盐酸萘甲唑啉在甲醇-乙酸乙酯体系中的动力学及结晶工艺

doi:10.16085/j.issn.1000-6613.2023-1210

摘要/Abstract

摘要：

盐酸萘甲唑啉（NPZ）是一种作用于循环系统的血管收缩类药物。针对原料药平均粒径偏小及粒度分布不均的问题，本文提出运用间歇动态法对NPZ在甲醇-乙酸乙酯体系中的结晶动力学进行研究，并系统考察了不同结晶工艺条件对晶体析出率、粒径以及变异系数的影响规律。结果表明：随着溶液过饱和度的增大，NPZ晶体成核机制由非均相成核转为均相成核，晶体表面生长符合连续生长模式；NPZ生长动力学模型、成核速率与生长速率方程分别为 $B 0 = 9.591 × 104 G 2.10$ 、 $B = 2.031 × 1020 e x p - 4.796 × 105 R T M T 0.309 Δ C 1.40 ω r 1.37$ 和 $G = 4.094 × 107 e x p - 8.358 × 105 R T Δ C 1.36$ 。优化的结晶工艺参数为：晶种加入量1.5%（质量分数）、结晶温度313.15K、搅拌速率200r/min、溶液过饱和度1.04、乙酸乙酯滴加速率7.037×10^-4L/min、乙酸乙酯与甲醇质量比4∶1、陈化时间2h。该条件下制得的NPZ晶体较原料药平均粒径增大30.49%、变异系数降低32.30%、堆密度提高14.65%、休止角改善7.62%、卡尔指数提升30.76%、豪斯那比优化26.99%，晶体粒径、粒度分布及流动性均得到明显改善。

关键词: 盐酸萘甲唑啉, 结晶, 动力学, 粒度分布, 优化

Abstract:

Naphazoline hydrochloride (NPZ) is a vasoconstrictor drug that acts on the circulatory system. However, it has some poor crystal properties such as small average particle size and uneven distribution of particle size. Intermittent dynamic method was proposed to investigate the crystallization kinetics of NPZ in methanol-ethyl acetate system, and the influence of different technological conditions on the yield, particle size and variable coefficient were systematically investigated. The experimental results showed the nucleation mechanism of NPZ changed from heterogeneous nucleation to homogeneous nucleation with increase of supersaturation, and the crystal surface growth process followed a continuous growth mode. Growth kinetics model, nucleation rate and growth rate equations were: $B 0 = 9.591 × 104 G 2.10$ , $B = 2.031 × 1020 e x p - 4.796 × 105 R T M T 0.309 Δ C 1.40 ω r 1.37$ and $G = 4.094 × 107 e x p - 8.358 × 105 R T Δ C 1.36$ ,respectively. The optimized conditions were as follows: crystal seed addition of 1.5%, crystallization temperature of 313.15K, stirring rate of 200r/min, supersaturation of 1.04, ethyl acetate addition rate of 7.037×10^-4L/min, ethyl acetate to methanol mass ratio of 4∶1 and aging time of 2h. Crystals prepared under above conditions had a 30.49% increase in average particle size, a 32.30% reduction in variable coefficient, a 14.65% increase in bulk density, a 7.62% improvement in repose angle, a 30.76% improvement in Carr's index, and a 26.99% improvement in Hausner's ratio. The crystal size, particle size distribution and flowability were all improved.

Key words: naphazoline hydrochloride, crystallization, kinetics, particle size distribution, optimization

中图分类号:

O781

何海霞, 万亚萌, 李帆帆, 牛心雨, 张静雯, 李涛, 任保增. 盐酸萘甲唑啉在甲醇-乙酸乙酯体系中的动力学及结晶工艺[J]. 化工进展, 2024, 43(8): 4230-4245.

HE Haixia, WAN Yameng, LI Fanfan, NIU Xinyu, ZHANG Jingwen, LI Tao, REN Baozeng. Kinetics and crystallization process of naphazoline hydrochloride in methanol-ethyl acetate system[J]. Chemical Industry and Engineering Progress, 2024, 43(8): 4230-4245.

图/表 21

参考文献 32

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甲醇质量分数	过饱和度	初级成核速率/N·m^-3·s^-1
甲醇质量分数	过饱和度	298.15K	303.15K	308.15K	313.15K
1.000	1.01	574.8	896.7	1716	1669
	1.02	992.1	1156	2149	2215
	1.03	1096	1327	2421	2615
	1.04	1450	1634	2884	2887
	1.05	1945	1827	3466	3568
	1.06	2268	2231	3987	4556
	1.07	2594	2420	4513	5277
	1.08	2783	2561	5251	6034
0.900	1.01	472.1	579.6	1038	1277
	1.02	644.3	805.0	1420	1593
	1.03	764.6	970.8	1610	1813
	1.04	1035	1220	1789	2046
	1.05	1396	1545	2334	2622
	1.06	1583	1839	2840	3347
	1.07	1744	1899	3434	3991
	1.08	1889	1955	3907	4330
0.800	1.01	270.7	393.3	480.7	1185
	1.02	403.6	539.7	605.9	1399
	1.03	491.5	655.5	662.5	1552
	1.04	581.0	711.4	812.8	1573
	1.05	694.4	873.3	981.2	2388
	1.06	800.7	1113	1203	2764
	1.07	946.8	1363	1465	3293
	1.08	1036	1570	1810	3671

