Details of Grant 

EPSRC Reference:	EP/K039229/1
Title:	Computationally Designed Templates for Exquisite Control of Polymorphic Form
Principal Investigator:	Price, Professor SL
Other Investigators:	Gaisford, Professor S Urquhart, Dr AJ Tocher, Professor DA Florence, Professor AJ
Researcher Co-Investigators:
Project Partners:	Cambridge Crystallographic Data Centre TTPCom Ltd
Department:	Chemistry
Organisation:	UCL
Scheme:	Standard Research
Starts:	01 October 2013	Ends:	30 June 2018	Value (£):	1,248,345
EPSRC Research Topic Classifications:	Chemical Structure Surfaces & Interfaces
EPSRC Industrial Sector Classifications:	Manufacturing
Related Grants:
Panel History:	Panel Date Panel Name Outcome 22 Apr 2013 EPSRC Physical Sciences Chemistry - April 2013 Announced
Summary on Grant Application 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.
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