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首页> 外文期刊>Journal of Crystal Growth >Dissolution study of active pharmaceutical ingredients using molecular dynamics simulations with classical force fields
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Dissolution study of active pharmaceutical ingredients using molecular dynamics simulations with classical force fields

机译：使用经典力场的分子动力学模拟对活性药物成分进行溶出度研究

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摘要

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,
机译：在模拟疏水，小分子活性药物成分阿司匹林，布洛芬和扑热息痛在水性介质中溶解的分子动力学时，评估了CHARMM，一般的Amber和OPLS力场的适用性。通过与以下方面的功能进行比较，可以与量子化学模拟或实验参考进行比较来评估力场：准确表示分子内和分子间的相互作用，适当再现晶格参数，充分描述热力学性质以及对溶出行为的定性描述。为了使这种方法在药物开发的早期阶段易于评估新型药物的溶出特性，使用在线资源（例如SWISS PARAM服务器）以及软件包ACPYPE和Maestro生成了力场参数文件。发现所有力场都以合理的精度再现分子间的相互作用，而一般的琥珀色和CHARMM力场显示出与量子力学计算的最佳一致性。除布洛芬外，所有模型物质均获得稳定的晶体本体结构，在布洛芬中，所有力场的晶格参数再现性和观察到的晶体稳定性均很差。发现用于评估固相到固相转变的固溶热与所有测试组合的实验数据在质量上是一致的，结果对于一般的琥珀色和CHARMM力场在定量上是最优的。对于阿司匹林和扑热息痛，获得了稳定的晶体-水界面。对于每个力场，模拟了30 ns的阿司匹林或扑热息痛与水的（100），（110），（011）和（001）界面。尽管通常认为这是罕见事件，但在某些模拟中，在310 K和环境压力条件下观察到溶解。 （C）2014年Elsevier By。版权所有，

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  • 来源
    《Journal of Crystal Growth》 |2014年第1期|122-130|共9页
  • 作者

    Greiner Maximilian; Elts Ekaterina; Schneider Julian; Reuter Karsten; Briesen Heiko;

  • 作者单位

    Tech Univ Munich, Chair Proc Syst Engn, Freising Weihenstephan, Germany;

    Tech Univ Munich, Chair Proc Syst Engn, Freising Weihenstephan, Germany;

    Tech Univ Munich, Chair Theoret Chem, Garching, Germany;

    Tech Univ Munich, Chair Theoret Chem, Garching, Germany;

    Tech Univ Munich, Chair Proc Syst Engn, Freising Weihenstephan, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    Computer simulation; Surfaces;

    机译：计算机仿真;表面;

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