The Formulation Science and Technology group (FSTG) of the Royal Society of Chemistry organised the Future Formulation meeting hosted by the Durham University. This was held on Wednesday 24th May 2017 at Durham University Business School.

The aim of the meeting was to provide a forum to showcase advances which will shape future formulation and provide insight into projects which were just starting up aimed at tackling some of the difficult formulation challenges across a diverse range of applications.

The UK has in recent years recognised the massive contribution which formulation makes to its economic activity, resources have been made available both through the setting up of the National Formulation Centre in County Durham and specific funding calls from EPSRC and Innovate UK.  This meeting  brought together some of the people who are shaping future formulation having been awarded grants under the EPSRC's "Future Formulation of Complex Products" call - have a read of the summary of the meeting below and a look at the programme for links to the project proposal and to the presentations the speakers made at the meeting.

Speakers:

  • Professor Ricky Wildman - University of Nottingham
  • Dr Jin Sun & Dr John Royer - University of Edinburgh
  • Dr Mojtaba Ghadiri - University of Leeds
  • Dr Robin Curtis - The University of Manchester
  • Dr Darragh Murnane - The University of Hertfordshire
  • Professor Panagiota Angeli - University College London
  • Professor Colin Bain - Durham University

Organising committee

Professor Colin Bain, Durham University
Dr Simon Gibbon, AkzoNobel RD&I
Darren Ragheb, CPI
Dr Helen Ryder, The University of Manchester

Summary of the Meeting

Simon Gibbon opened the meeting on behalf of the RSC's Formulation Science and Technology, thanking both the EPSRC for funding the Future Formulaton of Complex Products (FFCP) grants which are the basis of this meeting and Durham University for the splendid hosting of the meeting.

In 2017, the UK faces many unique challenges, not least of which is the considerable gap in productivity between the UK and other developed economies.  The considerable role that formualted products play in UK manufacturing means that formulation needs to contribute to filling this gap, for this future formulation practices need to have addressed today's challenges, no doubt combined with high throughput as highlighted at FSTG's April meeting (HTFS-III) and the UK's considerable investment clever characterisation equipment which will be discussed at the Clever Characterisation for Smarter Formulation meeting in November (CC4SF).

The FFCP grants cover a very diverse range of formulation challenges, but also have brought together a very diverse set of scientists and engineers to work on these projects, many from outside formulation. This diversity has created both a threat, that existing formulation knowledge may be missed, and an opportunity, that new knowledge will make difficult formulation challenges more tractable.  Hopefully this meeting will have helped to both mitigate the threat and further develop the opportunity, by starting to build the network and letting people see where they can participate and where they can seek help.  The hope is to continue with such meetings as the FFCP projects progress, probably on an annual basis.

Rebecca Williams and Ellen Meek from the EPSRC explained the role of FFCP call in fullfilling EPSRC's role in ensuring that the fundamental science advances meet the countries industrial challenges.  FFCP does not stand alone but combined with the 4 CDTs targetting formulation, soft matter and particulate products and hubs in continuous manufacture / crystallisation and food manufacture address the EPSRC's UK Prosperity vision in the area of formulated products.   The EPSRC is moving away from specific calls like FFCP, as these strategic areas are being addressed by the institute inniatives which are consuming the 40% EPRSC targetted budget and in future the balance will be adjusted to ensure that 60% funding goes to standard mode investigator led proposals across manufacturing the future, healthcare technologies, physical sciences and engineering.  The EPSRC aims to grow biophysics and soft matter physics funding.

The UK government has also invested heavily in formulation to fill the "value of death" (TRLs 4-7) with the creation of CPI's National Formulation Centre (NFC), as explained by John Carroll, CPI's Technical Strategy Director.  CPI has a key role in enabling companies to pull new technologies from academia into industrial production, and so it is not surprising that CPI is a partner in 5 of the FFCP grants.  NFC will create value for UK-based companies through formulation science enabling bigger, cheaper or faster innovation from strategic alliances and shared access to advanced capabilities, while ensuring its own sustainability.  The Formulation Lighthouse Vision 2030 sees increased productivity and simplification being achieved by predictive design.  Projects from the application of microfluidics for the prediction of stability for complex fluids to acceleration of the use of particle models in industry, while also ensuring that ultimate manufacture is considered from the start of any project.  The implementation of the technologies which are enabling the 4th Industrial Revolution are also seen as key, so a lubricant will be designed from a product model, once in use the product model will be improved from real-time monitoring in use, resulting in improved products.

