添加剂作用下阿司匹林结晶模拟和实验研究

doi:10.11949/0438-1157.20201770

化工学报 ›› 2021, Vol. 72 ›› Issue (9): 4796-4807.DOI: 10.11949/0438-1157.20201770

添加剂作用下阿司匹林结晶模拟和实验研究

李闯¹(),张扬¹(),刘小娟¹,王学重²()

^1.华南理工大学化学与化工学院，广东广州 510640
^2.北京石油化工学院新材料与化工学院，北京市恩泽生物质精细化工重点实验室，制药和结晶系统工程团队，北京 102617

收稿日期:2020-12-09 修回日期:2021-08-02 出版日期:2021-09-05 发布日期:2021-09-05
通讯作者: 张扬,王学重
作者简介:李闯（1994—），男，硕士研究生，1508536927@qq.com
基金资助:
国家自然科学基金重点项目(61633006);广东省应用型科技研发资金项目(2015B020232007);广东省自然科学基金项目(2017A030310262);广东省自然科学基金面上项目(2018A030313263);中央高校基本科研业务费专项资金(2017MS092);青海省科技计划项目(2021-GX-C10);北京石油化工学院恩泽生物质精细化工北京市重点实验室开放课题（药物连续结晶过程的在线监测和模拟）

Modeling and experimental study of additives on solution crystallization of aspirin

Chuang LI¹(),Yang ZHANG¹(),Xiaojuan LIU¹,Xuezhong WANG²()

^1.School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, Guangdong, China
^2.Pharmaceutical and Crystallization Process System Engineering Group, Beijing City Key Laboratory of Enze Biomass Fine Chemicals, College of New Materials and Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China

Received:2020-12-09 Revised:2021-08-02 Online:2021-09-05 Published:2021-09-05
Contact: Yang ZHANG,Xuezhong WANG

摘要/Abstract

摘要：

晶体形貌作为晶体产品的重要质量指标，不仅会影响产品流动性、稳定性、溶出速率和生物可利用度等产品的质量指标，还会对过滤、干燥、压片等下游操作造成影响。通过分子模拟的方法指导阿司匹林冷却-反溶剂结晶过程的添加剂筛选，以添加剂作为晶体形貌的改性剂，降低阿司匹林晶体的长径比优化晶体形貌。通过单因素实验考查了添加剂浓度、晶种加入量、降温速率、搅拌速率和加水速率对阿司匹林晶体产品形貌、流动性和粒度分布等的影响，确定了较优的工艺条件。实验结果表明加入聚乙烯吡咯烷酮（PVP）作为添加剂可以降低阿司匹林晶体长径比，获得形貌为短棱柱状的晶体产品，能够显著改变晶体形貌优化产品的流动性。

关键词: 结晶, 阿司匹林, 分子模拟, 添加剂, 聚乙烯吡咯烷酮, 晶体形貌, 优化

Abstract:

As an important quality indicator of crystalline products, crystal morphology could have major impact not only on such quality measures as solid flowability, stability, dissolution rate and bioavailability, but also on downstream operations such as filtration, drying, and tableting. In this work, molecular simulation was used to guide the selection of additives in the cooling anti-solvent crystallization process of aspirin. The additives were used as crystal morphology modifiers to reduce the aspect ratio of aspirin crystals in order to optimize the crystal morphology. The effects of additive concentration, seed crystal addition, cooling rate, stirring rate and water addition rate on the morphology, flowability and particle size distribution of aspirin crystal products were examined to determine the appropriate experimental conditions. The experimental result showed that the addition of polyvinylpyrrolidone (PVP) as an additive can reduce the aspect ratio of aspirin crystals and obtain short prismatic crystal products, which can significantly change the crystal morphology and optimize the flowability of the product.

Key words: crystallization, aspirin, molecular simulation, additives, polyvinylpyrrolidone, crystal morphology, optimization

中图分类号:

李闯, 张扬, 刘小娟, 王学重. 添加剂作用下阿司匹林结晶模拟和实验研究[J]. 化工学报, 2021, 72(9): 4796-4807.

Chuang LI, Yang ZHANG, Xiaojuan LIU, Xuezhong WANG. Modeling and experimental study of additives on solution crystallization of aspirin[J]. CIESC Journal, 2021, 72(9): 4796-4807.

