舒巴坦钠溶析结晶工艺优化
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摘要
目前舒巴坦钠粗品的提纯采用还原成舒巴坦酸后再经反应结晶合成舒巴坦钠的方式,耗时耗力且所需药品、试剂种类较多,不节能环保。针对该问题,采用正交实验L_(27)(3~(13))对舒巴坦钠的溶析结晶工艺进行优化,探明了6个因素6个交互作用对粒度、纯度以及两者的综合评分的影响,包括养晶时间(A)、溶析剂用量(B)、溶析剂中乙醇的体积分数(C)、溶析剂的滴加速率(D)、搅拌速率(E)、温度(F)以及养晶时间分别与溶析剂用量(A×B)、与溶析剂中乙醇的体积分数(A×C)的交互作用、溶析剂用量与溶析剂中乙醇的体积分数的交互作用(B×C),并得到了一组最优方案A_2B_2C_1D_3E_3F_2。通过该方案可获得纯度x>97%,体积平均粒度D[4,3]≈290μm,质量收率约为84%的舒巴坦钠产品,并发现杂质舒巴坦青霉胺对舒巴坦钠的粒度分布有一定的影响。在解决原有问题的基础上,合适粒度分布的舒巴坦钠产品也可为后续制剂工艺提供方便。
At present, the way of purifying sulbactam sodium is to synthesize sulbactam sodium by sulbactam acid, which is obtained by reduction reaction. The method is time-consuming, labor-intensive and requires a large variety of drugs and reagents, and is not energy-saving and environmentally friendly.For this problem, the orthogonal experiment L_(27)(3~(13))was used to optimize the anti-solvent crystallization of sulbactam sodium. The effects of six factors and three interactions on crystal size distribution, purity and comprehensive scores of the two were considered, included aging time(A), volume of anti-solvent used(B), volume fraction of ethanol in the anti-solvent(C), rate of addition of the anti-solvent(D), stirring rate(E), crystallization temperature(F), and the interaction between the aging time and the volume of the anti-solvent(A × B), the interaction between the aging time and the volume fraction of ethanol in the decanting agent(A × C), the interaction between the volume of the anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C). The results of variance analysis showed: the used volume of anti-solvent(B) has the most significant effect on crystal size distribution(CSD), but other factors and interactions are not significant; the volume fraction of ethanol in the anti-solvent(C), the dropping rate of the anti-solvent(D), the stirring rate(E) and the interaction between the aging time and the volume fraction of ethanol in the anti-solvent(A×C) have a highly significant impact on the purity, and both of interaction between the crystallization time and the volume of the anti-solvent(A×B), and the interaction between the volume of anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C) have a significant effect, but the others are not significant; when the significant level α is between 0.10 and0.025, considering the purity-CSD at a ratio of 70% and 30% respectively, volume of the anti-solvent used(B) and the volume fraction of ethanol in the anti-solvent(C) are highly significant, and others are not significant. The optimal operating level combination is A_2B_2C_1D_3E_3F_2. Repeated validation tests yielded:the purity of sulbactam sodium raw material can be increased from 79.58% to over 97% by only once antisolvent crystallization, and the crystal size distribution D[4,3] can be increased from 41.1μm to above 290μm. The mass fraction yield of sulbactam sodium obtained by multiple confirmatory experiments is about 84%. It is found that the impurity sulbactam penicillamine has a certain influence on the particle size distribution of sulbactam sodium. On the basis of solving the original problems, the sulbactam sodium product with suitable particle size distribution can also provide convenience for the subsequent preparation process.