All seven FFCP grants were represented at the meeting by one of the PIs / co-PIs, so while the speakers names are mentioned below they were representing there whole teams which are detailed in the presentations and the proposals, which you can find links to on the programme page.

3D printing has a high profile but acheiving full potential is limited by access to suitable raw materials, so Ricky Wildman at the University of Nottingham plus partners are creating a "Formulation for 3D printing".  While in theory 3D printing can create anything, in practice one of the major constraints is producing the "inks" which are able to retain their material properties after printing and achieve the required performance. There are not only a wide range of raw materials possible, but also many different printing technologies, so this project will focus on a limited range and address specific target applications.  One of the exciting targets is dialled in release from multiple actives - possible to sequence drug release with independent release profiles. However even having limited the materials, techniques and targets formulation is still a daunting task and so this project will use high throughput to accelerate the process.  The project will address 4 research challenges - how to rapidly formualte a sector specific library, how to formulate to deliver multiple actives in a single system, how to formulate for structure and texture via 3D printing and how to devleop new materials for 3D printing.  The high throughput methodology for 3D printing will be applied to each of these challenges.  The early results are looking promising having already screened 312 cominbations of new materials, determined 19 had correct drug delivery function and found 4 3D printable formulations to be scaled up - in less time than it normally takes to screen a single combination.

Jin Sun and John Royer introduced us to the complex world of high-solid content complex dispersions and the challenges they prevent for formualtion.  The team knows what it is like to walk on a corn starch dispersion, but more importantly similar complex rheological behaviour also governs the behaviour of drilling fluids, catalyst washcoats and paints, so this project will provide a predictive approach to formulation which will include the complex rheology.  The approach is to combine particle properties / interactions with fluid properties to first understand simple then complex flow allowing formualtion from laboratory to factory, they will build on previous understanding of shear thickening, jamming, unsteady flow and the role of van der Waals forces in aggregate formation and break-up.  Previous approaches have been based on an understanding of the hydrodynamics, but this does not fully account for interparticle interactions, specifially the role of friction as the team has recently shown.  The major themes are: maxising volume fraction of particles, interplay between friction and attraction, buidling in not simplifying complexity (flow geometry, polydisperse shape, non-Newtonian) and making sure that this is all relevant across laboratory to factory (extracting process-relevant information, developing predivie models).

Solids based formualtions have historically had few predictive tools available and been difficult to manufacture, so Mojtaba Ghadiri and team will develop a "Virtual Formulation Laboratory" (VFL) which will allow prediction and optimisation of manufacture of advanced solids based formulations.  The VFL will take hierarchical input at molecular, particle and bulk level to generate manufacturability indicators such as flow / arching, flooding, mixing / segregation, storage / caking, compaction / breakage.  Molecular dynamics approach at Leicester will predict adhesive interactions from surface free energy predictions which be compared with experimental inverse gas phase chromatography measurements at Imperial.  The team Leeds will take a wide range of particle properties and use these to predict flowability, mixing and segregation.  Finite element analysis will be used at Leicester to model powder compaction.  These will be backed up by measurement at Greenwich of flow, segregation and caking properties.  The VFL will also build on the work of existing programmes - CHARIOT, ADDoPT - whole spectrum pharmaceutical manufacturing and TIPOW / MAPP - powder flow in additive manufacturing.

The formulation of biopharmaceuticals is a growing challenge with their increasing importance in medicine, a key challenge for formulation is to control agregation of proteins.  Robin Curtis tolds us how the teams at Manchester and UCL are using high-throughput to explore understand aggregation, rheology, stability of protein:excipient formulations guided by modelling and aided by improved analytics allowing assessments to be made on smaller quantities, this allowing formualtion at an earlier stage of the development process.  Understand the role of pH and temperature in the aggregation and folding behaviour of proteins is key, with SAXS allowing the folding state of the protein to be probed.  The use of dynamic light scatterings follows colloidal stability and conformational stability, then static light scattering provides a measaure of aggregate growth.  Including excipients allows the interaction with proteins to be studied.  Modelling gives insight into the aggregation hot spots and hence how the protein needs to be protected showing how the excipient interacts.  Underpinning the work are key questions about that need new understanding - what structural / sequence features underpin aggregation?, what should be evaluated / modelled - does Tm predcit aggregation rates? does high temperature predict shelf stability? .. and will engineering allow prediction of aggregation rates / formulation excipient effects? lower aggregation rates? ...  The work is being kept grounded by working with partners who have interest in specific families of biopharmaceuticals and excipients.