图/表 20

图 1 阿司匹林结晶实验装置示意图1—蠕动泵; 2—浊度仪; 3—二维成像系统; 4—浊度探头; 5—二维成像系统探头; 6—机械搅拌; 7—热电偶温度计探头; 8—250 ml四口结晶器; 9—温度控制器(Julabo FP51); 10—带有浊度和图像采集和处理软件的计算机

Fig.1 Schematic of aspirin crystallization experiments

图 2 阿司匹林晶胞、AE理论晶习及实验晶习

Fig.2 Aspirin unit cell, AE morphology and experimental crystal habits

表1 AE模型模拟得到的阿司匹林晶体理论晶习及晶面占总晶面面积百分比

Table 1 Theoretical crystal habits and percentage of total crystal plane area obtained from AE model

Face	Multiplicity	面积占比/%
（1 0 0）	2	51.93
（1 1 0）	4	10.42
（0 1 1）	4	11.44
（0 0 2）	2	25.39
（1 1 -1）	4	0.60
（1 1 1）	4	0.22

图3 阿司匹林不同晶面上的原子及官能团分布

Fig.3 Atoms and functional groups on different crystal planes

图4 抑制阿司匹林晶体（0 1 1）面生长晶体形貌变化示意

Fig.4 Schematic diagram of morphological changes of crystals that inhibit the growth of aspirin crystals (0 1 1)

表2 添加剂在阿司匹林不同晶面的吸附能

Table 2 Adsorption energy of additives on different crystal faces of aspirin

添加剂（聚合度）	E_ads/(kcal/mol)
添加剂（聚合度）	（1 0 0）	（1 1 0）	（0 1 1）	（0 0 2）	（1 1 -1）	（1 1 1）
PVP（45）	-122.35	-135.69	-159.11	-129.30	-120.90	-90.74
PVP（90）	-220.06	-237.32	-277.11	-207.90	-180.92	-148.76
PVP（135）	-260.23	-303.76	-338.57	-256.32	-222.13	-195.33
HPMC（100）	-301.15	-211.30	-197.18	-311.26	-268.76	-268.81

图 5 阿司匹林在不同含水量乙醇水溶剂中的质量溶解度拟合曲线

Fig.5 Fitting curves of aspirin mass solubility in ethanol water solvent with different water content

表 3 阿司匹林质量溶解度拟合参数及最大溶解度

Table 3 Mass solubility fitting parameters and maximum solubility of aspirin

T/K	b₁	b₂	b₃	b₄	b₅	最大溶解度C_max×10^-2/(g/g)	w×10^-2	RMSD×10^-2
278.15	-2.105	1.990	-13.57	18.80	-16.62	13.21	8.772	0.1761
283.15	-1.921	1.953	-11.01	13.53	-13.98	16.14	10.66	0.0716
293.15	-1.538	1.895	-7.609	1.179	-0.708	24.20	12.80	0.1114
298.15	-1.349	2.144	-9.451	7.815	-7.170	29.65	13.15	0.1393
303.15	-1.130	1.716	-6.801	2.970	-3.928	36.17	13.53	0.1843
313.15	-0.790	1.934	-6.496	3.221	-4.178	52.91	16.31	0.2273
323.15	-0.436	2.340	-9.745	17.81	-17.69	78.37	20.21	0.3460
333.15	-0.082	0.551	4.396	-13.09	6.882	121.0	34.97	0.6620

图6 不同添加剂实验条件下阿司匹林晶体产品形貌

Fig.6 Observed morphology of aspirin crystals under different additive conditions

表4 不同添加剂条件下阿司匹林实验晶体长径比

Table 4 Experimental aspirin crystal aspect ratio under different additives

添加剂	统计数目	平均长径比
0	60	1.93±0.32
0.05% PVP K13-18	60	1.58±0.26
0.01% PVP K29-32	72	1.63±0.22
0.05% PVP K29-32	73	1.39±0.24
0.1% PVP K29-32	64	1.10±0.21
0.05% PVP K88-96	80	1.22±0.22
0.01% HPMC	52	3.81±1.25
0.05% HPMC	66	6.19±2.01
0.1% HPMC	78	7.62±2.41

表5 单因素实验条件汇总

Table 5 Summary of single factor experiment conditions

实验编号	添加剂浓度/%	晶种量/%	降温速率/ (K/min)	搅拌速率/(r/min)	加水速率/(ml/min)
1	0	1	0.3	250	5
2	0.01	1	0.3	250	5
3	0.05	1	0.3	250	5
4	0.10	1	0.3	250	5
5	0.05	0	0.3	250	5
6	0.05	0.5	0.3	250	5
7	0.05	3	0.3	250	5
8	0.05	1	0.1	250	5
9	0.05	1	0.5	250	5
10	0.05	1	0.3	150	5
11	0.05	1	0.3	350	5
12	0.05	1	0.3	250	20
13	0.05	1	0.3	250	一次性倾倒

