膜调控的头孢呋辛钠溶析-冷却耦合结晶成核介稳区测定及分析

doi:10.16085/j.issn.1000-6613.2023-0516

摘要/Abstract

摘要：

溶析-冷却耦合结晶可以提高结晶产率的同时，降低溶析剂的消耗量，是一种高效的耦合分离过程。传统的溶析结晶传质的界面往往受到宏观混合规模的限制，传质调控通常为亚毫米级，容易爆发成核，导致结晶产品的纯度差、平均粒度小、晶体粒度分布宽，因而需要更精确的调节策略。本文提出了一种新型的膜辅助溶析-冷却耦合结晶的方法，应用于头孢呋辛钠的结晶过程研究。其中，聚四氟乙烯（PTFE）中空纤维膜作为精确添加溶析剂和高效混合的界面，实现过饱和度的均匀分布。为了对比膜辅助溶析-冷却耦合结晶和传统耦合结晶方式的调控效果，对膜辅助溶析-冷却耦合结晶过程进行更为精确的调控，分别测量了传统和膜辅助条件下溶析-冷却耦合结晶的头孢呋辛钠-水-乙醇体系的介稳区宽度，计算了成核动力学参数。使用响应面方法和理论模型分析了冷却速率、溶析剂添加速率和溶析剂组分对介稳区宽度的影响，并比较了传统结晶和膜辅助结晶的介稳区特征。结果表明，膜辅助溶析-冷却耦合结晶的成核级数和成核速率常数（n=2.07，k_n =158.15）均小于常规耦合结晶（n=2.45，k_n =493.22），成核动力学方面更加温和，可调控性更强。

关键词: 膜辅助结晶, 介稳区, 溶析-冷却耦合结晶, 过程强化, 响应面方法

Abstract:

Combined cooling and antisolvent crystallization can improve the crystallization yield while reducing the consumption of antisolvent, which is an efficient coupled separation process. The interface of conventional mass transfer for antisolvent crystallization is often limited by the macroscopic mixing scale, and mass transfer regulation is usually sub-millimeter, which is prone to nucleation outbreaks, resulting in poor purity, small average size and wide crystal size distribution of crystalline products, thus requiring more precise regulation strategies. In this paper, a novel membrane-assisted combined cooling and antisolvent crystallization method was proposed and applied to the study of cefuroxime sodium crystallization process. Polytetrafluoroethylene (PTFE) hollow fiber membranes were used as an interface for precise addition of the antisolvent and efficient mixing to achieve a uniform distribution of supersaturation. To compare the regulation effects of membrane-assisted combined cooling and antisolvent crystallization with conventional crystallization method, the metastable zone width of the cefuroxime sodium-water-ethanol system with combined cooling and antisolvent crystallization under conventional and membrane-assisted conditions were measured and the nucleation kinetic parameters were calculated for precise regulation of the membrane assisted combined cooling and antisolvent crystallization process, respectively. The effects of cooling rate and antisolvent addition rate on the metastable zone width were analyzed using response surface methodology and theoretical models, and the metastable zone characteristics of conventional and membrane-assisted crystallization were compared. The results showed that the nucleation order and nucleation rate constant (n=2.07, k_n =158.15) of membrane-assisted combined cooling and antisolvent crystallization were smaller than conventional crystallization (n=2.45, k_n =493.22), and the nucleation process was gentler and more controllable. The research in this paper provides important basic theoretical data for further exploration of membrane-assisted combined cooling and antisolvent crystallization, and lays the foundation for crystallization process development and optimization.

Key words: membrane-assisted crystallization, metastable zone, combined cooling and antisolvent crystallization, process intensification, response surface methodology

中图分类号:

TQ028.3

张梁, 马骥, 贺高红, 姜晓滨, 肖武. 膜调控的头孢呋辛钠溶析-冷却耦合结晶成核介稳区测定及分析[J]. 化工进展, 2024, 43(1): 260-268.

ZHANG Liang, MA Ji, HE Gaohong, JIANG Xiaobin, XIAO Wu. Determination and analysis of combined cooling and antisolvent crystallization metastable zone width of cefuroxime sodium with membrane regulation[J]. Chemical Industry and Engineering Progress, 2024, 43(1): 260-268.

