尿素(520)晶面可控结晶的分子动力学模拟
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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101.325kPa、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。
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 kPaand 290 K, all 6 kinds of additives(trehalose, sucrose, glucose, sorbitol, lysine and arginine) can inhibit the growthof urea facet(520) to a certian extent.(2) The more negative adsorption energy of the additive on the facet(520) leadto the better inhibition of crystal growth, and the trehalose is the best inhibit for the growth of facet(520).(3) Thetype and number of the polar group which is carried by additive determine the interactive strength between additiveand crystal layer. In particular, trehalose and sucrose which contains 8 hydroxyl groups, have strong interaction withurea 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).
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 kPaand 290 K, all 6 kinds of additives(trehalose, sucrose, glucose, sorbitol, lysine and arginine) can inhibit the growthof urea facet(520) to a certian extent.(2) The more negative adsorption energy of the additive on the facet(520) leadto the better inhibition of crystal growth, and the trehalose is the best inhibit for the growth of facet(520).(3) Thetype and number of the polar group which is carried by additive determine the interactive strength between additiveand crystal layer. In particular, trehalose and sucrose which contains 8 hydroxyl groups, have strong interaction withurea 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).
引文
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[23] Bussi G, Zykova-Timan T, Parrinello M. Isothermal-isobaric molecular dynamics using stochastic velocity rescaling[J]. Journal of Chemical Physics, 2009, 130(7):2384.
[24]唐鼎元,贺友平,林斯太,等.紫外倍频晶体尿素的生长[J].人工晶体学报, 1982,(z1):82-83.Tang D Y, He Y P, Lin S T, et al. The growth of UV frequency doubling crystal urea[J]. Journal of Synthetic Crystals, 1982,(z1):82-83
[25] Janimak J J, Cheng S Z D, Giusti P A, et al. Isotacticity effect on crystallization and melting in polypropylene fractions(Ⅱ):Linear crystal growth rate and morphology study[J]. Macromolecules,1991, 24(9):2253-2260.
[26] Pimentel G C, Mcclellan A L. Hydrogen bond[J]. Annual Review of Physical Chemistry, 2003, 22(1):347-385.
[27] Michalet X. Mean square displacement analysis of Single-Particle trajectories with localization error[J]. Physical Review E Statistical Nonlinear&Soft Matter Physics, 2010, 100(3):041914.
[28]潘晓莉,李代禧,魏冬青.离子液体中胰岛素结构稳定性的分子动力学模拟[J].化工学报, 2016, 67(12):5215-5221.Pan X L, Li D X, Wei D Q. Structural stability of insulin in imidazolium ionic liquids by molecular simulation[J]. CIESC Journal, 2016, 67(12):5215-5221.
[29]郝保红,黄俊华.晶体生长机理的研究综述[J].北京石油化工学院学报, 2006, 14(2):58-64.Hao B H, Huang J H. Summary on the growth mechanism of crystal[J]. Journal of Beijing Institute of Petro-chemical Technology, 2006, 14(2):58-64
[30]姜兆华,孙德智,邵光杰.应用表面化学与技术[M].哈尔滨:哈尔滨工业大学出版社, 2002.Jiang Z H, Sun D Z, Shao G J. Applied Surface Chemistry and Technology[M]. Harbin:Harbin Institute of Technology Press,2002.
[2]宫海燕,李彩虹,王佩佩,等.杂质对溶液结晶过程影响的研究进展[J].化学与生物工程, 2010, 27(3):9-12.Gong H Y, Li C H, Wang P P, et al. Research progress of influence of impurities on solution crystallization[J].Chemistry&Bioengineering, 2010, 27(3):9-12
[3] Mikami T, Sakuma T, Hirasawai I. CSD-controlled reactive crystallization of SrSO4in the presence of polyethylenimine[J].Chemical Engineering Research&Design, 2010, 88(9):1200-1205.
[4]张相洋.杂质存在条件下的乳酸锌结晶行为研究[D].上海:华东理工大学, 2010.Zhang X Y. Crystallization behaviour of zinc lactate in presence of impurities[D]. Shanghai:East China University of Science and Technology, 2010.
[5] Zhang X, Qian G, Zhou X. Effects of different organic acids on solubility and metastable zone width of zinc lactate[J]. Journal of Chemical&Engineering Data, 2012, 57(57):2963–2970.
[6] Cashell C, Corcoran D, Hodnett B K. Effect of amino acid additives on the crystallization of L-glutamic acid[J]. Crystal Growth&Design, 2015, 5(2):593-597.
[7] Salvalaglio M, Vetter T, Giberti F, et al. Uncovering molecular details of urea crystal growth in the presence of additives[J].Journal of the American Chemical Society, 2012, 134(41):17221-17233.
[8]黄炳荣,贺友平,苏根博.尿素晶体生长研究[J].人工晶体学报, 1986, 15(2):85-89.Huang B R, He Y P, Su G B. Growth studies of urea crystals[J].Journal of Synthetic Crystals, 1986, 15(2):85-89.