表6 实验结果汇总

Table 6 Summary of experimental results

实验编号	D₁₀/μm	D₅₀/μm	D₉₀/μm	松装密度/(g/cm³)	振实密度/(g/cm³)	休止角/(°)	收率/%	CV/%
1	201	544	1030	0.41	0.52	43	88.91	56.37
2	144	438	886	0.58	0.67	33	88.61	62.74
3	144	363	712	0.72	0.78	26	88.33	57.13
4	107	270	496	0.71	0.75	29	88.15	53.37
5	71.2	269	521	0.39	0.51	45	88.73	61.04
6	105	291	549	0.53	0.63	30	88.65	58.01
7	139	558	1040	0.65	0.73	28	87.85	56.83
8	279	579	1080	0.61	0.73	31	88.75	51.13
9	147	437	1170	0.53	0.68	35	87.35	86.71
10	35.3	472	1110	0.43	0.56	41	88.55	83.96
11	121	358	901	0.68	0.73	30	88.43	80.66
12	86.6	294	570	0.73	0.77	26	88.41	58.21
13	50.8	542	988	0.70	0.75	30	88.17	64.13
原料	74.5	459	916	0.43	0.55	40	—	67.81

图7 不同添加剂浓度下阿司匹林晶体形貌

Fig.7 Crystal morphology of aspirin under different additive concentrations

图8 不同晶种量条件下阿司匹林晶体形貌

Fig.8 Crystal morphology of aspirin under different seed crystal conditions

图9 未加晶种条件下的阿司匹林结晶过程成核生长的形貌变化二维监测图

Fig.9 Two-dimensional monitoring diagram of the change of crystal morphology without seed crystal conditions

图10 不同降温速率条件下阿司匹林晶体形貌

Fig.10 Crystal morphology of aspirin under different cooling rates

图11 不同搅拌速率条件下阿司匹林晶体形貌

Fig.11 Crystal morphology of aspirin under different stirring rates

图12 不同加水速率条件下阿司匹林晶体形貌

Fig.12 Crystal morphology of aspirin under different water addition rates

图13 阿司匹林原料与优化产品的显微镜形貌对比

Fig.13 Comparison of the appearance of aspirin raw materials and optimized products

图 14 阿司匹林原料和优化产品PXRD表征结果

Fig.14 PXRD characterization results of aspirin raw materials and optimized products

