甲胺基阿维菌素苯甲酸盐原药结晶工艺优化
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摘要
结晶是一种重要的分离技术,广泛应用于冶金、化工、医药、食品等领域。本文针对先正达甲胺基阿维菌素苯甲酸盐生产过程中产品颗粒较细、产品质量不能满足日本市场要求、结晶时间偏长等问题,对甲胺基阿维菌素苯甲酸盐生产结晶过程进行了系统研究,提出了结晶优化新工艺。
采用对比试验方法研究了结晶浓度、苯甲酸醋酸丁酯溶液加料速度、结晶控温程序(降温速率和养晶时间)、搅拌速度、不良溶剂(析出剂)的加料量等结晶工艺控制条件对产品的质量、收率及批次耗用时间的影响,确定了甲胺基阿维菌素苯甲酸盐结晶优化操作条件。并经过中试(公斤试验)和大生产放大试验的进一步验证,试验结果表明,该结晶优化工艺不仅提高了产品质量,使得产品质量符合日本市场要求,并且提高了收率和产能,为公司创造了较好的经济效益。
Crystallization is an important separation technique which is widely used in the areas of metallurgy, chemical industry, pharmaceutical and food industry. Be aim to solve the problems of small particle size, product quality out of specification for Japan market, too long batch circle time in the manufacturing of Emamectin Benzoate. The crystallization process of Emamectin Benzoate was systematically investigated. And a new crystallization process was developed.
The comparison experiment method was used to investigate what the crystallization control conditions like concentration, charging speed of Benzoic acid in butyl acetate solution, crystallization temperature control loop (cooling rate and cystal holding time), stirring speed and charging quantity of unsoluble solvent impacted the product quality, yield and batch circle tme.The optimized ctystallization operational conditions were finally determined. The scale-up (kilo-lab) trial and plant trial were then conducted and the results showed that the new crystallization process could not only improve the product quality to meet the requirement of Japan market, but also increased yield and expanded the capacity. There was a good economic benefit to company.
采用对比试验方法研究了结晶浓度、苯甲酸醋酸丁酯溶液加料速度、结晶控温程序(降温速率和养晶时间)、搅拌速度、不良溶剂(析出剂)的加料量等结晶工艺控制条件对产品的质量、收率及批次耗用时间的影响,确定了甲胺基阿维菌素苯甲酸盐结晶优化操作条件。并经过中试(公斤试验)和大生产放大试验的进一步验证,试验结果表明,该结晶优化工艺不仅提高了产品质量,使得产品质量符合日本市场要求,并且提高了收率和产能,为公司创造了较好的经济效益。
Crystallization is an important separation technique which is widely used in the areas of metallurgy, chemical industry, pharmaceutical and food industry. Be aim to solve the problems of small particle size, product quality out of specification for Japan market, too long batch circle time in the manufacturing of Emamectin Benzoate. The crystallization process of Emamectin Benzoate was systematically investigated. And a new crystallization process was developed.
The comparison experiment method was used to investigate what the crystallization control conditions like concentration, charging speed of Benzoic acid in butyl acetate solution, crystallization temperature control loop (cooling rate and cystal holding time), stirring speed and charging quantity of unsoluble solvent impacted the product quality, yield and batch circle tme.The optimized ctystallization operational conditions were finally determined. The scale-up (kilo-lab) trial and plant trial were then conducted and the results showed that the new crystallization process could not only improve the product quality to meet the requirement of Japan market, but also increased yield and expanded the capacity. There was a good economic benefit to company.
引文
[1]朱丽梅.甲胺基阿维菌素苯甲酸盐与阿维菌素苯的杀虫活性研究[J].南京农专学报.2003,19(4)：28.
[2]邹磊,张玉华。阿维菌素的发展趋势[J].黑龙江医药.2006,19(3)：200.
[3]M H Fisher. Avermectin研究的最新进展[J].农药译丛.1991,13(3)：19-26.
[4]门振,温沛宏,徐波勇等.生物源杀虫剂.甲胺基阿维菌素苯甲酸盐[J].农药.2001,40(5)：43.
[5]刘永霞,李茂进,刘延忠等.农药甲胺基阿维菌素苯甲酸盐的致突变性研究[J].检测研究.2006,18(1)：72.
