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Computationally Designed Templates for Exquisite Control of Polymorphic Form

用于精确控制多晶型的计算设计模板

基本信息

批准号：
EP/K039229/1
负责人：
Sarah (Sally) Price
金额：
$ 159.06万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FK039229%2F1
关键词：
Computationally Designed Templates Exquisite Control

项目摘要

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.

许多有机分子以晶体的形式传递给我们，从食品，如巧克力中的可可脂，到颜料、推进剂和药物。有机分子可以采用一系列晶型或晶型，具有不同的性质，包括熔化温度、颜色、爆炸敏感性和溶解速度。这项提议将开发新的方法来预测和产生给定分子的更大范围的多态形式。即使分子不是以晶体形式提供的，对其结晶行为的详细了解对于优化制造工艺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。有机产品生产中的一个主要风险是意外出现替代多晶型，这是艾滋病毒药物利托那韦退出和重新配方的结果，以及帕金森病治疗的透皮贴片，一旦罗替戈汀在储存中意外重新结晶，这种贴片就变得不可靠。结晶化是一个两个阶段的过程，包括成核(形成稳定的分子簇)和生长(簇的增长，直到观察到可见的晶体)。许多多晶型的出现在产品开发的后期被归因于第一个晶体成核的困难。然而，存在的杂质分子以及与不同表面接触的杂质分子的变化可能会催化这种成核。在这个提案中，我们将探索不同的化学和物理表面对新的多晶型成核的影响。尽管在开发新产品时可以进行数千次结晶实验，但这是昂贵和耗时的，而且测试所有可能的条件是不切实际的。因此，选择特定的预测形式并设计实验以使这些形式首次成核的能力将多态转化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。这项研究还将提供对有机分子可以表现出的固态多样性的真实范围的更深层次的理解。EPSRC基础技术计划资助了“有机固态的控制和预测”，它建立了一种国际上独一无二的能力，可以预测给定分子的热力学上可行的多晶型范围。该项目展示了通过将抗癫痫药物从蒸气中结晶到受计算启发选择合适的相关分子模板晶体的方法，生产出一种经过大量研究的抗癫痫药物的独特新晶型的第一批晶体的能力。这一发现证明，使用针对特定计算预测多态的模板可以发现全新的形式。然而，如果我们要利用支撑科学的更广泛的应用，那么了解结构、表面、动力学和热力学之间的相互作用对于指导这一过程是至关重要的。这个跨学科的项目试图建立预测的多晶型和促进其形成的非均质表面之间的基本关系。我们将开发一系列方法来预测和选择可能的晶型，以及新的结晶实验和技术，包括喷墨打印。对一种晶体结构如何从另一种晶体结构生长的详细分子水平表征将产生对这一现象的基本理解，从而能够改进选择模板的标准。这将产生新的实验技术和计算机设计方法，可用于确保以最佳方式制造新的有机产品，而不会出现意外的多晶型风险。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?

DOI：
10.1021/acs.cgd.7b00842
发表时间：
2017-10-04
期刊：
Crystal growth & design
影响因子：
3.8
作者：
Braun DE;Lingireddy SR;Beidelschies MD;Guo R;Müller P;Price SL;Reutzel-Edens SM
通讯作者：
Reutzel-Edens SM

Rapid preparation of pharmaceutical co-crystals with thermal ink-jet printing