At present, the way of purifying sulbactam sodium is to synthesize sulbactam sodium by sulbactam acid, which is obtained by reduction reaction. The method is time-consuming, labor-intensive and requires a large variety of drugs and reagents, and is not energy-saving and environmentally friendly.For this problem, the orthogonal experiment L_(27)(3~(13))was used to optimize the anti-solvent crystallization of sulbactam sodium. The effects of six factors and three interactions on crystal size distribution, purity and comprehensive scores of the two were considered, included aging time(A), volume of anti-solvent used(B), volume fraction of ethanol in the anti-solvent(C), rate of addition of the anti-solvent(D), stirring rate(E), crystallization temperature(F), and the interaction between the aging time and the volume of the anti-solvent(A × B), the interaction between the aging time and the volume fraction of ethanol in the decanting agent(A × C), the interaction between the volume of the anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C). The results of variance analysis showed: the used volume of anti-solvent(B) has the most significant effect on crystal size distribution(CSD), but other factors and interactions are not significant; the volume fraction of ethanol in the anti-solvent(C), the dropping rate of the anti-solvent(D), the stirring rate(E) and the interaction between the aging time and the volume fraction of ethanol in the anti-solvent(A×C) have a highly significant impact on the purity, and both of interaction between the crystallization time and the volume of the anti-solvent(A×B), and the interaction between the volume of anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C) have a significant effect, but the others are not significant; when the significant level α is between 0.10 and0.025, considering the purity-CSD at a ratio of 70% and 30% respectively, volume of the anti-solvent used(B) and the volume fraction of ethanol in the anti-solvent(C) are highly significant, and others are not significant. The optimal operating level combination is A_2B_2C_1D_3E_3F_2. Repeated validation tests yielded:the purity of sulbactam sodium raw material can be increased from 79.58% to over 97% by only once antisolvent crystallization, and the crystal size distribution D[4,3] can be increased from 41.1μm to above 290μm. The mass fraction yield of sulbactam sodium obtained by multiple confirmatory experiments is about 84%. It is found that the impurity sulbactam penicillamine has a certain influence on the particle size distribution of sulbactam sodium. On the basis of solving the original problems, the sulbactam sodium product with suitable particle size distribution can also provide convenience for the subsequent preparation process.
引文
[1]程晓军,刘安祥,宋守忠.β-内酰胺类抗生素发展浅述[J].中国药业, 2001, 10(2):64-66.CHENG X J, LIU A X, SONG S Z. The development ofβ-lactam antibiotics[J]. China Pharmaceuticals, 2001, 10(2):64-66.
[2]蔡文辉,张文莉,付英梅,等.β-内酰胺酶抑制剂研究进展[J].中国抗生素杂志, 2013, 38(11):805-809.CAI W H, ZHANG W L, FU Y M, et al. Advances inβ-lactamase inhibitors[J]. Chinese Journal of Antibiotics, 2013, 38(11):805-809.
[3]茹仁萍,武谦虎.抗感染药物临床合理应用手册[M].北京:中国医药科技出版社, 2016:246.RU R P, WU Q H. Handbook of clinical rational use of anti-infective drugs[M]. Beijing:Chinese Medical Science and Technology Press,2016:246.
[4]陈兴娟,侯秀梅,曹欣祥,等.舒巴坦的工艺优化研究[J].化学中间体, 2007(2):30-36.CHEN X J, HOU X M, CAO X X, et al. Research of the optimizing process of sulbactam[J]. Chemical Intermediate, 2007(2):30-36.
[5]邱方利,潘富友.舒巴坦钠的合成[J].化学世界, 2006, 47(2):99-101.QIU F L, PAN F Y. Synthesis of sulbactam sodium[J]. Chemical World, 2006, 47(2):99-101.
[6]程宏辉,谢朝晖.舒巴坦钠合成工艺的研究[J].化学设计通讯,2001, 27(2):61-62.CHENG H H, XIE Z H. Study of the synthesis of sulbactam sodium[J].Chemical Design Communications, 2001, 27(2):61-62.
[7]姜浩伟.舒巴坦钠结晶工艺的改进[J].制剂技术, 2011, 20(8):48.JIANG H W. Improvement of sulbactam sodium crystallization process[J]. Formulation Technology, 2011, 20(8):48.
[8]吕烨,刘彦.舒巴坦钠结晶工艺的改进[J].黑龙江医药, 2006, 19(3):185-186.LüY, LIU Y. Improvement of crystallization of sulbactam sodium[J].Heilongjiang Medicine Jourrnal, 2006, 19(3):185-186.
[9]淄博鑫泉医药技术服务有限公司.舒巴坦钠的制备方法:CN10669974[P]. 2017-05-24.Zibo Xinquan Pharmaceutical Technology Service Co., Ltd.. Process for preparation of sulbactam sodium:CN106699774[P]. 2017-05-24.