图/表 11

图1 PTFE中空纤维膜的SEM图像

表1 聚四氟乙烯中空纤维膜的关键参数

外径/mm	内径/mm	水接触角/(°)	热导率/W·m^-1·K^-1	孔径/μm	孔隙率/%
1.6~1.8	0.8	107	0.17	0.2~0.25	39.84

表2 膜组件的关键参数

外径/mm	内径/mm	长度/mm	膜丝数量/根	装填密度/m²·m^-3	装填率/%
16	13	105	5	171	12.83

图2 传统溶析-冷却耦合结晶实验装置

图3 膜辅助溶析-冷却耦合结晶实验装置

图4 膜辅助溶析-冷却耦合结晶操作路线示意图

表3 常规溶析-冷却耦合结晶条件下头孢呋辛钠在水-乙醇体系中的介稳区实验数据

$R C$ /℃·min^-1	$R F$ /g·min^-1	$X m$	$T m e t$ /℃	$X m m e t$	Δ $C m e t$ /g_溶质·g_总溶剂^-1	$t n u c$ /min
0.05	0.23	0.833	27.78	0.846	0.00061	44
0.05	0.23	0.857	27.50	0.868	0.00045	50
0.05	0.47	0.833	28.77	0.848	0.00067	25
0.05	0.67	0.800	28.61	0.831	0.00158	28
0.05	0.67	0.857	28.87	0.871	0.00057	23
0.10	0.23	0.800	23.09	0.828	0.00143	70
0.10	0.23	0.857	24.47	0.869	0.00049	55
0.10	0.47	0.857	26.93	0.870	0.00054	31
0.10	0.67	0.800	27.06	0.833	0.00166	29
0.10	0.67	0.833	27.97	0.850	0.00077	20
0.20	0.23	0.800	13.81	0.832	0.00161	81
0.20	0.23	0.833	18.80	0.850	0.00075	56
0.20	0.47	0.800	21.53	0.833	0.00167	42
0.20	0.47	0.857	23.20	0.872	0.00059	34
0.20	0.67	0.833	25.46	0.852	0.00085	23

表3 常规溶析-冷却耦合结晶条件下头孢呋辛钠在水-乙醇体系中的介稳区实验数据

$R C$ /℃·min^-1	$R F$ /g·min^-1	$X m$	$T m e t$ /℃	$X m m e t$	Δ $C m e t$ /g_溶质·g_总溶剂^-1	$t n u c$ /min
0.05	0.23	0.833	27.78	0.846	0.00061	44
0.05	0.23	0.857	27.50	0.868	0.00045	50
0.05	0.47	0.833	28.77	0.848	0.00067	25
0.05	0.67	0.800	28.61	0.831	0.00158	28
0.05	0.67	0.857	28.87	0.871	0.00057	23
0.10	0.23	0.800	23.09	0.828	0.00143	70
0.10	0.23	0.857	24.47	0.869	0.00049	55
0.10	0.47	0.857	26.93	0.870	0.00054	31
0.10	0.67	0.800	27.06	0.833	0.00166	29
0.10	0.67	0.833	27.97	0.850	0.00077	20
0.20	0.23	0.800	13.81	0.832	0.00161	81
0.20	0.23	0.833	18.80	0.850	0.00075	56
0.20	0.47	0.800	21.53	0.833	0.00167	42
0.20	0.47	0.857	23.20	0.872	0.00059	34
0.20	0.67	0.833	25.46	0.852	0.00085	23

表4 膜辅助溶析-冷却耦合结晶条件下头孢呋辛钠在水-乙醇体系中的介稳区实验数据

$R C$ /℃·min^-1	$R F$ /g·min^-1	$X m$	$T m e t$ $/ ℃$	$X m m e t$ $(-)$	$Δ$ $C m e t$ /g_溶质·g_总溶剂^-1	$t n u c$ /min
0.05	0.24	0.833	25.14	0.854	0.00149	97
0.05	0.27	0.800	26.40	0.833	0.00164	72
0.05	0.43	0.800	27.41	0.837	0.00182	51
0.05	0.49	0.857	27.56	0.878	0.00085	48
0.05	0.67	0.833	27.83	0.861	0.00182	43
0.10	0.24	0.833	20.69	0.859	0.00144	93
0.10	0.26	0.800	21.31	0.836	0.00184	86
0.10	0.44	0.833	24.32	0.862	0.00156	56
0.10	0.66	0.800	25.88	0.843	0.00217	41
0.10	0.72	0.857	26.05	0.881	0.00098	39
0.20	0.22	0.833	5.91	0.863	0.00171	120
0.20	0.39	0.833	15.49	0.865	0.00179	72
0.20	0.43	0.857	16.99	0.881	0.00098	65
0.20	0.46	0.800	17.61	0.844	0.00223	61
0.20	0.69	0.800	21.37	0.847	0.00232	43

