Atomistic simulations of co-crystal formation via mechanochemistry

通过机械化学对共晶形成进行原子模拟

• 批准号: EP/P005004/1
• 负责人: Gareth Tribello
• 金额: $ 12.49万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FP005004%2F1
• 关键词: Atomistic; simulations; co; crystal; formation; Atomistic; simulations; co; crystal; formation

Most chemical synthesis is performed in solution because in this phase it is easy to ensure that there are a large number of reactive collisions between reactant molecules. In addition, solution chemistry is well understood and we thus have a high degree of control over the reactions that can be performed and the products that can be synthesised. The problem with this approach is twofold. Firstly, the solvents many solvents are environmentally unfriendly and secondly separating the product from the solution at the end of the reaction often requires distillation, which requires a large input of energy and which introduces an extra step to the whole process. It would thus be enormously beneficial if this step could be avoided and if the solvent could be eliminated. Mechanochemical reactions allow for just this possibility. In these processes the reactants are powdered crystals. These powders are mixed together and mechanical work is done on the mixture in, for example, a mortar and pestle, a ball mill or an extruder. Experiments have demonstrated that it is possible to do a wide range of reactions in this way i.e., "mechanochemically". Furthermore, these mechanochemical processes are seen in some quarters to be the best way to synthesise systems known as co-crystals in which one or more chemical components are packed together into an ordered, crystalline structure. However, wider use of these processes and commercialization of these technologies is prevented because of the relative lack of understanding of the fundamental mechanisms that are in play in these reactions. The aim of this project is to examine what happens in a mechanochemical reaction by performing molecular dynamics simulations using a computer. Such simulations are useful because it is possible to keep track of the positions of all the atoms at all times. This, however, is also the difficulty as specialized tools are required to make sense of large volume of high dimensional data that emerges from such simulations. One of our intentions is, therefore, to develop computational tools for studying these highly complex processes. Throughout the work a reaction between two pharmaceutically active molecules, aspirin and meloxicam, will be studied. We will construct models for nanoparticles composed of each of these molecule types and will use non-equilibrium molecular dynamics simulations to force collisions between these particles to occur. Collisions will be performed for a range of collision velocities and for a number of different collision geometries. We will investigate head on collisions between the particles and glancing collisions as well as collisions in which we will change the relative orientations of the two crystal structures. For all these various kinds of collisions we will investigate the degree to which the two chemical components mix and the degree to which the crystallinity of the structure is disrupted by the collision. This work will give us one of the first visualizations of the zone of reaction in a mechanochemical process. More importantly, however, it will provide us with a way of rationalising what is being observed in the reactive zone. This work will thus provide new fundamental insights into how and why these reactions proceed and will serve as a basis for future work on the comercial exploitation of these reactions.

大多数化学合成是在溶液中进行的，因为在此阶段，很容易确保反应物分子之间存在大量反应性碰撞。此外，溶液化学已得到充分了解，因此我们对可以进行的反应以及可以合成的产物具有高度的控制。这种方法的问题是双重的。首先，许多溶剂在环境上是不友好的，其次是在反应结束时与溶液分开的溶剂通常需要蒸馏，这需要大量的能量输入，并且为整个过程带来了额外的步骤。因此，如果可以避免此步骤以及可以消除溶剂，则将非常有益。机械化学反应只允许这种可能性。在这些过程中，反应物是粉状晶体。将这些粉末混合在一起，并在混合物中进行机械工作，例如砂浆和杵，球磨机或挤出机。实验表明，可以以这种方式进行多种反应，即“机械化学上”。此外，在某些方面可以看到这些机械化学过程是合成被称为共晶体系统的最佳方法，其中一种或多种化学成分将一个或多个化学成分堆积在一起成有序的结晶结构。但是，由于对这些反应中正在发挥的基本机制的了解相对缺乏了解，因此可以更广泛地使用这些过程和这些技术的商业化。该项目的目的是通过使用计算机进行分子动力学模拟来检查机械化学反应中发生的情况。这样的模拟很有用，因为可以始终跟踪所有原子的位置。但是，这也是困难，因为需要专门的工具才能理解从此类模拟中出现的大量高维数据。因此，我们的意图之一是开发用于研究这些高度复杂过程的计算工具。在整个工作中，将研究两个药物活性分子（阿司匹林和美洛昔康）之间的反应。我们将为由每种分子类型组成的纳米颗粒构建模型，并将使用非平衡分子动力学模拟迫使这些颗粒之间的碰撞发生。对于一系列碰撞速度和许多不同的碰撞几何形状，将进行碰撞。我们将研究颗粒与瞥见碰撞之间的碰撞以及我们将改变两个晶体结构的相对取向的碰撞。对于所有这些类型的碰撞，我们将研究两个化学成分混合在一起的程度以及结构的结构被碰撞破坏的程度。这项工作将为我们提供机械化学过程中反应区域的第一个可视化之一。但是，更重要的是，它将为我们提供合理化反应区域中观察到的内容的方法。因此，这项工作将提供有关这些反应如何以及为什么进行的新基本见解，并将作为对这些反应商业开发的未来工作的基础。