头孢氨苄连续结晶研究及应用

doi:10.16085/j.issn.1000-6613.2018-2109

摘要/Abstract

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。

关键词: 头孢氨苄, 连续结晶, 收率, 晶习, 粒度分布

Abstract:

The traditional production method of cefalexin is mostly intermittent crystallization, which has the 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 continuous crystallization process was designed according to the characteristics of electrical point crystallization such as cephalexin. The effects of initial concentration, residence time, stirring rate, pH of crystallization end point and seed strategy of cefalexin aqueous solution on the yield, crystal habit and particle size distribution of cefalexin continuous crystallization products were systematically studied by single factor method.The results of single factor experiment showed that the product yield and particle size distribution reached the ideal results when the concentration of cefalexin aqueous solution was 14%, the optimal residence time was 12min, the pH of the end point of crystallization was controlled around 4.8, and the amount of seed addition was 5%.The process can effectively control the supersaturation of the crystallization process in the metastable region and avoid nucleation. Compared with intermittent crystallization, the working time of two-stage continuous crystallization is reduced by 30%. Product crystal integrity, particle size distribution uniformity, yield can reach 96%. At present, this technology has successfully realized the industrialization application of a single production line with a scale of 500 tons/year.

Key words: cefalexin, continuous crystallization, yield, crystal habits, crystal size distribution

中图分类号:

R978.1⁺1

张军立, 龚俊波, 孙华, 段志钢, 胡卫国. 头孢氨苄连续结晶研究及应用[J]. 化工进展, 2019, 38(07): 3349-3354.

Junli ZHANG, Junbo GONG, Hua SUN, Zhigang DUAN, Weiguo HU. Study and application of the continuous crystallization process of cefalexin[J]. Chemical Industry and Engineering Progress, 2019, 38(07): 3349-3354.

图/表 17

图1 头孢氨苄结构式

图2 头孢氨苄连续结晶装置图

表1 不同头孢氨苄水溶液初始浓度下产品的收率

初始质量分数/%	收率/%	中值粒径d₅₀ /μm
10	73.6	20.3
12	86.4	19.7
14	96.5	21.0
16	94.1	13.5

图3 不同头孢氨苄水溶液初始浓度下产品粒度分布图

表2 不同停留时间下产品的收率

停留时间/min	收率/%	中值粒径d₅₀ /μm
24	95.9	20.1
16	96.3	27.8
12	96.4	26.9
9.6	96.1	9.1

图4 不同停留时间下产品粒度分布图

表3 不同搅拌速率下产品的收率

搅拌速率/r·min^-1	收率/%	中值粒径d₅₀/μm
30	94.1	76.3
35	94.4	88.4
40	96.6	22.3
45	95.1	20.7

图5 不同搅拌速率下产品的粒度分布图

表4 不同结晶pH下产品的收率

结晶终点pH	收率/%	中值粒径d₅₀/μm
4.4	85.6	29.6
4.6	90.7	27.8
4.8	96.3	23.5
5.0	94.2	26.9

图6 不同结晶终点pH下产品的粒度分布图

表5 不同晶种添加量下产品的收率

晶种添加量/%	收率/%	中值粒径d₅₀/μm
2.5	93.2	29.7
5.0	96.2	25.4
7.5	96.4	18.5

图7 不同晶种添加量下产品的粒度分布图

图8 晶体粒度分布随时间的变化图

表6 文献过饱和度数据

pH	x_A2	x_A1	过饱和度S
2.47	1.8610×10^-3	4.9740×10^-3	2.67
2.59	1.5711×10^-3	2.7370×10^-3	1.74
2.83	1.1843×10^-3	1.6030×10^-3	1.35

图9 优化前后产品的粒度分布图

图10 优化前产品的显微镜照片

图11 优化后产品的显微镜照片

参考文献 16

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