Zhao Xin S, Siepmann J Ilja, Xu Wei, Kiang Y-H, Sheth Agam R, Karaborni Sami
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA.
J Phys Chem B. 2009 Apr 30;113(17):5929-37. doi: 10.1021/jp808164t.
The pharmaceutical compound A, 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)propionic acid, is known to exist in five different crystalline forms that differ in the hydration state ranging from the anhydrous desolvate over hemihydrate, dihydrate, and tetrahydrate forms to the pentahydrate. The formation of the higher hydrates and the concomitant lattice expansion leads to undesirable tablet cracking at higher humidities. In this work, particle-based simulation techniques are used to explore the hydrate formation of compound A as a function of humidity. It is found that a simulation strategy employing Monte Carlo simulations in the isobaric-isothermal and Gibbs ensembles and transferable force fields, which are not parametrized against any experimental data for compound A, is able to yield satisfactory crystal structures for the anhydrate and pentahydrate and to predict the existence of all five hydrates.
药物化合物A，即3-{2-氧代-3-[3-(5,6,7,8-四氢[1,8]萘啶-2-基)丙基]咪唑烷-1-基}-3(S)-(6-甲氧基吡啶-3-基)丙酸，已知以五种不同的晶体形式存在，其水合状态不同，从无水去溶剂化物到半水合物、二水合物、四水合物形式再到五水合物。较高水合物的形成以及随之而来的晶格膨胀会导致在较高湿度下片剂出现不良开裂。在这项工作中，基于颗粒的模拟技术被用于探索化合物A的水合物形成与湿度的关系。结果发现，一种在等压-等温及吉布斯系综中采用蒙特卡罗模拟以及可转移力场的模拟策略，该策略未针对化合物A的任何实验数据进行参数化，能够得到无水物和五水合物的令人满意的晶体结构，并预测所有五种水合物的存在。