[10]杜海生,李凤侠,赵振华,等.反应结晶制备高质量的舒巴坦钠[J].山东化工, 2009, 38(4):18-19.DU H S, LI F X, ZHAO Z H, et al. A prosess of preparing high quanlity sulbactam sodium by reacting crystallization[J]. Shandong Chemical Industry, 2009, 38(4):18-19.
[11]国家药典委员会.中华人民共和国药典[M].北京:中国医药科技出版社, 2015:1423.National Pharmacopoeia Commission. People’s Republic of China pharmacopoeia[M]. Beijing:Chinese Medical Science and Technology Press, 2015:1423.
[12]巴艳,林悦凤.基础医学与临床.2[M].济南:山东大学出版社,2016:188.BA Y, LIN Y F. Basic medicine and clinical.2[M]. Jinan:Shandong University Press, 2016:188.
[13]胡延维,孙芸.舒巴坦钠结晶过程中的影响因素分析[J].苏州大学学报(医学版), 2003, 23(6):674-676.HU Y W, SUN Y. Analysis of factors influencing sulbactam sodium crystallization process[J]. Suzhou University Journal of Medical Science, 2003, 23(6):674-676.
[14]颜青,肖永红,何绥平.必须重视β-内酰胺类抗生素与其酶抑制剂复方制剂的科学开发[J].中国临床药学杂志, 2007, 16(4):259-261.YAN Q, XIAO Y H, HE S P. Scientific development of compound preparations ofβ-lactam antibiotics and their enzyme inhibitors[J].Chinese Journal of Clinical Pharmacy, 2007, 16(4):259-261.
[15]龚俊波,陈明洋,黄翠,等.面向清洁生产的制药结晶[J].化工学报,2015, 66(9):3271-3278.GONG J B, CHEN M Y, HUANG C, et al. Clean production of pharmaceutical crystallization[J]. CIESC Journal, 2015, 66(9):3271-3278.
[16] MULLIN J W. Crystallization[M]. 4th ed. Oxford:Reed Educational and Professional Publishing, 2001.
[17] KIM H J, YEO S D. Liquid antisolvent crystallization of griseofulvin from organic solutions[J]. Chemical Engineering Research and Design,2015, 97:68-76.
[18]刘敏,李玉兰,杨敏,等.高效液相色谱法测定舒巴坦钠的有关物质[J].中国药师, 2005, 8(6):469-472.LIU M, LI Y L, YANG M, et al. HPLC determination of related substances in sulbactam sodium[J]. China Pharmacist, 2005, 8(6):469-472.
[19]李玉兰,刘敏,王玉.舒巴坦钠中舒巴坦青霉胺杂质含量测定方法的建立[J].中国药师, 2005, 8(6):467-469.LI Y L, LIU M, WANG Y. Establishment of a method for the impurity determination of sulbactam penicillamine in sulbactam sodium[J].China Pharmacist, 2005, 8(6):467-469.
[20]胡大为,胡小芳,林丽莹.粉体粒度分布分形维数与流动性及硬脂酸镁改进流动性关系[J].中国粉体技术, 2007, 13(4):1-4.HU D W, HU X F, LIN L Y. Correlation of powders’particle size distribution fractal with flow ability and flow addition reagent magnesium stearate[J]. China Powder Technology, 2007, 13(4):1-4.
[21]刘瑞江,张业旺,闻崇炜.正交试验设计和分析方法研究[J].实验技术与管理, 2010, 27(9):52-55.LIU R J, ZHANG Y W, WEN C W. Study on the design and analysis methods of orthogonal experiment[J]. Experimental Technology and Management, 2010, 27(9):52-55.
[22]马博爱,龚俊波.阿奇霉素二水合物溶析结晶工艺优化[J].化学工业与工程, 2015, 32(1):37-40.MA B A, GONG J B. Optimization of crystallization process of azithromyc in dihydrate[J]. Chemical Industryand Engineering, 2015,32(1):37-40.
