Dissolution study of active pharmaceutical ingredients using molecular dynamics simulations with classical force fields
Dissolution study of active pharmaceutical ingredients using molecular dynamics simulations with classical force fields
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DOI：
10.1016/j.jcrysgro.2014.07.046
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发表时间：
2014-11-01
影响因子：
1.8
通讯作者：
Briesen, Heiko
中科院分区：
文献类型：
--
作者：
Greiner, Maximilian;Elts, Ekaterina;Briesen, Heiko
评估了 CHARMM、通用 Amber 和 OPLS 力场在模拟疏水性小分子活性药物成分阿司匹林、布洛芬和扑热息痛在水介质中溶解的分子动力学方面的适用性。通过与量子化学模拟或实验参考进行比较，基于以下能力来评估力场：准确表示分子内和分子间相互作用、适当再现晶格参数、充分描述热力学性质以及溶解行为的定性描述。为了使这种方法能够在药物开发的早期阶段轻松评估新候选药物的溶出特性，使用 SWISS PARAM 服务器以及软件包 ACPYPE 和 Maestro 等在线资源生成力场参数文件。所有力场都以合理的精度重现了分子间相互作用，一般的 Amber 和 CHARMM 力场显示出与量子力学计算的最佳一致性。除布洛芬外，所有模型物质都获得了稳定的晶体块结构，其中所有力场的晶格参数和观察到的晶体稳定性的再现都相当差。发现用于评估固体到溶液相变的溶解热与所有测试组合的实验数据定性一致，结果对于一般 Amber 和 CHARMM 力场在数量上是最佳的。对于阿司匹林和扑热息痛，获得了稳定的结晶水界面。对每个力场模拟阿司匹林或扑热息痛和水的 (100)、(110)、(011) 和 (001) 界面 30 ns。尽管通常认为这是一种罕见的事件，但在一些模拟中，在 310 K 和环境压力条件下观察到溶解。 (C) 2014 年爱思唯尔作者。版权所有，
The CHARMM, general Amber and OPLS force fields are evaluated for their suitability in simulating the molecular dynamics of the dissolution of the hydrophobic, small-molecule active pharmaceutical ingredients aspirin, ibuprofen, and paracetamol in aqueous media. The force Fields are evaluated by comparison with quantum chemical simulations or experimental references on the basis of the following capabilities: accurately representing intra- and intermolecular interactions, appropriately reproducing crystal lattice parameters, adequately describing thermodynamic properties, and the qualitative description of the dissolution behavior. To make this approach easily accessible for evaluating the dissolution properties of novel drug candidates in the early stage of drug development, the force field parameter files are generated using online resources such as the SWISS PARAM servers, and the software packages ACPYPE and Maestro. All force fields are found to reproduce the intermolecular interactions with a reasonable degree of accuracy, with the general Amber and CHARMM force fields showing the best agreement with quantum mechanical calculations. A stable crystal bulk structure is obtained for all model substances, except for ibuprofen, where the reproductions of the lattice parameters and observed crystal stability are considerably poor for all force fields. The heat of solution used to evaluate the solid-to-solution phase transitions is found to be in qualitative agreement with the experimental data for all combinations tested, with the results being quantitatively optimum for the general Amber and CHARMM force fields. For aspirin and paracetamol, stable crystal-water interfaces were obtained. The (100), (110), (011) and (001) interfaces of aspirin or paracetamol and water were simulated for each force field for 30 ns. Although generally expected as a rare event, in some of the simulations, dissolution is observed at 310 K and ambient pressure conditions. (C) 2014 Elsevier By. All rights reserved,