HABIT - Crystal Morphology from Crystallographic and Growth Environmental Factors

Lead Research Organisation: University of Leeds
Department Name: Process, Environmental and Material Eng


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.

Planned Impact

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.


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Description It is a well-known fact that more than 70% of speciality, fine chemical and pharmaceutical products involve processing of materials in their solid form at some stage of their synthesis, formulation and manufacture. Processes involving solid phases can be notoriously heterogeneous in nature and can concomitantly challenging to control and optimise. Most processed solids are crystalline and hence having a molecular-scale understanding of how the surfaces of crystalline particles interact with their processing environment through contact with both mother liquor and other solid materials is often critical in terms of achieving high-quality materials and products.

The above perspective sets the scene for this current work where crystallographic information on target materials is used through computational simulation to predict the crystal shape and surface properties of a range of organic materials. The calculations underpinning these simulations are based on science developed through previous EPSRC and industrial grants but through this work these simulations have been brought into the hands of professional process R&D practitioners within industry. This has led to the wide-scale adoption of this previously academic work within the industrial sphere.
Exploitation Route Up to now the dominant interests have been within the pharmaceutical and agrochemical sectors, however, the research has wider applications, e.g. in fuel sciences (cold flow behaviour in diesel), predicting stability and reactivity of formulation ingredients, energetic materials and nuclear waste storage suspensions.
Sectors Aerospace, Defence and Marine,Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Education,Energy,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Transport

URL http://www.engineering.leeds.ac.uk/synthonic/
Description Through this EPSRC Follow-on grant previously developed computational tools were customised for their wider use through integration with the Materials Mercury software system provided by the Cambridge Crystallographic Data Centre (CCDC). The new software VisualHABIT provided an enhanced graphical user interface (GUI) which enabled the use of these simulation tools within a practical industrial process R&D environment. The GUI design was developed through industrial workshops and case study work carried out in close collaboration with three industrial companies: Infineum, Pfizer and Syngenta. A number of workshops were held to engage industry. In particular a cross-industry workshop was held at the Institute of Physics in London (2/3/12). This involved CCDC, BMS, GSK, Intrinsiq, Novartis, QuinetiC, Pfizer, Syngenta. Additionally, one-to-one workshops were held with: Infinium, Abingdon (20-21/2/12) and Syngenta (17-18/5/12). A further cross-industry workshop was held at Leeds (4/10/12) involving Boehringer-Ingelheim, BMS, Infineum, Malvern, Mylan, Nalas Engineering, Novartis, Syngenta and Pfizer. Towards the end of the Follow-on Grant in 2012, Pfizer provided a further 2-years' of direct funding to continue the visualHABIT development (2012-13). This was followed by a further 3-years' funding from an industrial consortium of Boehringer Ingelheim, Novartis, Pfizer and Syngenta (2013-16). During this period further workshops with the industrial partners were arranged, a summary book chapter on Synthonic Engineering published and a landmark summer school "Engineering Crystallography: From Molecule to Crystal to Functional Form" was run in Erice, Italy in June 2015. An edited book based on the lectures given at the summer school is currently in its final stages of preparation and will shortly be published by Springer. Overall, the visualHABIT programme provides an important design resource for the prediction of the physical properties on the basis of their root molecular and crystallographic structure. Further development of the visualHABIT programme is currently being undertaken through the new ADDoPT (Advanced Digital Design of Pharmaceutical Therapeutics) research programme recently funded (2015-19) by BIS through its AMSCI funding programme. The ADDoPT programme consortium (AZ, BMS, BRITEST, CCDC, GSK, Perceptive Engineering, Pfizer, PSE and STFC's Hartree Centre) seeks to develop an integrated multi-scale modelling platform for the rapid design and development of advanced pharmaceutical products. VisualHABIT software is also well integrated with the undergraduate and taught postgraduate Chemical Engineering programmes at Leeds. It is also routinely applied in project work for the EPSRC's Centre for Doctoral Training in Complex Particulate Products and Processes. During the grant's period, the Leeds PI (Roberts) served on the Science Advisory Boards for the EPSRC's CMAC Centre, NSF's ERC in Structured Organic Particulate Systems, SFI's Synthesis and Solid-State Pharmaceutical Cluster and Pfizer's Pharmaceutical Sciences Strategy. These provided opportunities for ensuring the Critical Mass project's wider impact both industrially and internationally as well as impacting on policy at the highest levels.
First Year Of Impact 2011
Sector Chemicals,Digital/Communication/Information Technologies (including Software),Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

Description ADDoPT
Amount £4,486,808 (GBP)
Organisation Advanced Manufacturing Supply Chain Initiative (AMSCI) 
Sector Public
Country United Kingdom
Start 11/2015 
End 03/2019
Description INFORM2020
Amount £579,797 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 12/2020
Description Molecules, Clusters and Crystals: A multi-scale approach to understanding kinetic pathways in crystal nucleation from solution
Amount £1,299,408 (GBP)
Funding ID EP/I014446/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 05/2011 
End 10/2015
Description Synthonic Engineering
Amount £537,036 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 11/2011 
End 06/2014