Application of ionic liquids in pharmaceutical crystal engineering

doi:10.16085/j.issn.1000-6613.2018-1482

Chemical Industry and Engineering Progress ›› 2019, Vol. 38 ›› Issue (05): 2389-2401.DOI: 10.16085/j.issn.1000-6613.2018-1482

• Biochemical and pharmaceutical engineering • Previous Articles Next Articles

Application of ionic liquids in pharmaceutical crystal engineering

Zeren SHANG^1,^2,³(),Weiguo HU^1,^2,^3,⁴,Weiwei TANG^1,^2,³,Lina JIA^1,^2,³,Mingchen LI^1,^2,³,Yanxiao ZHAO^1,^2,³,Ning WEI^1,^2,³,Junbo GONG^1,^2,³()

1. National Engineering Research Center of Industry Crystallization Technology，School of Chemical Engineering and Technology，Tianjin University，Tianjin 300072, China
2. Collaborative Innovation Center of Chemical Science and Engineering Tianjin，Tianjin 300072, China
3. Key Laboratory of Modern Drug Delivery and High Efficiency in Tianjin University，Tianjin 300072, China
4. North China Pharmaceutical Company Ltd. ，Shijiazhuang 050015，Hebei，China

Received:2018-07-17 Revised:2019-01-03 Online:2019-05-05 Published:2019-05-05
Contact: Junbo GONG

离子液体在药物晶体工程中的应用

尚泽仁^1,^2,³(),胡卫国^1,^2,^3,⁴,汤伟伟^1,^2,³,贾丽娜^1,^2,³,李鸣晨^1,^2,³,赵燕晓^1,^2,³,魏宁^1,^2,³,龚俊波^1,^2,³()

1. 天津大学化工学院国家工业结晶工程技术研究中心，天津 300072
2. 天津化学化工协同创新中心，天津 300072
3. 现代药物传递及功能高效化天津市重点实验室，天津 300072
4. 华北制药股份有限公司，河北石家庄 050015

通讯作者: 龚俊波
作者简介:<named-content content-type="corresp-name">尚泽仁</named-content>（1994—），男，硕士研究生，研究方向为药物晶体工程。E-mail：<email>shangzeren@tju.edu.cn</email>。
基金资助:
国家自然科学基金(21676179、91634117、81361140344);国家科技重大专项(2017ZX07402003、2017ZX09101001);天津市科技计划(15JCZDJC33200)

Abstract

Abstract:

In recent years, using ionic liquids instead of traditional solvents to regurate various interactions in the crystallization process to obtain novel crystal structures is the research front of pharmaceutical crystal engineering. In ionic liquid systems, researchers have produced new pharmaceutical crystal forms or crystal habits which were not achievable with traditional solvents, and the corresponding mechanisms have also been studied preliminarily. In this review, the achievements of the use of ionic liquids in pharmaceutical crystal engineering were summaried, including the compositions and properties of ionic liquids, pharmaceutical solubilization, pharmaceutical polymorphs, crystal habits and formation of pharmaceutical co-crystals, and salts directed by ionic liquids. According to the intermolecular interaction, the mechanisms of these achievements were analyzed by infrared spectroscopy, molecular dynamics simulation and other means, in which hydrogen bond and van der Waals interaction have played an important role. The existing problems in this field include the selection of ionic liquids, the corresponding mechanism, and practical applications. The selection criteria for ionic liquids and in-depth mechanism research shall be the main research direction in the future.

Key words: ionic liquid, pharmaceutical crystal engineering, solubilization, intermolecular interaction

摘要：

近年来，使用离子液体替代传统溶剂参与调节结晶过程中的各种相互作用以获得新颖的晶体结构是药物晶体工程的研究前沿。研究人员在离子液体体系中得到了使用传统溶剂无法制得的药物晶型或晶习并进行了相应机理的初步探索。针对离子液体在药物晶体工程中的应用，本文从离子液体的组成和性质及其在药物增溶、药物晶型及晶习的调控和药物共晶及盐的制备几方面展开，首次综述了相关研究成果并基于红外光谱、分子动力学模拟等手段从相互作用的角度对机理进行分析，其中氢键和范德华力相互作用起到了重要影响。最后针对该领域现存的问题如离子液体的选择处于盲筛阶段，相应机理研究缺乏和应用范围不广泛，指出建立系统的离子液体选择标准和深入研究机理是未来的主要研究方向。

关键词: 离子液体, 药物晶体工程, 增溶, 分子间相互作用

CLC Number:

O645

Zeren SHANG, Weiguo HU, Weiwei TANG, Lina JIA, Mingchen LI, Yanxiao ZHAO, Ning WEI, Junbo GONG. Application of ionic liquids in pharmaceutical crystal engineering[J]. Chemical Industry and Engineering Progress, 2019, 38(05): 2389-2401.

