Computationally Designed Templates for Exquisite Control of Polymorphic Form

许多有机分子以晶体形式传递给我们，从巧克力中的可可脂等食品到色素、推进剂和药品。有机分子可以采用一系列晶体形式或多晶型，具有不同的性质，包括熔化温度、颜色、爆炸灵敏度和溶解速度。这一建议将开发新的方法来预测和产生一个给定分子的多态形式的扩展范围。即使分子不是以晶体形式传递，对其结晶行为的详细了解对于优化制造过程和设计产品以防止晶体形成（例如破坏液晶显示器）也是必要的。生产有机产品的一个主要风险是意外出现替代多晶，这导致HIV药物利托那韦（ritonavir）的停药和重新配方，以及一种帕金森病治疗的透皮贴片，一旦罗替戈汀在储存过程中意外重新结晶，就变得不可靠。结晶是一个两阶段的过程，包括成核（形成稳定的分子簇）和生长（簇的生长直到观察到可见的晶体）。在产品开发后期出现的许多多晶被归因于在第一个晶体成核的困难。然而，存在的杂质分子的变化和与不同表面的接触可能催化这种成核。在这个提议中，我们将探讨不同的化学和物理表面对新多晶形核的影响。尽管在开发一种新产品的过程中可以进行数千次结晶实验，但这既昂贵又耗时，而且要测试所有可能的条件是不切实际的。因此，选择特定的预测形状和设计实验以使这些形状首次成核的能力使多态性成为产品和工艺设计中的优势。它将允许选择和制造具有最适合分子预期应用的特定性质的晶体形式。这项研究还将对有机分子所能表现出的固态多样性的真实范围提供更深入的了解。EPSRC基础技术项目资助了“有机固态的控制和预测”项目，该项目建立了国际上独一无二的预测特定分子热力学可行多晶型范围的能力。这个项目已经证明了生产一种经过大量研究的抗癫痫药物的独特的新多晶的第一个晶体的能力，通过将其从蒸汽中结晶到相关分子的合适模板晶体的计算启发选择上。这一发现证明，使用针对特定计算预测的多晶型而设计的模板可以发现全新的形式。然而，如果我们要利用基础科学进行更广泛的应用，就必须了解结构、表面、动力学和热力学之间的相互作用。这个跨学科项目旨在建立预测的多晶与促进其形成的异质表面之间的基本关系。我们将开发一系列的方法来预测和选择可能的多晶型，以及新的结晶实验和技术，包括喷墨打印。一种晶体结构如何从另一种晶体结构中生长的详细分子水平特征将产生对这种现象的基本理解，从而使选择模板的标准得到改进。这将导致新的实验技术和计算机设计方法，可用于确保新的有机产品可以以最佳的方式生产，而不会出现意外的多形体风险。

Many organic molecules are delivered to us in crystalline form, ranging from foodstuffs such as the cocoa butter in chocolate, to pigments, propellants, and pharmaceuticals. Organic molecules can adopt a range of crystalline forms, or polymorphs, that have distinct properties, including melting temperature, colour, detonation sensitivity, and dissolution rate. This proposal will develop new ways of predicting and producing an extended range of polymorphic forms for a given molecule. Even when the molecule is not delivered in a crystalline form, a detailed understanding of its crystallisation behaviour is necessary for optimising the manufacturing process, and designing the product to prevent crystals forming (e.g. ruining a liquid crystal display). A major risk in the manufacture of organic products is the unanticipated appearance of an alternative polymorph, as resulted in the withdrawal and reformulation of the HIV medicine ritonavir, and of transdermal patches of a Parkinson's disease treatment that became unreliable once rotigotine re-crystallised unexpectedly on storage. Crystallisation is a two-stage process comprising nucleation (formation of stable clusters of molecules) and growth (growth of clusters until visible crystals are observed). The appearance of many polymorphs late in product development has been attributed to difficulties in nucleating the first crystals. However, changes in the impurity molecules present and contact with different surfaces may catalyse this nucleation. In this proposal we will explore the influence different chemical and physical surfaces have on nucleation of new polymorphs. Although many thousands of crystallisation experiments can be performed in developing a new product, this is costly and time consuming and it is impractical to test all possible conditions. Thus the ability to select specific predicted forms and design experiments to enable these forms to nucleate for the first time turns polymorphism into an advantage in product and process design. It would allow crystal forms to be selected and manufactured with the particular properties best suited to the intended application of the molecule. The research will also provide a deeper understanding of the true range of solid-state diversity that an organic molecule can display. The EPSRC Basic Technology program has funded "Control and Prediction of the Organic Solid State" which has established an internationally unique capability of predicting the range of thermodynamically feasible polymorphs for a given molecule. This project has demonstrated the capability to produce the first crystals of a distinctive new polymorph of a heavily studied anti-epileptic drug, by crystallising it from the vapour onto a computationally inspired choice of a suitable template crystal of a related molecule. This finding proves that totally new forms can be discovered using templates designed to target a particular computationally predicted polymorph. However, it is essential to understand the interplay between structure, surface, kinetics and thermodynamics in directing this process if we are to harness the underpinning science for wider applications.This interdisciplinary project seeks to establish the fundamental relationship between the predicted polymorph and the heterogeneous surface which promotes its formation. We will develop a range of methods for prediction and selection of likely polymorphs as well as novel crystallisation experiments and technologies, including inkjet printing. The detailed molecular level characterisation of how one crystal structure grows off another will produce a fundamental understanding of this phenomenon, allowing a refinement of the criteria for choosing the template. This will result in new experimental techniques and computer design methods that can be used to ensure that new organic products can be manufactured in in the optimal way without the risk of unexpected polymorphs appearing.