Solubility prediction, solvate and cocrystal screening as tools for rational crystal engineering
Solubility prediction, solvate and cocrystal screening as tools for rational crystal engineering
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DOI：
10.1111/jphp.12376
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发表时间：
2015-06-01
影响因子：
3.3
通讯作者：
Klamt, Andreas
中科院分区：
文献类型：
--
作者：
Loschen, Christoph;Klamt, Andreas
目的新药候选物越来越难溶是当前药物开发的一个主要问题。计算工具可以通过筛选合适的溶剂或通过识别增加生物利用度的潜在的新型共晶形成剂来解决这个问题。与其他更专业的方法相比，流体相热力学方法COSMO-RS（用于真实的溶剂的类导体筛选模型）允许全面处理药物溶解度、溶剂合物和共晶形成以及液体中的许多其他热力学性质。本文概述了最近COSMO-RS的发展，是药物开发的兴趣，并包含几个新的应用实例，溶解度预测和溶剂化物/共晶screening.MethodsFor所有属性预测COSMO-RS已被使用。COSMO-RS的基本概念包括使用筛选电荷密度计算的第一原理计算结合快速统计热力学计算的化合物在solution.Key findingThe快速和准确的药物溶解度的评估和识别合适的溶剂，溶剂化物或共晶形成者是现在可能的，并可用于补充现代药物开发。通过使用先前计算的分子碎片的数据库避免昂贵的量子化学计算来提高效率。SummaryCOSMO-RS理论可以应用于一系列物理化学性质，这些性质在合理的晶体工程中是感兴趣的。最值得注意的是，与实验参考数据相结合，在任何溶剂或溶剂混合物中准确的定量溶解度预测是可能的。此外，COSMO-RS可以扩展到共晶形成的预测，这导致相当大的预测精度有关共形成物筛选。在最近的一个变体中，避免了昂贵的量子化学计算，从而显著提高了速度和易用性。
ObjectivesThe fact that novel drug candidates are becoming increasingly insoluble is a major problem of current drug development. Computational tools may address this issue by screening for suitable solvents or by identifying potential novel cocrystal formers that increase bioavailability. In contrast to other more specialized methods, the fluid phase thermodynamics approach COSMO-RS (conductor-like screening model for real solvents) allows for a comprehensive treatment of drug solubility, solvate and cocrystal formation and many other thermodynamics properties in liquids. This article gives an overview of recent COSMO-RS developments that are of interest for drug development and contains several new application examples for solubility prediction and solvate/cocrystal screening.MethodsFor all property predictions COSMO-RS has been used. The basic concept of COSMO-RS consists of using the screening charge density as computed from first principles calculations in combination with fast statistical thermodynamics to compute the chemical potential of a compound in solution.Key findingThe fast and accurate assessment of drug solubility and the identification of suitable solvents, solvate or cocrystal formers is nowadays possible and may be used to complement modern drug development. Efficiency is increased by avoiding costly quantum-chemical computations using a database of previously computed molecular fragments.SummaryCOSMO-RS theory can be applied to a range of physico-chemical properties, which are of interest in rational crystal engineering. Most notably, in combination with experimental reference data, accurate quantitative solubility predictions in any solvent or solvent mixture are possible. Additionally, COSMO-RS can be extended to the prediction of cocrystal formation, which results in considerable predictive accuracy concerning coformer screening. In a recent variant costly quantum chemical calculations are avoided resulting in a significant speed-up and ease-of-use.