表4 膜辅助溶析-冷却耦合结晶条件下头孢呋辛钠在水-乙醇体系中的介稳区实验数据

$R C$ /℃·min^-1	$R F$ /g·min^-1	$X m$	$T m e t$ $/ ℃$	$X m m e t$ $(-)$	$Δ$ $C m e t$ /g_溶质·g_总溶剂^-1	$t n u c$ /min
0.05	0.24	0.833	25.14	0.854	0.00149	97
0.05	0.27	0.800	26.40	0.833	0.00164	72
0.05	0.43	0.800	27.41	0.837	0.00182	51
0.05	0.49	0.857	27.56	0.878	0.00085	48
0.05	0.67	0.833	27.83	0.861	0.00182	43
0.10	0.24	0.833	20.69	0.859	0.00144	93
0.10	0.26	0.800	21.31	0.836	0.00184	86
0.10	0.44	0.833	24.32	0.862	0.00156	56
0.10	0.66	0.800	25.88	0.843	0.00217	41
0.10	0.72	0.857	26.05	0.881	0.00098	39
0.20	0.22	0.833	5.91	0.863	0.00171	120
0.20	0.39	0.833	15.49	0.865	0.00179	72
0.20	0.43	0.857	16.99	0.881	0.00098	65
0.20	0.46	0.800	17.61	0.844	0.00223	61
0.20	0.69	0.800	21.37	0.847	0.00232	43

图5 在不同溶析剂质量分数下，lgαΔTmet'+βΔXmmet'和lgRC'+RA'的关系

表5 溶析剂组分Xm（0.8~0.853）、冷却速率RC'（0~1）和溶析剂添加速率RA'（0~1）对介稳区宽度的影响

固定参数	改变参数	$Δ$ T $m e t'$	\| $Δ$ X $m e t'$ \|	$Δ$ C $m e t'$
X_m 和 R $A'$	增大 R $C'$	↑	↑	↑
X_m 和 R $C'$	增大R $A'$	↓	↑	↑
R $C'$ 和 R $A'$	增大X_m	↓	↓	↓

表5 溶析剂组分Xm（0.8~0.853）、冷却速率RC'（0~1）和溶析剂添加速率RA'（0~1）对介稳区宽度的影响

固定参数	改变参数	$Δ$ T $m e t'$	\| $Δ$ X $m e t'$ \|	$Δ$ C $m e t'$
X_m 和 R $A'$	增大 R $C'$	↑	↑	↑
X_m 和 R $C'$	增大R $A'$	↓	↑	↑
R $C'$ 和 R $A'$	增大X_m	↓	↓	↓

