尿素(520)晶面可控结晶的分子动力学模拟

doi:10.11949/j.issn.0438-1157.20180521

化工学报 ›› 2019, Vol. 70 ›› Issue (1): 128-135.DOI: 10.11949/j.issn.0438-1157.20180521

尿素(520)晶面可控结晶的分子动力学模拟

蔡惊涛¹(),李代禧¹(),刘宝林¹,栾翰森²,郭柏松³,魏冬青⁴,王浩²

1. 上海理工大学食品科学与工程研究所，上海 200093
2. 中国医药工业研究总院，上海 201203
3. 上海东富龙科技股份有限公司注射剂实验室，上海 201108
4. 上海交通大学微生物代谢国家重点实验室，上海 200240

收稿日期:2018-05-21 修回日期:2018-10-23 出版日期:2019-01-05 发布日期:2019-01-05
通讯作者: 李代禧
作者简介:蔡惊涛(1993—)，男，硕士，<email>maxcaijingtao1993@foxmail.com</email>|李代禧（1975—），男，副教授，<email>dxli75@126.com</email>
基金资助:
上海市“创新行动计划”国际科技合作项目(12430702000);上海市自然科学基金项目(12ZR1420400)

Controllable crystallization of urea (520) crystal plane by molecular simulation

Jingtao CAI¹(),Daixi LI¹(),Baolin LIU¹,Hansen LUAN²,Baisong GUO³,Dongqing WEI⁴,Hao WANG²

1. Institute of Food Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
2. China State Institute of Pharmaceutical Industry, Shanghai 201203, China
3. Injection Laboratory, Shanghai Tofflon Science and Technology Co. Ltd., Shanghai 201108, China
4. State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai 200240, China

Received:2018-05-21 Revised:2018-10-23 Online:2019-01-05 Published:2019-01-05
Contact: Daixi LI

摘要/Abstract

摘要：

由于尿素结晶呈白色针状，晶貌单一，且传统结晶工艺不可控，严重影响药物的一致性评价结果。采用分子动力学模拟方法，从分子水平上研究不同种类的添加剂对尿素晶体生长的调控作用，揭示添加剂对药物晶体生长的调控机制。结果表明：① 六种添加剂(海藻糖、蔗糖、葡萄糖、山梨醇、赖氨酸、精氨酸)在101.325 kPa、290 K下相较于无添加剂时都能不同程度地抑制(520)晶面的生长；② 添加剂对尿素晶面(520)的吸附能越负，其抑制晶面生长效果越好，其中海藻糖抑制(520)晶面生长效果最好；③ 添加剂分子携带基团的种类与数目决定与晶层的相互作用的强弱，特别是海藻糖、蔗糖双糖类分子含有8个羟基，与晶层上的尿素分子氢键相互作用强，与溶液层中的溶质形成竞争性吸附，能更好抑制(520)晶面生长。

关键词: 分子模拟, 晶貌, 添加剂, 吸附, 聚集

Abstract:

Due to urea crystallization showing white needle, single crystal morphology and uncontrollable process of traditional crystallization, it seriously affects drug consistency evaluation. We adopt molecular dynamics simulation method to research regulating effect of different additives on urea crystal growth at molecular level, and reveal the regulation mechanism of additives on urea crystal growth. Finally, the experimental results show: ① At 101.325 kPa and 290 K, all 6 kinds of additives (trehalose, sucrose, glucose, sorbitol, lysine and arginine) can inhibit the growth of urea facet (520) to a certian extent. ② The more negative adsorption energy of the additive on the facet (520) lead to the better inhibition of crystal growth, and the trehalose is the best inhibit for the growth of facet (520). ③ The type and number of the polar group which is carried by additive determine the interactive strength between additive and crystal layer. In particular, trehalose and sucrose which contains 8 hydroxyl groups, have strong interaction with urea molecules on the urea layer,and they can form competitive adsorption with solutes in the solution layer. So they can better inhibit the growth of urea crystal facet (520).

