头孢氨苄连续结晶研究及应用
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摘要
头孢氨苄的传统生产方法多为间歇结晶,存在效率低、能耗高等弊端。为节约能耗、提高生产效率、缩短工时、降低成本,针对头孢氨苄等电点结晶的特点,本文设计了两级连续结晶工艺。采用单因素法系统研究了头孢氨苄水溶液初始浓度、停留时间、搅拌速率、结晶终点pH、晶种策略等因素对头孢氨苄连续结晶过程产品的收率、晶习及粒度分布的影响。单因素实验结果显示头孢氨苄水溶液质量分数为14%、最佳停留时间为12min、结晶终点pH控制在4.8附近、晶种添加量为5%时其产品收率、粒度分布均达到了理想的效果。该工艺能将结晶过程的过饱和度有效地控制在介稳区内,避免了爆发成核。与间歇结晶相比,两级连续结晶工艺的工时缩短30%。产品晶习完整,粒度分布均匀,收率可以达到96%。目前该工艺已成功实现单条生产线规模为500t/a的产业化应用。
The traditional production method of cefalexin is mostly intermittent crystallization, which hasthe disadvantages of low efficiency and high energy consumption. In order to save energy consumption,improve production efficiency, shorten working hours and reduce cost, a two-stage continuouscrystallization process was designed according to the characteristics of electrical point crystallization suchas cephalexin. The effects of initial concentration, residence time, stirring rate, pH of crystallization endpoint and seed strategy of cefalexin aqueous solution on the yield, crystal habit and particle sizedistribution of cefalexin continuous crystallization products were systematically studied by single factormethod.The results of single factor experiment showed that the product yield and particle size distributionreached the ideal results when the concentration of cefalexin aqueous solution was 14%, the optimal residence time was 12 min, the pH of the end point of crystallization was controlled around 4.8, and theamount of seed addition was 5%. The process can effectively control the supersaturation of the crystallizationprocess in the metastable region and avoid nucleation. Compared with intermittent crystallization, theworking time of two-stage continuous crystallization is reduced by 30%. Product crystal integrity, particlesize distribution uniformity, yield can reach 96%. At present, this technology has successfully realized theindustrialization application of a single production line with a scale of 500 tons/year.
The traditional production method of cefalexin is mostly intermittent crystallization, which hasthe disadvantages of low efficiency and high energy consumption. In order to save energy consumption,improve production efficiency, shorten working hours and reduce cost, a two-stage continuouscrystallization process was designed according to the characteristics of electrical point crystallization suchas cephalexin. The effects of initial concentration, residence time, stirring rate, pH of crystallization endpoint and seed strategy of cefalexin aqueous solution on the yield, crystal habit and particle sizedistribution of cefalexin continuous crystallization products were systematically studied by single factormethod.The results of single factor experiment showed that the product yield and particle size distributionreached the ideal results when the concentration of cefalexin aqueous solution was 14%, the optimal residence time was 12 min, the pH of the end point of crystallization was controlled around 4.8, and theamount of seed addition was 5%. The process can effectively control the supersaturation of the crystallizationprocess in the metastable region and avoid nucleation. Compared with intermittent crystallization, theworking time of two-stage continuous crystallization is reduced by 30%. Product crystal integrity, particlesize distribution uniformity, yield can reach 96%. At present, this technology has successfully realized theindustrialization application of a single production line with a scale of 500 tons/year.
引文
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[9] FURUTA M, MUKAI K, Cork D, et al. Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process[J]. Chemical Engineering and Processing,2016, 102:210-218.
[10] CYNTHIA A, CHALLENER. Considering continuous crystallization[J].Pharmaceutical Technology, 2015, 39(5):38-40.
[11] WANG Y G, XIAO Y, CHENG X, et al. An FPGA-based real-time maximum likelihood 3D position estimation for a continuous crystal PET detector[J]. Ieee Transactions on Nuclear Science, 2016, 63(1):37-43.
[12] THOMAS L, LORENZO M. On the nucleation and crystallization of nanoparticles in continuous-flow nonthermal plasma reactors[J].Journal of Vacuum Science&Technology B, 2014, 32(6):1-8.