[6]毕富春,徐凤波.甲胺基阿维菌素苯甲酸盐对粘虫的杀虫活性[J].农药.2001,8(1)：2-4.
[7]倪珏萍,侯华民,曾霞等.甲氨基阿维菌素苯甲酸盐与阿维菌素生物活性比较[J].现代农药.2003,2(3)：58.
[8]吴强恩,周志俊.甲胺基阿维菌素的毒理研究概况[J].中国公共卫生.2003,19(9)：1129-1130.
[9]徐克勋.精细有机化工原料及中间体手册[M].北京：化学工业出版社,1998.5-9.
[10]刘步林.农药剂型加工手册(第二版)[M].北京：化学工业出版社,1998.470.
[11]陈寿山.金属有机化合物合成手册[M].北京：化学工业出版社,1986.132.
[12]Chabala, John C, Fisher et al. Selective hydrogenation products of C-076 Compounds and derivatives thereof. US Patent 4,199,569.1980-04-22.
[13]Mrozik, HelmutH.4"-Deoxy-4"-methylamino avermectinB la/Blb EP 0 301 806 A2.1988—07.
[14]Linn, Bruce 0. Derivatives of 3' —and 3"-0-desmethyl avermectin compounds. EP 0 375 395 A2.1989-12.
[15]Helmut Mrozik, Matawan.4'—deoxy-4"-N-methylamino avermectinBla/ Blb. US Patent 4,874,749.1989—10.
[16]Raymond Cvetovich, Scotch Plains. Process for the Preparation of 4"-Amino Avermectin Compounds. US Patent 5,362,863.1994-11-08.
[17]Cvetovich, Raymond. Stable Salts of 4"-deoxy-4"-epimethylamino Avermectin Bla/Blb EP 0 465 121 A1.1991—06.
[18]Rene Beugelmans. Rdeuctive Deprotection of Allyl Ethers with Pd(Ph3) 4/NaBH4. Tetrahedron Letters.1994,135(25):4349—4350.
[19]Farer Lj, Heyes J, Rosen J et al. Determination of Emamectin Benzoate in Medicated Fish Feed. JAOAC Int.1999,82(6):1281—1287.
[20]Arlt, Dieter, Bonse et al.Method for the Production of Ivermectin US Patent 6,072,052.2000-06-06.
[21]宋周虎.甲胺基阿维菌素苯甲酸盐的合成(学位论文).天津：天津大学制药工程系,2002.30-38.
[22]罗亮明,李国珍.5-0-叔丁基二甲基硅基阿维菌素的合成[J].精细化工中间体.2003,33(3)：28-30.
[23]Yoshii K et al. Liquid Chromatographic Determination of Emamectin, Milbemectin, Ivennectin and Abamectin in Crops and Confirmation by Liquid Chromatography-Mass Spectrometry[J]. J Chromatogra.2000,896(1):75-85.
[24]Hu Xiao-min, Fei Guo-liang, Wang Jie-ping. Determination of Emamectin Benzoate by HPLC Veterinary pharmaceuticals and feed additive[J].Food Chem.2001,5:26.
[25]Feely W F, Crouch L S, Arison B H, et al. Photodegradation of 4"-(epi-methylamino)-4"-deoxyavermectin Bla Thin Films on Glass[J]. J. Agric. Food Chem..1992,40:691-696.
[26]Mushtaq M, Chukwudebe A C, Wrzesinski C, et al. Photodegradation of Emamectin Benzoate in Aqueous Solutions. J. Agric. Food Chem. 1998,46:1181-1191.
[27]Mallory F. Loewe, Raymond J. Cvetovich, Lisa M. DiMichele et al. Grabowski Glycosidation Route to 4"-epi-(Methylamino)-4"-Deoxyavermectin B, (MK-244E, mamectin Benzoate). J. Org. Chem.1994,59:7870-7875.
[28]徐静,王静康.维生素结晶过程研究(学位论文).天津：天津大学化学工程系,1996.25-30.
[29]李立强,尹秋响.维生素C钠盐结晶工艺优化(学位论文).天津：天津大学制药工程系,2003.7-12,26.
