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

doi:10.11949/j.issn.0438-1157.20180521

Abstract

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

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

CLC Number:

O 781

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.

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.

Figures/Tables 13

Fig.1 Unit cell structure of urea after optimization

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

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

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

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

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

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

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

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

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

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

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

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

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