Atomistic simulations of co-crystal formation via mechanochemistry

大多数化学合成是在溶液中进行的，因为在这个阶段很容易确保反应物分子之间有大量的反应碰撞。此外，我们对溶液化学有很好的理解，因此我们对可以进行的反应和可以合成的产品有很高的控制度。这种方法的问题是双重的。首先，溶剂-许多溶剂是环境不友好的，其次，在反应结束时从溶液中分离产物通常需要蒸馏，这需要大量的能量输入，并为整个过程引入了额外的步骤。因此，如果可以避免该步骤并且如果可以消除溶剂，则将是非常有益的。机械化学反应正好允许这种可能性。在这些方法中，反应物是粉末状晶体。将这些粉末混合在一起，并在例如研钵和研杵、球磨机或挤出机中对混合物进行机械功。实验已经证明可以以这种方式进行广泛的反应，即，“机械化学地”。此外，这些机械化学过程在某些方面被认为是合成称为共晶体的系统的最佳方式，其中一种或多种化学成分被包装在一起形成有序的晶体结构。然而，由于对这些反应中起作用的基本机制相对缺乏了解，这些工艺的广泛使用和这些技术的商业化受到阻碍。本项目的目的是通过使用计算机进行分子动力学模拟来研究机械化学反应中发生的情况。这种模拟是有用的，因为它可以随时跟踪所有原子的位置。然而，这也是一个困难，因为需要专门的工具来理解从这种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，将研究阿司匹林和美洛昔康两种药物活性分子之间的反应。我们将构建由这些分子类型组成的纳米颗粒模型，并将使用非平衡分子动力学模拟来迫使这些颗粒之间发生碰撞。碰撞将在一定范围的碰撞速度和许多不同的碰撞几何形状下进行。我们将研究粒子之间的正面碰撞和掠射碰撞，以及我们将改变两个晶体结构的相对取向的碰撞。对于所有这些不同种类的碰撞，我们将研究两种化学成分混合的程度以及碰撞破坏结构结晶度的程度。这项工作将给我们一个第一次可视化的反应区在机械化学过程。然而，更重要的是，它将为我们提供一种合理化反应区所观察到的情况的方法。因此，这项工作将提供新的基本见解如何以及为什么这些反应进行，并将作为未来的工作的基础上，这些反应的商业利用。

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.