尚泽仁, 胡卫国, 汤伟伟, 贾丽娜, 李鸣晨, 赵燕晓, 魏宁, 龚俊波. 离子液体在药物晶体工程中的应用[J]. 化工进展, 2019, 38(05): 2389-2401.

Figures/Tables 18

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药物名称	晶型	临床疗效	文献
甲苯达唑	晶型A，晶型B，晶型C	晶型C > 晶型A	[8]
法莫替丁	晶型A，晶型B，晶型C，晶型D	晶型B > 晶型A	[9]
棕榈氯霉素	晶型A，晶型B，晶型C	晶型B和晶型C > 晶型A	[10]
尼群地平	晶型Ⅰ，晶型Ⅱ，晶型Ⅲ，晶型Ⅳ	晶型Ⅳ > 晶型Ⅰ	[11]
利福定	晶型Ⅰ，晶型Ⅱ，晶型Ⅲ，晶型Ⅳ	晶型Ⅳ > 晶型Ⅱ	[12]

药物名称	晶型	临床疗效	文献
甲苯达唑	晶型A，晶型B，晶型C	晶型C > 晶型A	[8]
法莫替丁	晶型A，晶型B，晶型C，晶型D	晶型B > 晶型A	[9]
棕榈氯霉素	晶型A，晶型B，晶型C	晶型B和晶型C > 晶型A	[10]
尼群地平	晶型Ⅰ，晶型Ⅱ，晶型Ⅲ，晶型Ⅳ	晶型Ⅳ > 晶型Ⅰ	[11]
利福定	晶型Ⅰ，晶型Ⅱ，晶型Ⅲ，晶型Ⅳ	晶型Ⅳ > 晶型Ⅱ	[12]

名称	英文缩写	CAS #
1-丁基-3-甲基咪唑双三氟甲磺酰亚胺盐	[C₄mim][N(CF₃SO₂)₂]	174899-83-3
1-己基-3-甲基咪唑双三氟甲磺酰亚胺盐	[C₆mim][N(CF₃SO₂)₂]	382150-50-7
1-丁基-3-甲基咪唑四氟硼酸盐	[C₄mim][BF₄]	174501-65-6
1-己基-3-甲基咪唑四氟硼酸盐	[C₆mim][BF₄]	244193-50-8
1-烯丙基-3-乙基咪唑四氟硼酸盐	[aeim][BF₄]	945732-42-3
1-丁基-2,3-二甲基咪唑四氟硼酸盐	[bdmim][BF₄]	402846-78-0
1,3-二烯丙基咪唑四氟硼酸盐	[aaim][BF₄]	852699-06-0
1-乙基-3-甲基咪唑硫酸乙酯盐	[emim][EtSO₄]	342573-75-5
1-丁基-3-甲基咪唑六氟磷酸盐	[bmim][PF₆]	174501-64-5
1-乙基-3-甲基咪唑甲基磷酸酯盐	[emim][CH₃O(H)PO₂]	81994-80-1
1-己基-3-甲基咪唑六氟磷酸盐	[hmim][PF₆]	304680-35-1
1-乙基-3-甲基咪唑乙酸盐	[C₂mim][OAc]	143314-17-4
1-丁基-3-甲基咪唑溴盐	[C₄mim]Br	85100-77-2
三己基(十四烷基)鏻双(草酸根)硼酸盐	[P_6,6,6,14][BOB]	880497-87-0

