一种新型药用辅料阴离子交换树脂的合成

doi:10.5246/jcps.2025.02.009

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (2): 109-125.DOI: 10.5246/jcps.2025.02.009

一种新型药用辅料阴离子交换树脂的合成

殷站暖¹^,⁴, 孟祥欢², 冯颖淑³, 李可⁴, 唐欣怡⁴, 刘宏飞¹^,²^,⁴^,^*(), 何海冰⁴^,⁵^,^*(), 米伟⁶^,^*

^1. 安徽中医药大学, 安徽合肥 230000
^2. 江苏大学药学院, 江苏镇江 212013
^3. 镇江学院医药化工研究所镇江功能化学重点实验室, 江苏镇江 212028
^4. 江苏海之宏生物医药有限公司, 江苏南通 226100
^5. 沈阳药科大学药学系, 辽宁沈阳 110016
^6. 江西阿尔法高科药业有限公司, 江西萍乡 337000

收稿日期:2024-10-13 修回日期:2024-11-12 接受日期:2024-12-23 出版日期:2025-03-01 发布日期:2025-03-02
通讯作者: 刘宏飞, 何海冰, 米伟

Synthesis of a novel pharmaceutical excipient: An anion exchange resin

Zhannuan Yin¹^,⁴, Xianghuan Meng², Yingshu Feng³, Ke Li⁴, Xinyi Tang⁴, Hongfei Liu¹^,²^,⁴^,^*(), Haibing He⁴^,⁵^,^*(), Wei Mi⁶^,^*

¹ Anhui University of Chinese Medicine, Hefei 230000, Anhui, China
² College of Pharmacy, Jiangsu University, Zhenjiang 212013, Jiangsu, China
³ Zhenjiang Key Laboratory of Functional Chemistry, Institute of Medicine & Chemical Engineering, Zhenjiang College, Zhenjiang 212028, Jiangsu, China
⁴ Jiangsu Haizhihong Biopharmaceutical Co., Ltd., Nantong 226100, Jiangsu, China
⁵ Department of Pharmaceutics, Shen yang Pharmaceutical University, Shenyang 110016, Liaoning, China
⁶ Jiangxi Alpha Hi-tech Pharmaceutical Co., Ltd., Pingxiang, 337000, Jiangxi, China

Received:2024-10-13 Revised:2024-11-12 Accepted:2024-12-23 Online:2025-03-01 Published:2025-03-02
Contact: Hongfei Liu, Haibing He, Wei Mi
Supported by:
2023 Nantong Jianghai Talents Project, the Nantong Social Livelihood Science and Technology Plan for 2023, and the 2022 New Drugs and Platform Enhancement Project of the Yangtze Delta Drug Advanced Research Institute. Additionally, support was provided by the Zhenjiang Science and Technology Project (Grant No. SH2020048), the China Postdoctoral Science Foundation (Grant No. 2020M681532), the Jiangsu Planned Projects for Postdoctoral Research Funds (Grant No. 2020Z209), and the Natural Science Research Projects of Universities in Jiangsu Province (Grant No. 20KJD350001).

摘要/Abstract

摘要：

本研究旨在制备一种新型的药用辅料——阴离子交换树脂。首先, 采用悬浮聚合法合成了聚苯乙烯-二乙烯基苯微球。接下来, 以聚苯乙烯二乙烯基苯微球为基质, 用甲醇、甲醛和氯磺酸对其进行氯甲基化。通过优化反应条件, 用红外光谱、扫描电子显微镜和莫尔法对氯甲基化微球进行了表征。在合适的反应条件下, 产物呈均匀球形, 平均粒径约190 µm, 聚苯乙烯-二乙烯基苯微球可以成功引入氯含量为14.67%的氯甲基, 扫描电子显微镜显示反应后微球的外观没有显著变化。研究结果表明, 阴离子交换树脂已成功制备, 经过表征和质量研究, 离子交换树脂符合标准。

关键词: 悬浮聚合反应, 聚苯乙烯二乙烯基苯, 季铵化反应, 阴离子交换树脂, 流化床包衣法, 药动学研究

Abstract:

The aim of this study was to develop a novel pharmaceutical excipient: an anion exchange resin. Initially, polystyrene-divinylbenzene (PS-DVB) microspheres were synthesized via suspension polymerization. Subsequently, these microspheres served as a substrate for chloromethylation using methanol, formaldehyde, and chlorosulfonic acid. By optimizing the reaction conditions, the chloromethylated microspheres were characterized using infrared spectroscopy, scanning electron microscopy, and the Mohr method. Under optimal reaction conditions, the resulting products exhibited uniformity and spherical morphology, with an average particle size of approximately 190 µm. The PS-DVB microspheres effectively incorporated chloromethyl groups, as evidenced by a chlorine content of 14.67%. Scanning electron microscopy analysis indicated that the appearance of the microspheres remained largely unchanged post-reaction. Overall, the research findings demonstrated the successful preparation of the anion exchange resin. Characterization and quality assessment confirmed that the ion exchange resin met the required standards.