[30]王晓东,韩国华.维生素C生产技术的进展与发展方向.医药工程设计[J].1995,6(5)：32-34.
[31]马静,王玉红,陈建峰等.反溶剂重结晶法制备硫酸沙丁胺醇颗粒[J].北京化工大学学报.2003,30(6)：12-14.
[32]王静康,结晶.化工工程手册[M].北京：北京化学工业出版社,1996.219-222.
[33]Kakkad, R., Smith, J., Lau, W. S. et al. Crystallized Si films by low-temperature rapid thermal annealing of amorphous silicon[J]. Journal of Applied Physics.1989,65(5):2069-2072.
[34]Horita, Susumu, Kaki, Hirokazu, Nishioka, Kensuke et al. Surface modification of an amorphous Si thin film crystallized by a linearly polarized Nd:YAG pulse laser beam[J]. Journal of Applied Physics. 2007,102(1):013501-013510.
[35]Suzuki, Takao, Sequeda, Federico, Do, Hoa et al. Magnetic and processing[J]. Journal of Applied Physics.1990,67(9):4435-4437.
[36]陈芬儿,余红霞,万江陵等.硫酸沙丁胺醇的合成研究I[J].中国药物化学杂志.1993,5(3)：215-217
[37]Aliotta, F., Di Marco, G., Ober, R.et al. Effect of a nucleating agent on lamellar growth in melt-crystallizing polyethylene oxide[J]. Journal of Applied Physics.2003,93(9):5839-5841.
[38]Li Xiang(李响).Studies on the optimization of xylos crystallization from the condensation of hydrolysated cotton seed hulls[D]. Tianjin:Tianjin University,2008.36.
[39]Gabas N, Laguerie C. Batch crystallization of d2xylose by programmed cooling or by programmed adding of ethanol[J]. Chemical Engineering Science.1992,47(12):3148.
[40]蔡建国,周展云.超临界流体GAS重结晶过程的过饱和度与产品的颗粒形态[J].高校化学工程学报.1996,10(3)：323.
[41]王晓东,韩国华.维生素C生产技术的进展与发展方向[J].医药工程设计.1995,5：32-34.
[42]T. Noguchi. Appearance of single-crystalline properties in finepatterned Si thin film transistors (TFT's) by solid phase crystallization (SPC) [J]. Jpn. J. Appl. Phys. Lett..1993,32:1584.
[43]S-W. Lee, S-K, Joo. Low temperature poly-Si thin-film transistor fabrication my metal-induced lateral crystallization[J]. IEEE Electron Device Lett..1996,17:160.
[44]K. Zellama, P. Germain, S. Squelard et al. Crystallization in amorphous silicon. J. Appl. Phys..1979,50:6995.
[45]V. Subramanian, P. Dankoski, F. L. Degertekin, B. T et al. Saraswat. Controlled two-step solid-phase crystallization for high performance polysilicon TFT's[J]. IEEE Electron Device Lett. 1997,18:378.
[46]Reverchon E, Della Porta G, Pallado P. Supercritical antisolvent precipitation of salbutamol micropartiOcles [J]. Powder Technology. 2001,114:17.
[47]王建龙,徐春彦.重结晶制备粉体RDX工艺研究[J].华北工学院学报.1997,18 (3)：262.
[48]蔡建国.超临界流体重结晶[J].现代化工.1994,8(12)：46.
[49]孙华.洛伐他汀结晶过程研究[D].天津：天津大学化学工程,2006.19-21.
[50]丁绪淮,谈遒.工业结晶(第一版)[M].北京：化学工业出版社,1995.139.
[51]陆杰,王静康.操作参数对普鲁卡因青霉素晶体粒度的影响[J].高校化学工程学报.1999,13(6)：554-557.
[52]王弘,罗文波,于淑娟等.妥布霉素结晶过程中影响因素的研究及参数优[J].中国抗生素杂志.2002,27(4)：221-222.
[2]邹磊,张玉华。阿维菌素的发展趋势[J].黑龙江医药.2006,19(3)：200.
[3]M H Fisher. Avermectin研究的最新进展[J].农药译丛.1991,13(3)：19-26.
