R Byrn, Solid-State Chemistry of drugs, New York: Academic Press, 1982
[52]James R, Marsh, Solubility of Antibiotics in Twenty-six Solvents.Ⅲ, Journal of the A.O.A.C.1967,50:457～462
[53]程能林,胡声闻 编,溶剂手册,北京:化学工业出版社,1986年第1版
[54] Handbook of chemistry and physics,70th edition, CRC press, 1989-1990: C-681-C-683
[55]Williamn F,Solubilities-Inorganic and Metal-Organic Compounds, American Chemical Society, Washington D C,4th edition,1965,volⅡ:159～1001
[56]MingZhu, Solubility and Density of the Disodium Salt Hemiheptahydrate of Ceftriaxone in Water+ Ethanol Mixtures,Chem.Eng.Data,2001,46:175～176
[2]丁绪淮,谈 遒,工业结晶,北京:化学工业出版社,1985
[3]Mullin J W, Crystallization 2nd Ed, London: butterworths, 1993
[4]国家药典委员会,中华人民共和国药典2000年版,北京：化学工业出版社，2000
[5]Authority of the United States Pharmacopoeia Convention, The United States Pharmacopoeia, US: Pharmacopoeia convention, Inc. Twin brook parkway, Rockville,MD,20852,2000
[6]涂林,余方键,国产注射用头孢曲松钠的质量现状,中国药事,2002, 16(1):45～46
[7]Monguzzi，Riccardo,Improved process for the preparation of Ceftriaxone, EP:0399094,1990-11-28
[8]赵茜,高大维等,红霉素溶析结晶过程中原溶剂对其晶习及纯度的影响研,中国抗生素杂志,1999,24（6）:410～414
[9]李绍芬,反应工程,北京:化学工业出版社,1989
[10]杨冰,实用最优化方法及计算机程序,哈尔滨：哈尔滨船工程学院出版社，1994
[11]张克从等,晶体生长,北京:科学出版社,1981
[12]Jinng H H, Maccabe W L,Solubitity of MgSO4·7H2O,Ind.Eng.Chem 1985, 15:54～56
[13]谈遒，冯仁君,有机物系结晶介稳区的研究[硕士学位论文]，天津：天津大学化工系，1989
[14]朱自强,姚善泾,金彰礼 编著,流体相平衡原理及其应用,浙江: 浙江大学出版社,1990
[15]Stanley M.Walas,化工相平衡,韩世钧 等译,北京:中国石化出版社,1991
[16]Howskih, Ksiazczak A, Pietrzyk S,Solvent activity along a saturation line and solubility of hydrogen bonding solids,J Phys Chem,1980,84:975～979
[17]Ostwald,W.Z.Phys.Chem,1900,34:493～503
[18]蔡志刚,王静康,卞星青霉素钾盐蒸发结晶过程的研究,博士论文,天津：天津大学化工系
[19] British Pharmacopoeia 2000,Volume Ⅱ,1350～1353
[20] Randolph AD,Larson MA,Theroy of Particulate Processes,New York: Academic Press,1971
[21]Rao Cnrfrs,Gophalakrishnan J著,刘新生 译,固态化学的新方向-结构、合成、性质、反应性和材料设计,长春:吉林大学出版社,1990,162～166
[22] Mersmann A,et al.Sep.Technol,1992,2:85～97
[23]Mersmann A, General prediction of statistically mean growth rates of a crystal collective, Journal of Crystal Growth,1995,147,181～193
[24]Nyvlt J,Crystal Growth,1968,34:377
[25]Larson M A,et al.A.I.Ch.E.Symp,1976,68:41～47
[26]Abegg C F,Stevens J D,Larson M.A,AICHE J,1968,14:188
[27]Mydlarz J,Jones A.G,Chem.Eng.J,1993,53:125
[28]Janse A H,Proceedings of 11th Symposuim on Industrial Crystallizaion
1997,1658～1644
[29]Liang B,Hartel R W,J.Cryst.Growth,1991,108: 129
[30]David,Marchal P,Chem Eng Sci,1991,46(1):205～213
[31]David,Marchal P,Chem Eng Technal,1995,18:302～309
[32]Taodao Sugimoto,Kinetics of reaction –controlled Ostwald ripening in steady state of precipitate,Journal of Colloid and Interface Science, 1978,63:369～377
[33]陆杰,反应结晶研究（博士学位论文）,天津大学,1997
[34]范伟平,吴月,苯丙酮酸钠盐结晶过程,化工学报,1998,49(1):87～91
[35]陆杰,王静康,反应结晶过程研究,化学工业与工程,1999,16(1):58～61
[36] B Farkas,K Horvath,Z Szent-Kirrallyi,Elaboration of a test method for examination of polymorphism of active pharmaceutical ingredients, 15th ISIC,Sorrento:2002,587～592
[37]F Haselhuhn, M Kind,Pseudo-polymorphic behavior of precipitated calcium-oxalate,15th ISIC,Sorrento:2002,41～46
[38]Matynia A,Wierzboska B,Crystallization study in the ascorbic acid-isopropanol-water system,Chem Stosow,1989,33(1):113～126
[39] Tavare N S,Crystallization kinetics from transients of a MSMPR crystallizer,Can J Chem Eng,1986,64(5):752
[40]Davies MB,Austin J,Partridge D,Vitamin C(Its chemistry and biochemistry),Cambridge:The Royal Society of Chemistry,1991
[41]Bodor B，Dodony I,Crystallization of vitamin C under different experimental conditions,Hung J Ind Chem,1995,23(4):289～291
[42] Abegg CF,Stevens JD,Larson M A,Crystal Size Distribution in Continuous Crystallizers When Growth Rate is Size Dependent,AIChJ
Journal,1968,Vol(14):118～122
[43] MOSSER S,ALFASSIZ B,Separation of the KX-KXO3-KXO4(X=Cl, Br, I)system by “solventing-out” processes, Sep Sci Technol,1983,18:166
[44]Paulo A,Barata, Salting-out precipitation of potassium dehydrogenate phosphate(KDP)II.Influence of agitation intensity, Journal of Crystal Growth,1996,163:426～433
[45]B Marcant,R David, Experimental evidence for and precipitation of micromixing effects in precipitation,AIChE.1991,37:1698～1707
[46]张四维,抗生素分离精制工作中若干问题的探讨,医药工业,1988.19（3）:137.
[47]谢巾英,杜荣翠,张键,灰黄霉素的微粒结晶,抗生素,1981.6（1）:16
[48] Klug D L,Handbook of industrialcrystallization,Boston:A.S.Meyerson, Butterworth-heinemann,1993,61～79
[49]Sudha,Crystlline Solids, Advanced Drug Delivery Reviews,2001,48:3～26
[50]Rajendra K, Khankari, Pharmaceutial hydrates, Thermochimica Acta, 1995，248:61
[51]S R Byrn, Solid-State Chemistry of drugs, New York: Academic Press, 1982
[52]James R, Marsh, Solubility of Antibiotics in Twenty-six Solvents.Ⅲ, Journal of the A.O.A.C.1967,50:457～462
[53]程能林,胡声闻 编,溶剂手册,北京:化学工业出版社,1986年第1版
[54] Handbook of chemistry and physics,70th edition, CRC press, 1989-1990: C-681-C-683
[55]Williamn F,Solubilities-Inorganic and Metal-Organic Compounds, American Chemical Society, Washington D C,4th edition,1965,volⅡ:159～1001
[56]MingZhu, Solubility and Density of the Disodium Salt Hemiheptahydrate of Ceftriaxone in Water+ Ethanol Mixtures,Chem.Eng.Data,2001,46:175～176