[23]王海蓉,张春桃,王永莉.加晶种控制头孢曲松钠溶析结晶产品粒度分布的研究[J].中国抗生素杂志, 2009, 34(6):337-340.WANG H R, ZHANG C T, WANG Y L. Stuudies on the control of crystal size distribution of ceftriaxone sodium in dilution crystallization by seeding[J]. Chinese Journal of Antibiotics, 2009, 34(6):337-340.
[24]尹永恒,鲍颖,王永莉,等.诱导头孢噻肟钠结晶过程研究[J].化学工业与工程, 2014, 31(2):48-53.YIN Y H, BAO Y, WANG Y L, et al. Induced crystallization of cefotaxime sodium[J]. Chemical Industry and Engineering, 2014, 31(2):48-53.
[25]刘宝树. 5'-鸟苷酸二钠溶析结晶过程研究[D].天津:天津大学,2007.LIU B S. Study on crystallization process of disodium 5'-guanylate[D].Tianjin:Tianjin University, 2007.
[26] WANG H Y, WARD J D. Seeding and optimization of batch reactive crystallization[J]. Industrial and Engineering Chemistry Research,2015, 54(38):9360-9368.
[27]李永曙,刘继阳,梅丽琴,等.注射用美洛西林钠溶析结晶工艺研究[J].中国抗生素杂志, 2010, 35(5):353-356.LI Y S, LIU J Y, MEI L Q, et al. Study on solvent-out crystallization process of mezlocillin sodium for injection[J]. Chinese Journal of Antibiotics, 2010, 35(5):353-356.
[28]鲍颖.盐酸大观霉素溶析结晶过程研究[D].天津:天津大学, 2003.BAO Y. Study on the process of dilution crystallization of spectinomycin dihydrochloride[D]. Tianjin:Tianjin University, 2003.
[29]孙华.洛伐他汀结晶过程研究[D].天津:天津大学, 2006.SUN H. Study on the crystallization process of lovastatin[D]. Tianjin:Tianjin University, 2006.
[30]庄楚强,何春雄.应用数理统计基础[M].广州:华南理工大学出版社, 2011:222-284.ZHUANG C Q, HE C X. Applied mathematical statistics foundation[M]. Guangzhou:South China University of Technology Publishing House, 2011:222-284.
[31]王雪雁.一种治疗传染性疾病的舒巴坦钠化合物及其制备方法:CN10486946[P]. 2015-04-30.WANG X Y. Sulbactam sodium compound for treating infectious disease and its preparing:CN10486946[P]. 2015-04-30.
[32]张丕德,龙晓英.正交设计与数据分析在药学研究中的应用(Ⅱ)[J].广东药学院学报, 2009, 25(6):648-657.ZHANG P D, LONG X Y. Application of orthogonal design and data analysis in pharmaceutical research(Ⅱ)[J]. Journal of Guangdong Pharmaceutical College, 2009, 25(6):648-657.
[33]陈翔,梁卫玖.建立Excel宏快速处理正交试验设计数据[J].中国卫生检验杂志, 2009, 19(11):2696-2697.CHEN X, LIANG W J. Establish Excel macro to quickly process orthogonal experimental design data[J]. Chinese Journal of Health Laboratory Technology, 2009, 19(11):2696-2697.
[2]蔡文辉,张文莉,付英梅,等.β-内酰胺酶抑制剂研究进展[J].中国抗生素杂志, 2013, 38(11):805-809.CAI W H, ZHANG W L, FU Y M, et al. Advances inβ-lactamase inhibitors[J]. Chinese Journal of Antibiotics, 2013, 38(11):805-809.
[3]茹仁萍,武谦虎.抗感染药物临床合理应用手册[M].北京:中国医药科技出版社, 2016:246.RU R P, WU Q H. Handbook of clinical rational use of anti-infective drugs[M]. Beijing:Chinese Medical Science and Technology Press,2016:246.
[4]陈兴娟,侯秀梅,曹欣祥,等.舒巴坦的工艺优化研究[J].化学中间体, 2007(2):30-36.CHEN X J, HOU X M, CAO X X, et al. Research of the optimizing process of sulbactam[J]. Chemical Intermediate, 2007(2):30-36.
[5]邱方利,潘富友.舒巴坦钠的合成[J].化学世界, 2006, 47(2):99-101.QIU F L, PAN F Y. Synthesis of sulbactam sodium[J]. Chemical World, 2006, 47(2):99-101.
