Control and Prediction of the Organic Solid State: Translating the Technology

许多有机分子可以采用一种以上的固体结晶形式，包括仅在分子排列上不同的多晶型物。这可以用于开发具有优化物理特性的新特种材料，如非线性光学系数或分子电子学，但当新形式在生产或储存过程中意外出现时，它可能会对质量控制造成灾难性影响，就像某些药物一样。然而，控制可能的固体形式的多样性的因素知之甚少。有人说，一个分子的多晶型的数量取决于寻找它们所花费的时间和金钱。这当然是一个因素，当为制药公司研究的系统中约有90%被发现具有多种固体形式时，剑桥结构数据库中只有不到5%的条目具有两种或更多种结构。新有机材料的开发及其制造过程中的质量控制需要更科学的方法来了解晶体结构的可能范围。CPOSS项目一直在开发一种计算方法，用于预测分子的哪些晶体结构在能量足够低的情况下可能形成。我们还开发了一个工作流程，包括一个独特的强大的自动溶剂结晶系统，即使是我们用来验证该方法的高度研究的系统，也能发现许多新的结晶形式。通过将这些结果与其他实验和计算机模拟工作相结合，多学科CPOSS团队正在开发一种分子水平的图像，以确定哪些计算的低能结构可以在实验中发现几种特定分子，从溶剂的影响到表面甚至杂质。我们甚至在实验发现阿司匹林、扑热息痛和吡拉西坦之前就预测了它们可能的新晶体结构！这项翻译补助金将使CPOSS团队的核心能够使用他们在与广泛的合作者合作解决特定有机固态问题时开发的计算和实验技术。这些领域包括分子电子和光学材料、含能材料、颜料、农用化学品和药物。因此，我们将开发精确计算哪些晶体结构是可能的方法，并建立如何使用计算的结构和实验结果，以有效地确定哪些晶体结构可能被发现，以及获得它们的最有效途径。已知和假设的晶体结构及其性质的CPOSS数据库，当覆盖广泛的有机分子时，将为多晶型预测和控制提供基础技术。该项目将为学术和工业有机固态研究科学家提供这些补充技术。

Many organic molecules can adopt more than one solid crystalline form, including polymorphs which differ only in the arrangement of the molecules. This can be exploited in the development of new speciality materials with optimised physical properties such as non-linear optical coefficients or molecular electronics, but it can prove disastrous for quality control when the new form appears unexpectedly during production or storage, as has occurred for some pharmaceuticals. However, the factors that control the diversity of possible solid forms are poorly understood. It has been said that the number of polymorphs of a molecule depends on the time and money spent looking for them. This is certainly a factor, when about 90% of systems studied for pharmaceutical companies are found to have multiple solid forms, and less than 5% of entries in the Cambridge Structural Database have two or more structures. The development of new organic materials and quality control in their manufacture requires a more scientific approach to understanding the possible range of crystal structures.The CPOSS project has been developing a computational method of predicting which crystal structures of a molecule are sufficiently low in energy that they might be able to form. We have also developed a workflow, including a uniquely powerful automated solvent crystallisation system, which is discovering many new crystalline forms even for the highly studied systems we used to validate the approach. By combining these results with other experimental and computer simulation work, the multi-disciplinary CPOSS team are developing a molecular level picture of what determines which of the computed low energy structures can be found experimentally for several specific molecules, ranging from the influence of solvent, to that of surfaces and even impurities. We even predicted possible new crystal structures of aspirin, paracetamol and piracetam before they were experimentally found! This Translation grant will enable the core of the CPOSS team to use the computational and experimental technologies they have developed in work with a broad range of collaborators on their particular organic solid state problems. These areas include molecular electronics and optical materials, energetic materials, pigments, agrochemicals and pharmaceuticals. Thus, we will develop methods of accurately computing which crystal structures are possible, and establish how to use the computed structures and experimental results to effectively determine which crystal structures might be found and the most efficient route to obtaining them. The CPOSS databases of known and hypothetical crystal structures and their properties, when covering a wide range of organic molecules, will provide a basic technology for polymorph prediction and control. This project will make available these complementary techniques to both academic and industrial organic solid state research scientists.