Determination and analysis of combined cooling and antisolvent crystallization metastable zone width of cefuroxime sodium with membrane regulation

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

Abstract

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

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

CLC Number:

TQ028.3

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.

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.

Figures/Tables 11

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

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

$R C$ /℃·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

$R C$ /℃·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

$R C$ /℃·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

$R C$ /℃·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

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	↓	↓	↓

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	↓	↓	↓

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