[6]程宏辉,谢朝晖.舒巴坦钠合成工艺的研究[J].化学设计通讯,2001, 27(2):61-62.CHENG H H, XIE Z H. Study of the synthesis of sulbactam sodium[J].Chemical Design Communications, 2001, 27(2):61-62.
[7]姜浩伟.舒巴坦钠结晶工艺的改进[J].制剂技术, 2011, 20(8):48.JIANG H W. Improvement of sulbactam sodium crystallization process[J]. Formulation Technology, 2011, 20(8):48.
[8]吕烨,刘彦.舒巴坦钠结晶工艺的改进[J].黑龙江医药, 2006, 19(3):185-186.LüY, LIU Y. Improvement of crystallization of sulbactam sodium[J].Heilongjiang Medicine Jourrnal, 2006, 19(3):185-186.
[9]淄博鑫泉医药技术服务有限公司.舒巴坦钠的制备方法:CN10669974[P]. 2017-05-24.Zibo Xinquan Pharmaceutical Technology Service Co., Ltd.. Process for preparation of sulbactam sodium:CN106699774[P]. 2017-05-24.
[10]杜海生,李凤侠,赵振华,等.反应结晶制备高质量的舒巴坦钠[J].山东化工, 2009, 38(4):18-19.DU H S, LI F X, ZHAO Z H, et al. A prosess of preparing high quanlity sulbactam sodium by reacting crystallization[J]. Shandong Chemical Industry, 2009, 38(4):18-19.
[11]国家药典委员会.中华人民共和国药典[M].北京:中国医药科技出版社, 2015:1423.National Pharmacopoeia Commission. People’s Republic of China pharmacopoeia[M]. Beijing:Chinese Medical Science and Technology Press, 2015:1423.
[12]巴艳,林悦凤.基础医学与临床.2[M].济南:山东大学出版社,2016:188.BA Y, LIN Y F. Basic medicine and clinical.2[M]. Jinan:Shandong University Press, 2016:188.
[13]胡延维,孙芸.舒巴坦钠结晶过程中的影响因素分析[J].苏州大学学报(医学版), 2003, 23(6):674-676.HU Y W, SUN Y. Analysis of factors influencing sulbactam sodium crystallization process[J]. Suzhou University Journal of Medical Science, 2003, 23(6):674-676.
[14]颜青,肖永红,何绥平.必须重视β-内酰胺类抗生素与其酶抑制剂复方制剂的科学开发[J].中国临床药学杂志, 2007, 16(4):259-261.YAN Q, XIAO Y H, HE S P. Scientific development of compound preparations ofβ-lactam antibiotics and their enzyme inhibitors[J].Chinese Journal of Clinical Pharmacy, 2007, 16(4):259-261.
[15]龚俊波,陈明洋,黄翠,等.面向清洁生产的制药结晶[J].化工学报,2015, 66(9):3271-3278.GONG J B, CHEN M Y, HUANG C, et al. Clean production of pharmaceutical crystallization[J]. CIESC Journal, 2015, 66(9):3271-3278.
[16] MULLIN J W. Crystallization[M]. 4th ed. Oxford:Reed Educational and Professional Publishing, 2001.
[17] KIM H J, YEO S D. Liquid antisolvent crystallization of griseofulvin from organic solutions[J]. Chemical Engineering Research and Design,2015, 97:68-76.
[18]刘敏,李玉兰,杨敏,等.高效液相色谱法测定舒巴坦钠的有关物质[J].中国药师, 2005, 8(6):469-472.LIU M, LI Y L, YANG M, et al. HPLC determination of related substances in sulbactam sodium[J]. China Pharmacist, 2005, 8(6):469-472.
[19]李玉兰,刘敏,王玉.舒巴坦钠中舒巴坦青霉胺杂质含量测定方法的建立[J].中国药师, 2005, 8(6):467-469.LI Y L, LIU M, WANG Y. Establishment of a method for the impurity determination of sulbactam penicillamine in sulbactam sodium[J].China Pharmacist, 2005, 8(6):467-469.