INFORM 2020 will overcome the barriers to formulation for pulmonary drug delivery, not least of which is agglomeration of the drug excipient combination, resulting in the particle size being too large to reach the correct areas of the lungs.  Darragh Murnane from Herfordshire explained how INFORM 2020 will provide the science to allow the use of the materials science tetrahedron to link the material properties through manufacturing paratemeters to product performance.  A series of hypotheses will be tested 1/ computational pharmaceutics will calculate particle surface energy and inter-particle forces to predict agglomeration behaviour, 2/ experimental approach will assess particle / agglomerate bulk / surface properties to understand agglomeration behaviour, 3/ combining understanding of powder microstructure with measure of agglomerate forces will enable rational design of formulations (X-ray computer tomography will be used to directly image the powder microstructures formed, giving confirmation that the understanding is correct), 4/ computational models with powder microstructure and cohesion will allow improved formulation, 5/ computational pharmaceutics and digital design can be used to engineer function / manufacturability / performance into products.

Oral products are typically non-Newtonian particle suspensions and as such present manufacturing challenges, Pangiota Angeli from UCL how CORAL will provide the fundamental understanding and methodologies to aid their manufacture.  A multiscale approach of mathematical analysis, numerical simulation and advanced experimentation will elucidate the relationship between nonlinear rheology and microscale interactions and develop tools to model the role of process conditions in determining rheology.  A range of techniques will be used to charaterise rheology from microscale to bulk, combined with imaging to study the structures formed.  Constitutive equations will be derived to describe this complex rheology based on the microscale interactions.  Computational fluid dynamics will take this understanding a stage further adding extra complexity of polydisperse, non spherical particles to predict the complex mixture rheology.  Scale-up and manufacturing will be tackled by validating the CFD code and investigation of the real mixtures - rheology, flow patterns, leading to routes for continuous manufacture of complex non-Newtonian particulate suspensions.

Control of droplet drying is a key parameter of many formulated systems - inks, agrochemicals, coatings across a wide range of applications and industries.  Colin Bain at Durham's will develop a predictive understanding of droplet drying so that it can be used to produce microstructured particles and thin films.  Formulation not only needs to ensure that the correct wet system is produced, but that the transition from wet to dry will produce the correct structure, whether alone or in contact with a substrate dependent on the application.  The work will cover free drops, drops on surface and process scale supported by theory / modelling.  A wide range of techniques allow properties of interest to be studied: optical tweezers - droplet droplet interactions; surface changes as a function of time; viscosity as a function of time; particle motion inside a drying droplet (coffee ring); binary solvent mixture - surface tension effects.  These studies will allow modelling of processes such as spray drying.

While the projects all address very different areas of formulation, there are a number of common features where they will hopefully be able to help and learn from eachother.  The formulation of particles whether dry or in suspension offer a number of challenges, not least of which is the reality that even with a single particle chemistry, dispersity of particle size and shape, mean that a complex mixture already exists, many previous modelling / simulation approaches have been unable to deal with this complexity - FFCP projects are now including this level of complexity which is necesary to move towards predictive formulation.  Mechanistic understanding of interactions whether between fluids and solids or between liquids alone or between solids alone, are now able to take account of the real geometry of the interface across multiple interfaces - giving a true understanding of everything from droplet drying on a surface to dry particle agglomeration in an inhaler.  Many of the projects show a pragmatic multi-scale approach where molecular or even atomic understanding is used to guide formulation, but bulk performance measures are still used to optimise the formulation.

The FSTG is looking forward to next year's meeting and seeing the progress which has been made in the individual projects, also hopefully seeing some new interactions that FFCP has generated.  The first of these was the meeting at CPI's National Formulation Centre in Sedgefield which was held the day after the Future Formulation meeting attended by 20 of the Future Formulation Meeting delegates.

The meeting ended with 3 views of "Revolutionary Formulation" and a general discusison on the future of formulation science in the UK.

Once again the FSTG would like to thank the EPSRC for funding the FFCP call and Durham University for hosting the meeting on a sunny day in Durham.

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