甲醇质量分数	过饱和度	初级成核速率/N·m^-3·s^-1
甲醇质量分数	过饱和度	298.15K	303.15K	308.15K	313.15K
1.000	1.01	574.8	896.7	1716	1669
	1.02	992.1	1156	2149	2215
	1.03	1096	1327	2421	2615
	1.04	1450	1634	2884	2887
	1.05	1945	1827	3466	3568
	1.06	2268	2231	3987	4556
	1.07	2594	2420	4513	5277
	1.08	2783	2561	5251	6034
0.900	1.01	472.1	579.6	1038	1277
	1.02	644.3	805.0	1420	1593
	1.03	764.6	970.8	1610	1813
	1.04	1035	1220	1789	2046
	1.05	1396	1545	2334	2622
	1.06	1583	1839	2840	3347
	1.07	1744	1899	3434	3991
	1.08	1889	1955	3907	4330
0.800	1.01	270.7	393.3	480.7	1185
	1.02	403.6	539.7	605.9	1399
	1.03	491.5	655.5	662.5	1552
	1.04	581.0	711.4	812.8	1573
	1.05	694.4	873.3	981.2	2388
	1.06	800.7	1113	1203	2764
	1.07	946.8	1363	1465	3293
	1.08	1036	1570	1810	3671

温度/K	甲醇质量分数	界面张力/×10^-5J·m^-2		表面熵因子		特征因子
温度/K	甲醇质量分数	均相成核	非均相成核	均相成核	非均相成核	特征因子
298.15	1.000	5.801	2.140	0.02534	9.350×10^-3	0.05019
303.15	1.000	5.287	1.819	0.02272	7.810×10^-3	0.04069
308.15	1.000	5.720	1.774	0.02418	7.500×10^-3	0.02986
313.15	1.000	6.321	1.959	0.02630	8.150×10^-3	0.02976
298.15	0.900	5.595	1.878	0.02445	8.210×10^-3	0.03782
303.15	0.900	5.372	1.982	0.02309	8.520×10^-3	0.05023
308.15	0.900	6.323	1.932	0.02673	8.170×10^-3	0.02851
313.15	0.900	6.405	1.802	0.02664	7.490×10^-3	0.02225
298.15	0.800	5.496	2.012	0.02401	8.790×10^-3	0.04907
303.15	0.800	6.214	1.940	0.02670	8.340×10^-3	0.03044
308.15	0.800	6.254	1.722	0.02644	7.280×10^-3	0.02089
313.15	0.800	5.765	1.638	0.02398	6.810×10^-3	0.02294

温度/K	甲醇质量分数	界面张力/×10^-5J·m^-2		表面熵因子		特征因子
温度/K	甲醇质量分数	均相成核	非均相成核	均相成核	非均相成核	特征因子
298.15	1.000	5.801	2.140	0.02534	9.350×10^-3	0.05019
303.15	1.000	5.287	1.819	0.02272	7.810×10^-3	0.04069
308.15	1.000	5.720	1.774	0.02418	7.500×10^-3	0.02986
313.15	1.000	6.321	1.959	0.02630	8.150×10^-3	0.02976
298.15	0.900	5.595	1.878	0.02445	8.210×10^-3	0.03782
303.15	0.900	5.372	1.982	0.02309	8.520×10^-3	0.05023
308.15	0.900	6.323	1.932	0.02673	8.170×10^-3	0.02851
313.15	0.900	6.405	1.802	0.02664	7.490×10^-3	0.02225
298.15	0.800	5.496	2.012	0.02401	8.790×10^-3	0.04907
303.15	0.800	6.214	1.940	0.02670	8.340×10^-3	0.03044
308.15	0.800	6.254	1.722	0.02644	7.280×10^-3	0.02089
313.15	0.800	5.765	1.638	0.02398	6.810×10^-3	0.02294

停留时间/min	悬浮密度/kg·m^-3	斜率	生长速率/μm·min^-1	初始粒度密度对数值	初始粒度密度/10¹⁹μm^-4	初始成核速率/×10⁴L·min^-1
10	5.64	-0.26692	0.37464	45.195	4.2483	15.916
15	6.46	-0.26378	0.25274	44.281	1.7034	4.3051
20	6.98	-0.63040	0.19009	43.867	1.1251	2.1387
25	7.64	-0.23503	0.17019	43.961	1.2370	2.1053
30	8.06	-0.23454	0.14212	44.145	1.4870	2.1134
35	8.38	-0.23379	0.12221	43.702	9.5488	1.1669
40	8.84	-0.23354	0.10705	43.818	1.0723	1.1449
45	9.38	-0.22802	0.097460	43.302	0.64000	0.62372