Key words: molecular simulation, crystal morphology, additive, adsorption, aggregation

中图分类号:

O 781

蔡惊涛, 李代禧, 刘宝林, 栾翰森, 郭柏松, 魏冬青, 王浩. 尿素(520)晶面可控结晶的分子动力学模拟[J]. 化工学报, 2019, 70(1): 128-135.

Jingtao CAI, Daixi LI, Baolin LIU, Hansen LUAN, Baisong GUO, Dongqing WEI, Hao WANG. Controllable crystallization of urea (520) crystal plane by molecular simulation[J]. CIESC Journal, 2019, 70(1): 128-135.

图/表 13

图1 优化后的尿素晶胞结构

Fig.1 Unit cell structure of urea after optimization

表1 尿素晶胞参数

Table 1 Unit cell parameter of urea

Force field	a/?	b/?	c/?	α/(°)	β/(°)	γ/(°)
experiment^[14]	5.662	5.662	4.716	90.0	90.0	90.0
COMPASS	5.558	5.558	4.636	90.0	90.0	90.0

表2 不同种类添加剂溶液体系的组成

Table 2 Models and detail components for simulation

System	Additives	N _additive	N _crystal	N _urea	N _water
A0 A1	none trehalose	0 40	252 252	1000 1000	1300 1295
A2	sucrose	40	252	1000	1294
A3	sorbitol	40	252	1000	1297
A4	glucose	40	252	1000	1299
A5	L-lysine	40	252	1000	1294
A6	L-arginine	40	252	1000	1304

图2 EM法预测尿素晶貌

Fig.2 Crystal morphology of urea predicted by the EM model

表3 EM法预测尿素在真空下主要晶面族

Table 3 Main crystal planes of urea predicted by the EM model

d _hkl /?

(110)

(001)

4.00

4.72

172.80

330.33

38.00

16.12

表4 添加剂在(520)晶面上的吸附能

Table 4 Adsorption energy of each additive on the facet (520)

Additives	Number (N _ads )	E′ _ads /(kJ/mol)
urea trehalose	421.69±3.375 78.75±0.687	-4.46±0.380 -34.00±0.691
sucrose	80.79±1.123	-33.38±0.384
sorbitol	112.82±1.496	-20.33±0.441
glucose	136.88±2.188	-16.68±0.476
L-lysine	119.11±3.393	-5.66±0.256
L-arginine	97.25±0.648	-5.39±0.230

图3 不同种类添加剂下(520)晶面模拟100 ns的生长情况

Fig.3 Growing status of the facet (520) with different additives after 100 ns simulation

图4 不同种类添加剂下体系模拟100 ns的密度分布及生长速率

Fig.4 Density distribution and growth rate of each system with different additives after 100 ns simulation

图5 不同添加剂在(520)晶面上的吸附数和生长速率

Fig.5 Adsorbed number and growth rate of different additives on facet (520)

图6 分布在晶层上与溶液层中特定添加剂的均方根位移与扩散系数

Fig.6 Mean square displacement and diffusion coefficient of specific additives distributed on crystal face and in solution layer

图7 各体系溶液层中尿素分子扩散系数与各特定添加剂周围聚集尿素分子数

Fig.7 Diffusion coefficient of urea molecular and urea number around each particular additive in each system solution layer

图8 B1、B2、B3、B4体系的海藻糖分子构象与密度分布

Fig.8 Trehalose molecular conformation and density distribution in B1, B2, B3 and B4 systems

图9 B1、B4体系特定海藻糖分子与晶面作用的氢键数和距离参数

Fig.9 Hydrogen bond number and distance between specific trehalose molecule and crystal molecule in B1 and B4 systems

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尿素(520)晶面可控结晶的分子动力学模拟

Controllable crystallization of urea (520) crystal plane by molecular simulation

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