[20]胡大为,胡小芳,林丽莹.粉体粒度分布分形维数与流动性及硬脂酸镁改进流动性关系[J].中国粉体技术, 2007, 13(4):1-4.HU D W, HU X F, LIN L Y. Correlation of powders’particle size distribution fractal with flow ability and flow addition reagent magnesium stearate[J]. China Powder Technology, 2007, 13(4):1-4.
[21]刘瑞江,张业旺,闻崇炜.正交试验设计和分析方法研究[J].实验技术与管理, 2010, 27(9):52-55.LIU R J, ZHANG Y W, WEN C W. Study on the design and analysis methods of orthogonal experiment[J]. Experimental Technology and Management, 2010, 27(9):52-55.
[22]马博爱,龚俊波.阿奇霉素二水合物溶析结晶工艺优化[J].化学工业与工程, 2015, 32(1):37-40.MA B A, GONG J B. Optimization of crystallization process of azithromyc in dihydrate[J]. Chemical Industryand Engineering, 2015,32(1):37-40.
[23]王海蓉,张春桃,王永莉.加晶种控制头孢曲松钠溶析结晶产品粒度分布的研究[J].中国抗生素杂志, 2009, 34(6):337-340.WANG H R, ZHANG C T, WANG Y L. Stuudies on the control of crystal size distribution of ceftriaxone sodium in dilution crystallization by seeding[J]. Chinese Journal of Antibiotics, 2009, 34(6):337-340.
[24]尹永恒,鲍颖,王永莉,等.诱导头孢噻肟钠结晶过程研究[J].化学工业与工程, 2014, 31(2):48-53.YIN Y H, BAO Y, WANG Y L, et al. Induced crystallization of cefotaxime sodium[J]. Chemical Industry and Engineering, 2014, 31(2):48-53.
[25]刘宝树. 5'-鸟苷酸二钠溶析结晶过程研究[D].天津:天津大学,2007.LIU B S. Study on crystallization process of disodium 5'-guanylate[D].Tianjin:Tianjin University, 2007.
[26] WANG H Y, WARD J D. Seeding and optimization of batch reactive crystallization[J]. Industrial and Engineering Chemistry Research,2015, 54(38):9360-9368.
[27]李永曙,刘继阳,梅丽琴,等.注射用美洛西林钠溶析结晶工艺研究[J].中国抗生素杂志, 2010, 35(5):353-356.LI Y S, LIU J Y, MEI L Q, et al. Study on solvent-out crystallization process of mezlocillin sodium for injection[J]. Chinese Journal of Antibiotics, 2010, 35(5):353-356.
[28]鲍颖.盐酸大观霉素溶析结晶过程研究[D].天津:天津大学, 2003.BAO Y. Study on the process of dilution crystallization of spectinomycin dihydrochloride[D]. Tianjin:Tianjin University, 2003.
[29]孙华.洛伐他汀结晶过程研究[D].天津:天津大学, 2006.SUN H. Study on the crystallization process of lovastatin[D]. Tianjin:Tianjin University, 2006.
[30]庄楚强,何春雄.应用数理统计基础[M].广州:华南理工大学出版社, 2011:222-284.ZHUANG C Q, HE C X. Applied mathematical statistics foundation[M]. Guangzhou:South China University of Technology Publishing House, 2011:222-284.
[31]王雪雁.一种治疗传染性疾病的舒巴坦钠化合物及其制备方法:CN10486946[P]. 2015-04-30.WANG X Y. Sulbactam sodium compound for treating infectious disease and its preparing:CN10486946[P]. 2015-04-30.
[32]张丕德,龙晓英.正交设计与数据分析在药学研究中的应用(Ⅱ)[J].广东药学院学报, 2009, 25(6):648-657.ZHANG P D, LONG X Y. Application of orthogonal design and data analysis in pharmaceutical research(Ⅱ)[J]. Journal of Guangdong Pharmaceutical College, 2009, 25(6):648-657.
[33]陈翔,梁卫玖.建立Excel宏快速处理正交试验设计数据[J].中国卫生检验杂志, 2009, 19(11):2696-2697.CHEN X, LIANG W J. Establish Excel macro to quickly process orthogonal experimental design data[J]. Chinese Journal of Health Laboratory Technology, 2009, 19(11):2696-2697.