Computationally Designed Templates for Exquisite Control of Polymorphic Form

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.

This project would have a major impact on the pharmaceutical and other speciality organic chemical industries in enhancing current solid form screening approaches to accelerate solid form selection from an extended range of structures. This change from having to work around the limitations of solid form to exploiting the real extent of diversity will allow manufacturers to tailor products to application requirements through crystallisation control. This research is fundamental to the control and prediction of the organic solid-state. Vitally, the industrial crystallisation process could be designed in full knowledge of the crystal energy landscape and phase diagram, preventing the reoccurrence of the ritonavir crisis and ensuring the "Quality by Design" that failed for rotigotine.
This project is a key step in effectively turning polymorphism into an advantage that can be rationally included in product development, rather than the threat that the new form may be accidentally templated during late stage development or production. This research proposal will provide knowledge and tools to introduce the degree of control over solid-form that synthetic chemists enjoy for molecular structure. Eventually, the combination of computational modelling and novel crystallisation methods could be used to produce the whole range of crystal structures and associated properties for a given molecule. This could lead to a more effective and efficient integration of industrial drug discovery and development by using samples (and available crystal structures) of synthetic intermediates and the closely related molecules used in biological testing. The crystal energy landscape of the active pharmaceutical ingredient (API) would be analysed for the possibility of polymorphs that had not been found by traditional screening. Any such target form could be analysed for possible templates, either directly from the crystals of, or fabricated using, the related molecules. Inkjet printing could be used to rapidly confirm the effect of possible synthetic impurities on the crystallisation of the API, as well as discover targeted forms. The novel form may have better properties, and so be selected for development of the product, in which case either seeding or optimised nucleation templates could be used in production. In all cases, knowledge of all possible solid forms enhances the "Quality by Design" of the product.
The better, theoretically-based and experimentally-validated, understanding of the nucleation and growth of one crystal structure on a heterogeneous surface would have implications for a wide range of "nucleation and growth" problems, which occur throughout the environment. The greater understanding of the importance of surfaces in crystallisation processes will also help researchers in materials and surface science and nanotechnology develop new capabilities. For example, can such disciplines deliver 2D surfaces that mimic template crystal requirements? There are therefore significant opportunities for cross-fertilisation of ideas with other disciplines to achieve new solutions to materials design.
The adaption of the inkjet printer will make it suitable for producing metastable polymorphs by allowing fine control of the aerosol and evaporation times and temperature differences. The system will have application to production of other novel physical forms, including cocrystals, as well as to creation of heterogeneous products, such as drug-excipient blends and oral films. Similarly, the development of software to model organic condensed phase systems and of many experimental organic solid state analytical techniques will also enhance research in related areas.