HABIT - Crystal Morphology from Crystallographic and Growth Environmental Factors

This proposal seeks EPSRC Follow-On grant funding to fund the technical and commercial development and integration of molecular modelling software (HABIT and SYSTSEARCH) developed by the crystallisation science and engineering research group at the University of Leeds which enables the prediction of the crystal shape and related surface chemistry of pharmaceutical, fine chemical and energy solid phase products and their mediation by their crystallisation environment. The predictive approach developed draws down on the modelled material's crystallographic structure together with the application of appropriate empirical inter-atomic/molecular force-field parameters through which the structure's key inter-molecular interactions (supra-molecular synthons) for both host (homo-synthons) and growth environment (hetero-synthons related to e.g. solvent, additives and impurities) can be identified, characterised regarding their strength and directivity and related to the product's physical and chemical properties. The work has been developed through a previous EPSRC senior fellowship programme and a number or associated EPSRC research grants. Commercialisation is envisaged through re-engineering the software based on user requirements, afforded through the data-bases and software of the Cambridge Crystallographic Data Centre (CCDC) and, through this, providing a significant enhancement of the predictive resources available to both academic and industrial research groups. The commercially robust software package, HABIT2011, will be offered through CCDC and directly to end user customers. The Synthonic Engineering identity will be established as an internal project, initially internally incubated within the University and later established as a spin off company. Synthonic Engineering will support the continuing technical and scientific development/enhancement of the HABIT2011 software; facilitate product licensing opportunities for other potential users; and provide consultancy, know-how and contract research support to the commercial sector. The utility of the modelling will be embedded within 4 key representative end-user companies: pharmaceuticals (Pfizer), agrochemicals (Syngenta), fuels (Infineum) and nuclear processing (National Nuclear Laboratory) through applications demonstrators on commercial compounds and at least one scientific instrument company (Malvern Instruments). These companies will also provide membership for a steering board to ensure the project's currency to the industrial sector.

This Follow-on project will enable industrial users to make use of scientific crystallisation engineering models, embodied in the commercialised HABIT2011 software developed from the HABIT and SYSTSEARCH research codes for improved control of product form (in particular, crystal morphology). Control of crystal morphology and, in particular the impact of crystal growth modifiers (CGMs) on morphology, underpins the processing of a wide range of chemical products and processes with > 80% of chemical products involving processing in the form of crystalline particles at some stage. It is well known that the impact of crystal morphology problems at manufacturing scales can be profound. The best known example of the impact of crystal morphology is the Ritonavir AIDS drug made by Abbott Laboratories introduced in 1996. After 18 months on the market, a unknown, more stable and concomitantly less soluble (bio-available) polymorph was detected in manufacture necessitating the withdrawal of the drug for reformulation with concomitant loss of > 170M in sales. Whilst this was a polymorph registration problem, the underlying cause was almost certainly a process change resulting in a chemical composition that allowed the nucleation and growth of the stable polymorph form - a crystal growth modifier. The beneficiaries will be research users involved in development of crystalline materials for a range of pharmaceutical and fine chemical products. The impact of CGMs will be evaluated with examples taken from the product streams of the 4 end-user companies collaborating on this follow-on grant project, spanning agrochemicals, biofuels, pharmaceuticals and nuclear waste storage as well as at least one scientific instrument company. An example of just one of these areas relates to an agrochemical product manufactured in the UK at 8K te/annum. After several batches at full scale, the final product filter became blocked due to a change in the shape of the crystals from large cubes to very thin plates. This catastrophic effect on filtration stopped the launch of the product. The underlying cause was the build-up of CGMs on recycle that specifically inhibited the growth of one face of the crystal. The solution lay in modification of the chemistry upstream of the crystallisation involving a further 20% capital expenditure to solve and taking nearly 2 years to recover full production at an estimated loss in sales of 27M. With many fine chemical compounds values can be at least an order of magnitude greater and hence this kind of manufacturing problem is very costly. All fine chemical crystallisation processes rely on quickly transforming materials in solution to the solid state. Leaving product in the solution at the end of the process, results in lost material. CGMs can substantially increase the solution composition at the end of the crystallisation by blocking the growing faces. If an average improvement of just 1% could be achieved across the product range of the industrial collaborator, then this would result in substantial savings across the consortium partners. Secondary beneficiaries of the project are all those users of products which have been developed quicker and at lower cost. At the extremes, This may mean medicines can be brought to market in a shorter time to save lives, crops may be grown with improved yields and nuclear reprocessing will be safer and more efficient. Through a new collaboration with partner Cambridge Crystallographic Data Centre, the project will enable investigators and researchers to enhance or develop new skills, in crystallisation science, software engineering and business strategy. Commercial realisation will only be made possible by the combination of skills, infrastructure and resources of these two partners, making the partnership of longer term benefit to both organisations.