图6 膜辅助结晶和传统结晶RC'和RA'对ΔTmet'、ΔXmmet'和ΔCmet'的响应面图（a）、（c）、（e）及响应差值图（b）、（d）、（f）

参考文献 34

1	黄炎, 孙海龙, 孟子超, 等. 溶析结晶在医药领域的研究进展[J]. 化工进展, 2019, 38(5): 2380-2388.
	HUANG Yan, SUN Hailong, MENG Zichao, et al. Progress in antisolvent crystallization in pharmaceutical field[J]. Chemical Industry and Engineering Progress, 2019, 38(5): 2380-2388.
2	DARMALI Christine, MANSOURI Shahnaz, YAZDANPANAH Nima, et al. Mechanisms and control of impurities in continuous crystallization: A review[J]. Industrial & Engineering Chemistry Research, 2019, 58(4): 1463-1479.
3	WANG Ting, LU Haijiao, WANG Jingkang, et al. Recent progress of continuous crystallization[J]. Journal of Industrial and Engineering Chemistry, 2017, 54: 14-29.
4	鲍颖, 王永莉, 王静康. 溶析结晶研究进展[J]. 化学工业与工程, 2004, 21(6): 438-443.
	BAO Ying, WANG Yongli, WANG Jingkang. Progress in dilution crystallization[J]. Chemical Industry and Engineering, 2004, 21(6): 438-443.
5	LI Jin, SHENG Lei, Linghan TUO, et al. Membrane-assisted antisolvent crystallization: Interfacial mass-transfer simulation and multistage process control[J]. Industrial & Engineering Chemistry Research, 2020, 59(21): 10160-10171.
6	DI PROFIO Gianluca, STABILE Carmen, CARIDI Antonella, et al. Antisolvent membrane crystallization of pharmaceutical compounds[J]. Journal of Pharmaceutical Sciences, 2009, 98(12): 4902-4913.
7	BARRETT Mark, Des O'GRADY, CASEY Eoin, et al. The role of meso-mixing in anti-solvent crystallization processes[J]. Chemical Engineering Science, 2011, 66(12): 2523-2534.
8	LINDENBERG Christian, Martin KRÄTTLI, CORNEL Jeroen, et al. Design and optimization of a combined cooling/antisolvent crystallization process[J]. Crystal Growth & Design, 2009, 9(2): 1124-1136.
9	ZHAO Yingying, HOU Baohong, JIANG Xiaobin, et al. Determination of thermodynamics in various solvents and kinetics of cefuroxime sodium during antisolvent crystallization[J]. Journal of Chemical & Engineering Data, 2012, 57(3): 952-956.
10	KNOX Michael, TRIFKOVIC Milana, ROHANI Sohrab. Combining anti-solvent and cooling crystallization: Effect of solvent composition on yield and meta stable zone width[J]. Chemical Engineering Science, 2009, 64(16): 3555-3563.
11	LENKA Maheswata, SARKAR Debasis. Combined cooling and antisolvent crystallization of l-asparagine monohydrate[J]. Powder Technology, 2018, 334: 106-116.
12	YANG Y, NAGY Z K. Combined cooling and antisolvent crystallization in continuous mixed suspension, mixed product removal cascade crystallizers: Steady-state and startup optimization[J]. Industrial & Engineering Chemistry Research, 2015, 54(21): 5673-5682.
13	RAGAB D, ROHANI S, SAMAHA M W, et al. Crystallization of progesterone for pulmonary drug delivery[J]. Journal of Pharmaceutical Sciences, 2010, 99(3): 1123-1137.
14	LENKA Maheswata, SARKAR Debasis. Improving crystal size distribution by internal seeding combined cooling/antisolvent crystallization with a cooling/heating cycle[J]. Journal of Crystal Growth, 2018, 486: 130-136.
15	YANG Y, NAGY Z K. Advanced control approaches for combined cooling/antisolvent crystallization in continuous mixed suspension mixed product removal cascade crystallizers[J]. Chemical Engineering Science, 2015, 127: 362-373.
16	ROSA C A DA, BRAATZ R D. OpenCrys: Open-source software for the multiscale modeling of combined antisolvent and cooling crystallization in turbulent flow[J]. Industrial & Engineering Chemistry Research, 2018, 57(34): 11702-11711.
17	欧雪娇, 张春桃, 李雪伟, 等. 膜结晶技术的研究进展[J]. 现代化工, 2016, 36(8): 14-18.
	Xuejiao OU, ZHANG Chuntao, LI Xuewei, et al. Advances in membrane crystallization technology[J]. Modern Chemical Industry, 2016, 36(8): 14-18.
18	邵冠瑛, 贺高红, 姜晓滨. 膜辅助添加晶种的过硫酸铵冷却结晶在线监测与过程调控[J]. 化工进展, 2022, 41(12): 6226-6234.