[13] CHOU C H, CHAN W S, LEE I C, et al. High-performance singlecrystal like strained silicon nanowire thin-film transistors via continuous wave laser crystallization[J]. IEEE Electron Device Letters,2015,36(4):348-350.
[14] DENGYUE C, DHANANJAY S, KAMALESH K, et al. Continuous preparation of polymer coated drug crystals by solid hollow fiber membrane-based cooling crystallization[J]. International Journal of Pharmaceutics, 2016, 499:395-402.
[15] ZHANG D J, XU S J, DU S C, et al. Progress of pharmaceutical continuous crystallization[J]. Engineering, 2017, 3:354-364.
[16]林兰兰.头孢氨苄一水合物反应结晶过程研究[D].天津:天津大学, 2017.LIN L L. A study on reactive crystallization process of cefalexin monohydra[D].Tianjin:Tianjin University, 2017.
[2]顾勤兰,王泽,尤启冬.一步结晶法合成头孢氨苄[J].中国药师,2006, 9(1):3-4.GU Q L, WANG Z, YOU Q D. Synthesis of cefalexin by one step crystallization[J].China Pharmacist, 2006, 9(1):3-4.
[3] LAAN V D J M. Mutant penicillin G acylases:US8541199[P]. 2013-09-24
[4] JOSEPH B W H, JOSEPH V D T W J, MARINUS D R. Process for the preparation of an antibiotic:WO022610[P]. 1997-06-26
[5] LIU W J, MA C Y, WANG X Z. Novel impinging jet and continuous crystallizer design for rapid reactive crystallization of pharmaceuticals[J]. Procedia Engineering, 2015,102:499-507.
[6] KOZIK A, MATYNIA A, PIOTROWSKI K. Continuous reaction crystallization of struvite from diluted aqueous solutions of phosphate(Ⅴ)ions in DT MSMPR crystallizer[J]. Procedia Engineering, 2012,42(5):313-322.
[7]王静康,卫宏远,张元谋.工业结晶分离技术研究新进展[J].化工学报, 1993, 44(5):565-574.WANG J K, WEI H Y, ZHANG Y M. Studes on unsteady-state behavior of continuous crystallization processes[J]. Journal of Chemical Industry and Engineering(China),1993, 44(5):565-574.
[8]尹秋响,王静康. MSMPR连续结晶器的多定态[J].化工学报, 1997,48(6):692-698.YIN Q X,WANG J K. Multiplicity in continuous MSMPR crystallization[J]. Journal of Chemical Industry and Engineering(China),1997, 48(6):692-698.
[9] FURUTA M, MUKAI K, Cork D, et al. Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process[J]. Chemical Engineering and Processing,2016, 102:210-218.
[10] CYNTHIA A, CHALLENER. Considering continuous crystallization[J].Pharmaceutical Technology, 2015, 39(5):38-40.
[11] WANG Y G, XIAO Y, CHENG X, et al. An FPGA-based real-time maximum likelihood 3D position estimation for a continuous crystal PET detector[J]. Ieee Transactions on Nuclear Science, 2016, 63(1):37-43.
[12] THOMAS L, LORENZO M. On the nucleation and crystallization of nanoparticles in continuous-flow nonthermal plasma reactors[J].Journal of Vacuum Science&Technology B, 2014, 32(6):1-8.
[13] CHOU C H, CHAN W S, LEE I C, et al. High-performance singlecrystal like strained silicon nanowire thin-film transistors via continuous wave laser crystallization[J]. IEEE Electron Device Letters,2015,36(4):348-350.
[14] DENGYUE C, DHANANJAY S, KAMALESH K, et al. Continuous preparation of polymer coated drug crystals by solid hollow fiber membrane-based cooling crystallization[J]. International Journal of Pharmaceutics, 2016, 499:395-402.
[15] ZHANG D J, XU S J, DU S C, et al. Progress of pharmaceutical continuous crystallization[J]. Engineering, 2017, 3:354-364.
[16]林兰兰.头孢氨苄一水合物反应结晶过程研究[D].天津:天津大学, 2017.LIN L L. A study on reactive crystallization process of cefalexin monohydra[D].Tianjin:Tianjin University, 2017.