参考文献 32

1	Gupta K M, Yin Y N, Poornachary S K, et al. Atomistic simulation to understand anisotropic growth behavior of naproxen crystal in the presence of polymeric additives[J]. Crystal Growth & Design, 2019, 19(7): 3768-3776.
2	Jing D D, Liu A L, Wang J K, et al. Study on crystal morphology of penicillin sulfoxide in different solvents using binding energy[J]. Organic Process Research & Development, 2015, 19(3): 410-415.
3	Liang Z Z, Yi Q H, Wang W, et al. A systematic study of solvent effect on the crystal habit of dirithromycin solvates by computer simulation[J]. Computers & Chemical Engineering, 2014, 62: 56-61.
4	An J H, Choi G J, Kim W S. Polymorphic and kinetic investigation of adefovir dipivoxil during phase transformation[J]. International Journal of Pharmaceutics, 2012, 422(1/2): 185-193.
5	Parimaladevi P, Srinivasan K. Influence of supersaturation level on the morphology of α-lactose monohydrate crystals[J]. International Dairy Journal, 2014, 39(2): 301-311.
6	Wang C, Zhang X, Du W, et al. Effects of solvent and supersaturation on crystal morphology of cefaclor dihydrate: a combined experimental and computer simulation study[J]. CrystEngComm, 2016, 18(47): 9085-9094.
7	Liang Z Z, Zhang M, Wu F, et al. Supersaturation controlled morphology and aspect ratio changes of benzoic acid crystals[J]. Computers & Chemical Engineering, 2017, 99: 296-303.
8	Tan W H, Yang X Y, Duan X Z, et al. Understanding supersaturation-dependent crystal growth of L-alanine in aqueous solution[J]. Crystal Research and Technology, 2016, 51(1): 23-29.
9	李兰菊, 李秀喜, 徐三. 阿司匹林结晶过程的在线分析[J]. 化工学报, 2018, 69(3): 1046-1052.
	Li L J, Li X X, Xu S. Online monitor of Aspirin crystallization process[J]. CIESC Journal, 2018, 69(3): 1046-1052.
10	Yin Y N, Chow P S, Tan R B H. Molecular simulation study of the effect of various additives on salbutamol sulfate crystal habit[J]. Molecular Pharmaceutics, 2011, 8(5): 1910-1918.
11	Li Z H, Shi P, Yang Y, et al. Tuning crystallization and stability of the metastable polymorph of dl-methionine by a structurally similar additive[J]. CrystEngComm, 2019, 21(24): 3731-3739.
12	Zhang Y, Liu J J, Wan J, et al. Two dimensional population balance modelling of crystal growth behaviour under the influence of impurities[J]. Advanced Powder Technology, 2015, 26(2): 672-678.
13	Clydesdale G, Thomson G B, Walker E M, et al. A molecular modeling study of the crystal morphology of adipic acid and its habit modification by homologous impurities[J]. Crystal Growth & Design, 2005, 5(6): 2154-2163.
14	Weissbuch I, Lahav M, Leiserowitz L. Toward stereochemical control, monitoring, and understanding of crystal nucleation[J]. Crystal Growth & Design, 2003, 3(2): 125-150.
15	Kuvadia Z B, Doherty M F. Effect of structurally similar additives on crystal habit of organic molecular crystals at low supersaturation[J]. Crystal Growth & Design, 2013, 13(4): 1412-1428.
16	Poornachary S K, Lau G, Chow P S, et al. The effect and counter-effect of impurities on crystallization of an agrochemical active ingredient: stereochemical rationalization and nanoscale crystal growth visualization[J]. Crystal Growth & Design, 2011, 11(2): 492-500.
17	Tian F, Baldursdottir S, Rantanen J. Effects of polymer additives on the crystallization of hydrates: a molecular-level modulation[J]. Molecular Pharmaceutics, 2009, 6(1): 202-210.
18	Vetter T, Mazzotti M, Brozio J. Slowing the growth rate of ibuprofen crystals using the polymeric additive pluronic F₁₂₇[J]. Crystal Growth & Design, 2011, 11(9): 3813-3821.
19	Klapwijk A R, Simone E, Nagy Z K, et al. Tuning crystal morphology of succinic acid using a polymer additive[J]. Crystal Growth & Design, 2016, 16(8): 4349-4359.
20	Ilevbare G A, Liu H Y, Edgar K J, et al. Effect of binary additive combinations on solution crystal growth of the poorly water-soluble drug, ritonavir[J]. Crystal Growth & Design, 2012, 12(12): 6050-6060.
21	Simone E, Cenzato M V, Nagy Z K. A study on the effect of the polymeric additive HPMC on morphology and polymorphism of ortho-aminobenzoic acid crystals[J]. Journal of Crystal Growth, 2016, 446: 50-59.
22	Gao Y, Olsen K W. Drug-polymer interactions at water-crystal interfaces and implications for crystallization inhibition: molecular dynamics simulations of amphiphilic block copolymer interactions with tolazamide crystals[J]. Journal of Pharmaceutical Sciences, 2015, 104(7): 2132-2141.
23	Han D D, Yu B, Liu Y M, et al. Effects of additives on the morphology of thiamine nitrate: the great difference of two kinds of similar additives[J]. Crystal Growth & Design, 2018, 18(2): 775-785.
24	Mao X L, Song X F, Lu G M, et al. Effect of additives on the morphology of calcium sulfate hemihydrate: experimental and molecular dynamics simulation studies[J]. Chemical Engineering Journal, 2015, 278: 320-327.
25	Su N N, Wang Y L, Xiao Y, et al. Mechanism of influence of organic impurity on crystallization of sodium sulfate[J]. Industrial & Engineering Chemistry Research, 2018, 57(5): 1705-1713.
26	Donnamaria M C, Xammar Oro J R. The role of hydrogen bonds in an aqueous solution of acetylsalicylic acid: a molecular dynamics simulation study[J]. Journal of Molecular Modeling, 2011, 17(10): 2485-2490.
27	于红琴. 卡马西平多晶型的研究[D].广州:华南理工大学, 2016.
	Yu H Q. Study on the polymorph of carbamazepine [D].Guangzhou: South China University of Technology, 2016.
28	Zhan N X, Zhang Y, Wang X Z. Solubility of N-tert-butylbenzothiazole-2-sulfenamide in several pure and binary solvents[J]. Journal of Chemical & Engineering Data, 2019, 64(3): 1051-1062.
29	Zhang Y, Jiang Y B, Zhang D K, et al. Metastable zone width, crystal nucleation and growth kinetics measurement in anti-solvent crystallization of β-artemether in the mixture of ethanol and water[J]. Chemical Engineering Research and Design, 2015, 95: 187-194.
30	杨丽君, 刘茜, 杨胜勇, 等. 从头算方法研究五元杂环与苯环相互作用[J]. 计算机与应用化学, 2012, 29(4): 461-464.
	Yang L J, Liu Q, Yang S Y, et al. Ab initio calculations of interactional energies between penta-heterocycles and benzene[J]. Computers and Applied Chemistry, 2012, 29(4): 461-464.
31	Pudasaini N, Upadhyay P P, Parker C R, et al. Downstream processability of crystal habit-modified active pharmaceutical ingredient[J]. Organic Process Research & Development, 2017, 21(4): 571-577.
32	Wu K, Ma C Y, Liu J J, et al. Measurement of crystal face specific growth kinetics[J]. Crystal Growth & Design, 2016, 16(9): 4855-4868.