名称	英文缩写	CAS #
1-丁基-3-甲基咪唑双三氟甲磺酰亚胺盐	[C₄mim][N(CF₃SO₂)₂]	174899-83-3
1-己基-3-甲基咪唑双三氟甲磺酰亚胺盐	[C₆mim][N(CF₃SO₂)₂]	382150-50-7
1-丁基-3-甲基咪唑四氟硼酸盐	[C₄mim][BF₄]	174501-65-6
1-己基-3-甲基咪唑四氟硼酸盐	[C₆mim][BF₄]	244193-50-8
1-烯丙基-3-乙基咪唑四氟硼酸盐	[aeim][BF₄]	945732-42-3
1-丁基-2,3-二甲基咪唑四氟硼酸盐	[bdmim][BF₄]	402846-78-0
1,3-二烯丙基咪唑四氟硼酸盐	[aaim][BF₄]	852699-06-0
1-乙基-3-甲基咪唑硫酸乙酯盐	[emim][EtSO₄]	342573-75-5
1-丁基-3-甲基咪唑六氟磷酸盐	[bmim][PF₆]	174501-64-5
1-乙基-3-甲基咪唑甲基磷酸酯盐	[emim][CH₃O(H)PO₂]	81994-80-1
1-己基-3-甲基咪唑六氟磷酸盐	[hmim][PF₆]	304680-35-1
1-乙基-3-甲基咪唑乙酸盐	[C₂mim][OAc]	143314-17-4
1-丁基-3-甲基咪唑溴盐	[C₄mim]Br	85100-77-2
三己基(十四烷基)鏻双(草酸根)硼酸盐	[P_6,6,6,14][BOB]	880497-87-0

名称英文缩写	熔点/°C	黏度25℃/Pa?s	亲水/疏水
[C₄mim][N(CF₃SO₂)₂]	-4.9	0.0511	亲水
[C₆mim][N(CF₃SO₂)₂]	-10.5	0.0705	亲水
[C₄mim][BF₄]	-17.0	0.0949	亲水
[C₆mim][BF₄]	-81.0	0.1456	疏水
[aeim][BF₄]	—	—	亲水
[bdmim][BF₄]	39.7	0.6500	亲水
[aaim][BF₄]	4.3	—	亲水
[emim][EtSO₄]	-65.0	0.0962	亲水
[bmim][PF₆]	10.9	0.2740	疏水
[emim][CH₃O(H)PO₂]	—	0.1564 ^①	亲水
[hmim][PF₆]	-80.0	0.4830	疏水
[C₂mim][OAc]	< -20.0	0.1285	亲水
[C₄mim]Br	72.9	0.0570 ^②	亲水
[P_6,6,6,14][BOB]	—	0.6150 ^①	亲水

Application of ionic liquids in pharmaceutical crystal engineering

离子液体在药物晶体工程中的应用

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晶型	结晶方法	溶剂	文献
晶型Ⅰ无水物（C₂₀H₃₂N₅O₈P）	冷却结晶	丙酮+二正丁醚	[60]
晶型Ⅱ二水合物（C₂₀H₃₂N₅O₈P·2H₂O）	溶析结晶	甲醇/水	[60]
晶型Ⅲ溶剂化物（C₂₀H₃₂N₅O₈P·CH₃OH）	蒸发结晶	甲醇	[60]
晶型Ⅳ盐型（C₂₀H₃₂N₅O₈P·C₄H₄O₄）	冷却结晶	异丙醇+富马酸	[60]
晶型Ⅴ无水物（C₂₀H₃₂N₅O₈P）	喷雾干燥	乙醇	[61]
晶型Ⅵ一水合物（C₂₀H₃₂N₅O₈P·H₂O）	蒸发结晶	二氯甲烷+甲醇+水蒸气	[62]
晶型Ⅶ溶剂化物（C₂₀H₃₂N₅O₈P·C₄H₁₀O）	溶析结晶	正丁醇/己烷	[63]
晶型Ⅷ无水物（C₂₀H₃₂N₅O₈P）	溶析结晶	[aeim][BF₄]/水	[31]
晶型Ⅸ半水合物（C₂₀H₃₂N₅O₈P·0.5H₂O）	溶析结晶	[aeim][BF₄]/水	[31]
晶型Ⅹ无水物（C₂₀H₃₂N₅O₈P）	溶析结晶	二氯甲烷/正己烷	[64]
晶型Ⅺ无水物（C₂₀H₃₂N₅O₈P）	溶析结晶	[aeim][BF₄]/[bdmim][BF₄]	[32,33]

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