Key words: Suspension polymerization reaction, Polystyrene-divinylbenzene, Quaternarization reaction, Anion exchange resin, Fluidized bed coating method, Pharmacokinetic research

Supporting:

殷站暖, 孟祥欢, 冯颖淑, 李可, 唐欣怡, 刘宏飞, 何海冰, 米伟. 一种新型药用辅料阴离子交换树脂的合成[J]. 中国药学(英文版), 2025, 34(2): 109-125.

Zhannuan Yin, Xianghuan Meng, Yingshu Feng, Ke Li, Xinyi Tang, Hongfei Liu, Haibing He, Wei Mi. Synthesis of a novel pharmaceutical excipient: An anion exchange resin[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(2): 109-125.

图/表 29

Figure 1. Synthetic route of PS-DVB microspheres.

Table 1. Factors for the synthesis of PS-DVB microspheres.

Figure 2. Chloromethylation reaction route of PS-DVB.

Figure 3. Synthesis route of strong basic anion exchange resin.

Figure 4. SEM of 1% DVB crosslinked PS-DVB polymers (×100, ×500) (A); SEM of 2% DVB crosslinked PS-DVB polymers (×100, ×500) (B); SEM of 3% DVB crosslinked PS-DVB polymers (×50, ×500) (C).

Figure 5. SEM of polymers prepared at the amount of PVA is 5% of the amount of styrene (×100, ×1000) (A); SEM of polymers prepared at the amount of PVA is 7.5% of the amount of styrene (×50, ×3000) (B); SEM of polymers prepared at the amount of PVA is 10% of the amount of styrene (×100, ×1000) (C).

Figure 6. SEM of polymers prepared at the amount of BPO is 4% of the amount of styrene (×50, ×1000) (A); SEM of polymers prepared at the amount of BPO is 3% of the amount of styrene (×50, ×200) (B); SEM of polymers prepared at the amount of BPO is 2% of the amount of styrene (×50, ×200) (C).

Table 2. Saturated swelling degree and apparent density of PS-DVB.

Figure 7. SEM of polymers with a stirring speed of 700 r/min (×50, ×500) (A); SEM of polymers with a stirring speed of 1000 r/min (×100, ×1000) (B); SEM of polymers with a stirring speed of 1300 r/min (×100, ×500) (C).

Figure 8. Histogram of polymers with a stirring speed of 700 r/min; Histogram of polymers with a stirring speed of 1000 r/min. Histogram of polymers with a stirring speed of 1300 r/min.

Figure 9. FTIR of PS-DVB microsphere polymer.

Figure 10. Thermogravimetric curve of PS-DVB microspheres.

Figure 11. Histogram of PS-DVB polymers.

Figure 12. Effect of chloromethylation reagent dosage on chlorine content.

Figure 13. Effect of chloromethylation reaction temperature on chlorine content.

Figure 14. Effect of chloromethylation reaction time on chlorine content.

Table 3. Effect of different catalysts on chlorine content.

Figure 15. Effect of catalyst amount (FeCl3) on chlorine content.

Table 4. Saturated swelling degree and apparent density of PS-DVB-Cl.

Figure 16. FTIR of PS-DVB-Cl microspheres.

Figure 17. The thermogravimetric curve of PS-DVB-Cl microspheres.

Figure 18. Effect of reaction time on nitrogen content.

Figure 19. Effect of quaternization reagent dosage on nitrogen content.

Figure 20. Effect of reaction temperature on nitrogen content.

Table 5. Saturated swelling degree and apparent density of anion exchange resin.

Figure 21. FTIR of anion exchange resin.

Figure 22. The thermogravimetric curve of strongly basic anion exchange resin.

Table 6. Loss on drying of imported resin and self-made resin.

Table 7. Residue of ignition of imported resin and self-made resin.

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一种新型药用辅料阴离子交换树脂的合成

Synthesis of a novel pharmaceutical excipient: An anion exchange resin

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