Computationally Designed Templates for Exquisite Control of Polymorphic Form

Lead Research Organisation: University College London
Department Name: Chemistry


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.

Planned Impact

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.


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Price SL (2016) Can computed crystal energy landscapes help understand pharmaceutical solids? in Chemical communications (Cambridge, England)

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Price SL (2018) Control and prediction of the organic solid state: a challenge to theory and experiment†. in Proceedings. Mathematical, physical, and engineering sciences

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Reilly AM (2016) Report on the sixth blind test of organic crystal structure prediction methods. in Acta crystallographica Section B, Structural science, crystal engineering and materials

Description We have developed a reproducible method of templating new polymorphs by subliming the molecule and allowing it to crystallise onto a crystal of a related molecule that has a very similar structure to the computationally predicted structure of the desired polymorph. This is a new experimental method for finding new polymorphs that uses the output of our evolving crystal structure prediction methods, to determine whether there are meta-stable polymorphs that have not been found by conventional industrial screening methods. We have successfully applied the method to produce novel polymorphs in two families of pharmaceuticals, that had previously been subjected to a wide variety of polymorph screening techniques and have very different types of interactions. However, the computational modelling tool that has been developed for assessing the possibility of templating shows that the matching of the surface structure of the template to that of the targeted new polymorph has to be very precise, which is a limitation.
We have also explored the use of inkjet printing to find new polymorphs, and made many observations as to how the confinement in tiny droplets affects crystallisation from solution. This has added to our understanding of the factors that control polymorphism, as it is usually metastable forms that are produced in the droplets.
The project has developed crystal structure prediction methods to be applied to a wider range of molecules. It has made important advances in determining how to design an experiment to find a predicted polymorph, which are likely to be most important when dealing with a family of related molecules.

We have shown the effect of the crystalline surface on the polymoprh produced in the hydration of olanzapine and the nature of facile polymorphic changes in desloratidine i.e. added to our knowledge of how polymorphism in pharmaceuticals differs from that of smaller organic molecules.
Exploitation Route Extended use of CSP to predict putative polymorphs and then devise an experiment to find them. This has been discussed with pharmceutical company scientists who are using commerical CSP results and wish to find certain computer generated structures. New ways of using inkjet printer for nano-science and sensors are being investigated.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

Description The method of computationally predicting, and then designing an experiment to find new physical forms of drug molecules is having impact on the approach used in the pharmaceutical industry for solid form screening, a key stage in pharmaceutical development. The basic premise of the award, that crystal structure prediction studies could allow the design of templates to produce the polymorph for the first time has been demonstarted by this project for two distinct pharmaceutically relevant families of molecules. This has been noted by the pharmaceutical solid form development teams in industry, which are increasingly using crystal structure prediction services from the growing number of companies offering these computational modelling services to industry. The impact of this project is to suggest how industry could use the output of a CSP study (i.e. crystal structures of polymorphs that have not been observed in routine screening but appear thermodynamically plausible) to determine whether they have crystals of related molecules that might template the first sample of a new polymorph. The PI has discussed this with scientists from a variety of pharmaceutical companies, sometimes as pre-competitive research, and sometimes as confidential consultancy work. The ink-jet printer is being used to prepare more accurate sensors for atmospheric pollutants (in conjunction with the Mary Rose Trust, NPL and the SEAHA CDT). The application of inkjet printing for the production of new formulations of drugs is being pursued as a potential application.
First Year Of Impact 2018
Sector Chemicals,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal

Description Eli Lilly Research Agreement
Amount $167,578 (USD)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 11/2014 
End 05/2016
Description Eli Lilly Research Funding
Amount $1,409,787 (USD)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 07/2017 
End 07/2021
Description Horizon2020-FETOPEN
Amount € 2,886,323 (EUR)
Funding ID 736899 MagnaPharm 
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 01/2017 
End 12/2019
Description Lilly Research Awards Program
Amount $297,371 (USD)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 01/2013 
End 01/2015
Title Crystal Structure Navigator 
Description A database of the cell parameters, energies and properties of computer generated organic crystal structures for organic molecules. 
Type Of Material Database/Collection of data 
Year Produced 2006 
Provided To Others? Yes  
Impact We provide the structrues for those wishing to confirm that a novel polymorph was generated in our crystal structure prediction study or to further invesitgate the structrues, for example, reranking their likelihood of being observed with a new model. 
Title Data for: "Reversible, Two-Step Single-Crystal to Single-Crystal Phase Transitions between Desloratadine Forms I, II, and III" 
Description This dataset is a collection of the experimental data used in the publication "Reversible, Two-Step Single-Crystal to Single-Crystal Phase Transitions between Desloratadine Forms I, II, and III". The details of the different types of data, the type of data and the software used to analyse the data are provided in the readme file attached. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Description DMACRYS - Energy minimisation package to simulate rigid molecules with multipoles This package models crystals of rigid molecules, allowing lattice energy minimisation and the calculation of second derivative properties such as phonon frequencies and mechanical properties. It is designed to use anisotropic atom-atom model intermolecular potentials, particularly distributed multipole electrostatic models, but also has the capability of using distributed polarizabilities and anisotropic repulsion. 
Type Of Technology Software 
Year Produced 2014 
Impact The program is being licensed by UCL-B, and maintained and updated, with the 2014 release version being 2.0.8. There are licenses to industry and a large number of academic research groups throughout the world.