编辑推荐 0

Metrics

阅读次数

全文

223

HTML			PDF

最新录用	在线预览	正式出版	最新录用	在线预览	正式出版
0	0	11	9	0	203

来源	本网站	其他网站

次数	124	99
比例	56%	44%

摘要

693

最新录用	在线预览	正式出版

52	0	641

来源	本网站	其他网站

次数	438	255
比例	63%	37%

[1]	杨欣, 王文, 徐凯, 马凡华. 高压氢气加注过程中温度特征仿真分析[J]. 化工学报, 2023, 74(S1): 280-286.
[2]	于宏鑫, 邵双全. 水结晶过程的分子动力学模拟分析[J]. 化工学报, 2023, 74(S1): 250-258.
[3]	何松, 刘乔迈, 谢广烁, 王斯民, 肖娟. 高浓度水煤浆管道气膜减阻两相流模拟及代理辅助优化[J]. 化工学报, 2023, 74(9): 3766-3774.
[4]	陈哲文, 魏俊杰, 张玉明. 超临界水煤气化耦合SOFC发电系统集成及其能量转化机制[J]. 化工学报, 2023, 74(9): 3888-3902.
[5]	宋明昊, 赵霏, 刘淑晴, 李国选, 杨声, 雷志刚. 离子液体脱除模拟油中挥发酚的多尺度模拟与研究[J]. 化工学报, 2023, 74(9): 3654-3664.
[6]	胡建波, 刘洪超, 胡齐, 黄美英, 宋先雨, 赵双良. 有机笼跨细胞膜易位行为的分子动力学模拟研究[J]. 化工学报, 2023, 74(9): 3756-3765.
[7]	赵佳佳, 田世祥, 李鹏, 谢洪高. SiO₂-H₂O纳米流体强化煤尘润湿性的微观机理研究[J]. 化工学报, 2023, 74(9): 3931-3945.
[8]	齐聪, 丁子, 余杰, 汤茂清, 梁林. 基于选择吸收纳米薄膜的太阳能温差发电特性研究[J]. 化工学报, 2023, 74(9): 3921-3930.
[9]	傅予, 刘兴翀, 王瀚雨, 李海敏, 倪亚飞, 邹文静, 雷月, 彭永姗. F₃EACl修饰层对钙钛矿太阳能电池性能提升的研究[J]. 化工学报, 2023, 74(8): 3554-3563.
[10]	陈国泽, 卫东, 郭倩, 向志平. 负载跟踪状态下的铝空气电池堆最优功率点优化方法[J]. 化工学报, 2023, 74(8): 3533-3542.
[11]	刘文竹, 云和明, 王宝雪, 胡明哲, 仲崇龙. 基于场协同和耗散的微通道拓扑优化研究[J]. 化工学报, 2023, 74(8): 3329-3341.
[12]	邢雷, 苗春雨, 蒋明虎, 赵立新, 李新亚. 井下微型气液旋流分离器优化设计与性能分析[J]. 化工学报, 2023, 74(8): 3394-3406.
[13]	张曼铮, 肖猛, 闫沛伟, 苗政, 徐进良, 纪献兵. 危废焚烧处理耦合有机朗肯循环系统工质筛选与热力学优化[J]. 化工学报, 2023, 74(8): 3502-3512.
[14]	诸程瑛, 王振雷. 基于改进深度强化学习的乙烯裂解炉操作优化[J]. 化工学报, 2023, 74(8): 3429-3437.
[15]	汪林正, 陆俞冰, 张睿智, 罗永浩. 基于分子动力学模拟的VOCs热氧化特性分析[J]. 化工学报, 2023, 74(8): 3242-3255.

添加剂作用下阿司匹林结晶模拟和实验研究

Modeling and experimental study of additives on solution crystallization of aspirin

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 20

参考文献 32

相关文章 15

编辑推荐 0

Metrics

本文评价