	SHAO Guanying, HE Gaohong, JIANG Xiaobin. On-line monitoring and process control of membrane-assisted seeding for ammonium persulfate cooling crystallization[J]. Chemical Industry and Engineering Progress, 2022, 41(12): 6226-6234.
19	孙国鑫, 苟萌萱, 周诚, 等. 高浓度Na⁺//NO₃ ^-, SO₄ ^2--H₂O溶液的膜蒸馏结晶耦合过程调控[J]. 化工学报, 2022, 73(7): 3078-3089.
	SUN Guoxin, GOU Mengxuan, ZHOU Cheng, et al. Membrane distillation crystallization coupling process for the treatment of high concentration Na⁺//NO₃ ^-, SO₄ ^2--H₂O solution[J]. CIESC Journal, 2022, 73(7): 3078-3089.
20	盛磊, 脱凌晗, 姜晓滨, 等. 有机膜精确调控传质的新型溶析结晶及过程强化[J]. 化工进展, 2020, 39(5): 1692-1700.
	SHENG Lei, Linghan TUO, JIANG Xiaobin, et al. Novel antisolvent crystallization and process intensification via the accurate mass transfer control of the organic membrane[J]. Chemical Industry and Engineering Progress, 2020, 39(5): 1692-1700.
21	SHENG Lei, LI Jin, HE Gaohong, et al. Visual study and simulation of interfacial liquid layer mass transfer in membrane-assisted antisolvent crystallization[J]. Chemical Engineering Science, 2020, 228: 116003.
22	盛磊, 李培钰, 牛宇超, 等. 微尺度过程强化的结晶颗粒制备研究进展[J]. 化工学报, 2021, 72(1): 143-157.
	SHENG Lei, LI Peiyu, NIU Yuchao, et al. Progresses in the preparation of micro-scale process-enhanced crystalline particles[J]. CIESC Journal, 2021, 72(1): 143-157.
23	JIN C, CHEN D, SIRKAR K K, et al. An extended duration operation for solid hollow fiber membrane-based cooling crystallization[J]. Powder Technology, 2020, 365: 106-114.
24	DI PROFIO Gianluca, CURCIO Efrem, FERRARO Serena, et al. Effect of supersaturation control and heterogeneous nucleation on porous membrane surfaces in the crystallization of l-glutamic acid polymorphs[J]. Crystal Growth & Design, 2009, 9(5): 2179-2186.
25	SHAO Guanying, HE Zeman, XIAO Wu, et al. On-line monitoring and analysis of membrane-assisted internal seeding for cooling crystallization of ammonium persulfate[J]. Chemical Engineering Science, 2022, 263: 118081.
26	郭盛争, 吴送姑, 苏鑫, 等. 莱鲍迪苷A溶解度与介稳区宽度的测定及其结晶过程研究[J]. 化工学报, 2021, 72(8): 3997-4008.
	GUO Shengzheng, WU Songgu, SU Xin, et al. Determination of solubility and metastable zone width of rebaudioside A and study on its crystallization process[J]. CIESC Journal, 2021, 72(8): 3997-4008.
27	ZHOU Ling, WANG Zhao, ZHANG Meijing, et al. Determination of metastable zone and induction time of analgin for cooling crystallization[J]. Chinese Journal of Chemical Engineering, 2017, 25(3): 313-318.
28	RAMAKERS L A, MCGINTY J, BECKMANN W, et al. Investigation of metastable zones and induction times in glycine crystallization across three different antisolvents[J]. Crystal Growth & Design, 2020, 20(8): 4935-4944.
29	Jaroslav NÝVLT. Kinetics of nucleation in solutions[J]. Journal of Crystal Growth, 1968, 3/4: 377-383.
30	LENKA Maheswata, SARKAR Debasis. Determination of metastable zone width, induction period and primary nucleation kinetics for cooling crystallization of L[J]. Journal of Crystal Growth, 2014, 408: 85-90.
31	LENKA Maheswata, SARKAR Debasis. Determination of metastable zone width and nucleation kinetics for combined cooling and antisolvent crystallization of L-asparagine monohydrate in water-isopropanol mixture[J]. Journal of Crystal Growth, 2018, 501: 66-73.
32	DE FAVERI D, TORRE P, PEREGO P, et al. Optimization of xylitol recovery by crystallization from synthetic solutions using response surface methodology[J]. Journal of Food Engineering, 2004, 61(3): 407-412.
33	OUYANG Jinbo, NA Bing, LIU Zhirong, et al. Determination of solubility and nucleation kinetics of valnemulin hydrochloride solvate[J]. Journal of Solution Chemistry, 2019, 48(4): 413-426.
34	CHEN Xiaofeng, XU Juan, GU Jia, et al. Measurement and correlation of the solubility of gestodene in 11 pure and binary mixed solvent systems at temperatures from 283.15 to 323.15 K[J]. Journal of Chemical & Engineering Data, 2021, 66(10): 3776-3787.

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