[4]门振,温沛宏,徐波勇等.生物源杀虫剂.甲胺基阿维菌素苯甲酸盐[J].农药.2001,40(5)：43.
[5]刘永霞,李茂进,刘延忠等.农药甲胺基阿维菌素苯甲酸盐的致突变性研究[J].检测研究.2006,18(1)：72.
[6]毕富春,徐凤波.甲胺基阿维菌素苯甲酸盐对粘虫的杀虫活性[J].农药.2001,8(1)：2-4.
[7]倪珏萍,侯华民,曾霞等.甲氨基阿维菌素苯甲酸盐与阿维菌素生物活性比较[J].现代农药.2003,2(3)：58.
[8]吴强恩,周志俊.甲胺基阿维菌素的毒理研究概况[J].中国公共卫生.2003,19(9)：1129-1130.
[9]徐克勋.精细有机化工原料及中间体手册[M].北京：化学工业出版社,1998.5-9.
[10]刘步林.农药剂型加工手册(第二版)[M].北京：化学工业出版社,1998.470.
[11]陈寿山.金属有机化合物合成手册[M].北京：化学工业出版社,1986.132.
[12]Chabala, John C, Fisher et al. Selective hydrogenation products of C-076 Compounds and derivatives thereof. US Patent 4,199,569.1980-04-22.
[13]Mrozik, HelmutH.4"-Deoxy-4"-methylamino avermectinB la/Blb EP 0 301 806 A2.1988—07.
[14]Linn, Bruce 0. Derivatives of 3' —and 3"-0-desmethyl avermectin compounds. EP 0 375 395 A2.1989-12.
[15]Helmut Mrozik, Matawan.4'—deoxy-4"-N-methylamino avermectinBla/ Blb. US Patent 4,874,749.1989—10.
[16]Raymond Cvetovich, Scotch Plains. Process for the Preparation of 4"-Amino Avermectin Compounds. US Patent 5,362,863.1994-11-08.
[17]Cvetovich, Raymond. Stable Salts of 4"-deoxy-4"-epimethylamino Avermectin Bla/Blb EP 0 465 121 A1.1991—06.
[18]Rene Beugelmans. Rdeuctive Deprotection of Allyl Ethers with Pd(Ph3) 4/NaBH4. Tetrahedron Letters.1994,135(25):4349—4350.
[19]Farer Lj, Heyes J, Rosen J et al. Determination of Emamectin Benzoate in Medicated Fish Feed. JAOAC Int.1999,82(6):1281—1287.
[20]Arlt, Dieter, Bonse et al.Method for the Production of Ivermectin US Patent 6,072,052.2000-06-06.
[21]宋周虎.甲胺基阿维菌素苯甲酸盐的合成(学位论文).天津：天津大学制药工程系,2002.30-38.
[22]罗亮明,李国珍.5-0-叔丁基二甲基硅基阿维菌素的合成[J].精细化工中间体.2003,33(3)：28-30.
[23]Yoshii K et al. Liquid Chromatographic Determination of Emamectin, Milbemectin, Ivennectin and Abamectin in Crops and Confirmation by Liquid Chromatography-Mass Spectrometry[J]. J Chromatogra.2000,896(1):75-85.
[24]Hu Xiao-min, Fei Guo-liang, Wang Jie-ping. Determination of Emamectin Benzoate by HPLC Veterinary pharmaceuticals and feed additive[J].Food Chem.2001,5:26.
[25]Feely W F, Crouch L S, Arison B H, et al. Photodegradation of 4"-(epi-methylamino)-4"-deoxyavermectin Bla Thin Films on Glass[J]. J. Agric. Food Chem..1992,40:691-696.
[26]Mushtaq M, Chukwudebe A C, Wrzesinski C, et al. Photodegradation of Emamectin Benzoate in Aqueous Solutions. J. Agric. Food Chem. 1998,46:1181-1191.
[27]Mallory F. Loewe, Raymond J. Cvetovich, Lisa M. DiMichele et al. Grabowski Glycosidation Route to 4"-epi-(Methylamino)-4"-Deoxyavermectin B, (MK-244E, mamectin Benzoate). J. Org. Chem.1994,59:7870-7875.