[9] Piana S, Reyhani M, Gale J D. Simulating micrometre-scale crystal growth from solution[J]. Nature, 2005, 438(7064):70-73.
[10]李代禧,栾瀚森,郭柏松,等.实用计算药剂学——有效的药剂学工具[J].中国医药工业杂志, 2017, 48(12):1673-1684.Li D X, Luan H S, Guo B S, et al. Applied computational pharmaceutics:an efficient pharmaceutical tool[J]. Chinese Journal of Pharmaceuticals, 2017, 48(12):1673-1684.
[11] Rapaport D C. Molecular dynamics simulation[J]. Computing in Science&Engineering, 2002, 1(1):70-71.
[12] Allen F H, Davies J E. The Cambridge Structural Database:a quarter of a million crystal structures and rising[J]. Acta Crystallographica, 2002, 58(3):380–388.
[13] Sun H. COMPASS:An ab initio force-field optimized for condensed-phase applications over view with details on alkane and benzene compounds[J]. Journal of Physical Chemistry B,1998, 102(38):7338-7364.
[14] Sklar N, Senko M E, Post B. Thermal effects in urea:the crystal structure at 140°C and at room temperature[J]. Acta Crystallographica, 2010, 14(7):716-720.
[15] Massaro F R, Moret M, Bruno M, et al. Equilibrium and growth morphology of oligoacenes:periodic bond chains(PBC)analysis of tetracene crystal[J]. Crystal Growth&Design, 2011, 11(10):4639-4646.
[16] Hartman P, Bennema P. The attachment energy as a habit controlling factor(Ⅰ):Theoretical considerations[J]. Journal of Crystal Growth, 1980, 49(1):145-156.
[17] Liu N, Zhou C, Shu Y J, et al. Molecular dynamics simulations on crystal morphology of N-guanylurea-dinitramide[J]. Chemical Journal of Chinese Universities, 2017, 38(12):2231-2237.
[18] van der Spoel D, Lindahl E, Hess B, et al. GROMACS:fast,flexible, and free[J]. Journal of Computational Chemistry, 2005, 26(16):1701-1718.
[19] Lindorfflarsen K, Piana S, Palmo K, et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field[J].Proteins Structure Function&Bioinformatics, 2010, 78(8):1950–1958.
[20] Abascal J L F, Vega C. A general purpose model for the condensed phases of water:TIP4P/2005[J]. Journal of Chemical Physics, 2005, 123(23):234505.
[21] Darden T, York D, Pedersen L. Particle mesh Ewald:an N?log(N)method for ewald sums in large systems[J]. Journal of Chemical Physics, 1998, 98(12):10089-10092.
[22] Mudi A, Chakravarty C. Effect of the Berendsen thermostat on the dynamical properties of water[J]. Molecular Physics, 2004, 102(7):681-685.
[23] Bussi G, Zykova-Timan T, Parrinello M. Isothermal-isobaric molecular dynamics using stochastic velocity rescaling[J]. Journal of Chemical Physics, 2009, 130(7):2384.
[24]唐鼎元,贺友平,林斯太,等.紫外倍频晶体尿素的生长[J].人工晶体学报, 1982,(z1):82-83.Tang D Y, He Y P, Lin S T, et al. The growth of UV frequency doubling crystal urea[J]. Journal of Synthetic Crystals, 1982,(z1):82-83
[25] Janimak J J, Cheng S Z D, Giusti P A, et al. Isotacticity effect on crystallization and melting in polypropylene fractions(Ⅱ):Linear crystal growth rate and morphology study[J]. Macromolecules,1991, 24(9):2253-2260.
[26] Pimentel G C, Mcclellan A L. Hydrogen bond[J]. Annual Review of Physical Chemistry, 2003, 22(1):347-385.
[27] Michalet X. Mean square displacement analysis of Single-Particle trajectories with localization error[J]. Physical Review E Statistical Nonlinear&Soft Matter Physics, 2010, 100(3):041914.
[28]潘晓莉,李代禧,魏冬青.离子液体中胰岛素结构稳定性的分子动力学模拟[J].化工学报, 2016, 67(12):5215-5221.Pan X L, Li D X, Wei D Q. Structural stability of insulin in imidazolium ionic liquids by molecular simulation[J]. CIESC Journal, 2016, 67(12):5215-5221.
[29]郝保红,黄俊华.晶体生长机理的研究综述[J].北京石油化工学院学报, 2006, 14(2):58-64.Hao B H, Huang J H. Summary on the growth mechanism of crystal[J]. Journal of Beijing Institute of Petro-chemical Technology, 2006, 14(2):58-64
[30]姜兆华,孙德智,邵光杰.应用表面化学与技术[M].哈尔滨:哈尔滨工业大学出版社, 2002.Jiang Z H, Sun D Z, Shao G J. Applied Surface Chemistry and Technology[M]. Harbin:Harbin Institute of Technology Press,2002.
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