[28]徐静,王静康.维生素结晶过程研究(学位论文).天津：天津大学化学工程系,1996.25-30.
[29]李立强,尹秋响.维生素C钠盐结晶工艺优化(学位论文).天津：天津大学制药工程系,2003.7-12,26.
[30]王晓东,韩国华.维生素C生产技术的进展与发展方向.医药工程设计[J].1995,6(5)：32-34.
[31]马静,王玉红,陈建峰等.反溶剂重结晶法制备硫酸沙丁胺醇颗粒[J].北京化工大学学报.2003,30(6)：12-14.
[32]王静康,结晶.化工工程手册[M].北京：北京化学工业出版社,1996.219-222.
[33]Kakkad, R., Smith, J., Lau, W. S. et al. Crystallized Si films by low-temperature rapid thermal annealing of amorphous silicon[J]. Journal of Applied Physics.1989,65(5):2069-2072.
[34]Horita, Susumu, Kaki, Hirokazu, Nishioka, Kensuke et al. Surface modification of an amorphous Si thin film crystallized by a linearly polarized Nd:YAG pulse laser beam[J]. Journal of Applied Physics. 2007,102(1):013501-013510.
[35]Suzuki, Takao, Sequeda, Federico, Do, Hoa et al. Magnetic and processing[J]. Journal of Applied Physics.1990,67(9):4435-4437.
[36]陈芬儿,余红霞,万江陵等.硫酸沙丁胺醇的合成研究I[J].中国药物化学杂志.1993,5(3)：215-217
[37]Aliotta, F., Di Marco, G., Ober, R.et al. Effect of a nucleating agent on lamellar growth in melt-crystallizing polyethylene oxide[J]. Journal of Applied Physics.2003,93(9):5839-5841.
[38]Li Xiang(李响).Studies on the optimization of xylos crystallization from the condensation of hydrolysated cotton seed hulls[D]. Tianjin:Tianjin University,2008.36.
[39]Gabas N, Laguerie C. Batch crystallization of d2xylose by programmed cooling or by programmed adding of ethanol[J]. Chemical Engineering Science.1992,47(12):3148.
[40]蔡建国,周展云.超临界流体GAS重结晶过程的过饱和度与产品的颗粒形态[J].高校化学工程学报.1996,10(3)：323.
[41]王晓东,韩国华.维生素C生产技术的进展与发展方向[J].医药工程设计.1995,5：32-34.
[42]T. Noguchi. Appearance of single-crystalline properties in finepatterned Si thin film transistors (TFT's) by solid phase crystallization (SPC) [J]. Jpn. J. Appl. Phys. Lett..1993,32:1584.
[43]S-W. Lee, S-K, Joo. Low temperature poly-Si thin-film transistor fabrication my metal-induced lateral crystallization[J]. IEEE Electron Device Lett..1996,17:160.
[44]K. Zellama, P. Germain, S. Squelard et al. Crystallization in amorphous silicon. J. Appl. Phys..1979,50:6995.
[45]V. Subramanian, P. Dankoski, F. L. Degertekin, B. T et al. Saraswat. Controlled two-step solid-phase crystallization for high performance polysilicon TFT's[J]. IEEE Electron Device Lett. 1997,18:378.
[46]Reverchon E, Della Porta G, Pallado P. Supercritical antisolvent precipitation of salbutamol micropartiOcles [J]. Powder Technology. 2001,114:17.
[47]王建龙,徐春彦.重结晶制备粉体RDX工艺研究[J].华北工学院学报.1997,18 (3)：262.
[48]蔡建国.超临界流体重结晶[J].现代化工.1994,8(12)：46.
[49]孙华.洛伐他汀结晶过程研究[D].天津：天津大学化学工程,2006.19-21.
[50]丁绪淮,谈遒.工业结晶(第一版)[M].北京：化学工业出版社,1995.139.
[51]陆杰,王静康.操作参数对普鲁卡因青霉素晶体粒度的影响[J].高校化学工程学报.1999,13(6)：554-557.
[52]王弘,罗文波,于淑娟等.妥布霉素结晶过程中影响因素的研究及参数优[J].中国抗生素杂志.2002,27(4)：221-222.