Wednesday 16th May 2018, The Centre for Additive Manufacturing, University of Nottingham - #futureformulation
The Formulation Science and Technology group (FSTG) of the Royal Society of Chemistry worked with the University of Nottingham to organise the 2nd Future Forumulation meeting to bring together the researchers working as part of the EPSRC's Future Formulation funding award. The University of Nottingham kindly hosting the meeting at the Centre for Additive Manufacturing.
The 1st Future Formulation meeting was held in Durham in 2017, just after the Future Formulation of Complex Products grants had started, so the 2nd Future Formulation meeting was an oppotunity to hear about the exciting progress being made towards the future of formulation.
The aim of the meeting was to provide a forum to showcase advances which will shape future formulation and provided insight into projects which have now been running for over a year and started 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 proposals and to the presentations the speakers made at the meeting.
- Professor Colin Bain - Durham University
- Dr Jin Sun, University of Edinburgh & Dr Mark Haw, University of Strathclyde
- Dr Csaba Sinka - University of Leicester
- Dr Robin Curtis - The University of Manchester
- Dr Darragh Murnane - The University of Hertfordshire
- Professor Panagiota Angeli - University College London
- Professor Ricky Wildman - University of Nottingham
Professor Ricky Wildman, University of Nottingham
Professor Colin Bain, Durham University
Dr Simon Gibbon, AkzoNobel RD&I
Liz Grylls, CPI
Dr Helen Ryder, The University of Manchester
In 2016 the EPSRC funded the 7 Future Formulation of Complex Products (FFCP) projects with £14million over 3-4 years. So in 2017 Simon Gibbon as Chair of the RSC's Formulation Science and Technology Group with Professor Colin Bain of Durham University organised the first Future Formulation meeting in Durham to share the visions of the project with the wider formulation community and allow the different projects teams to network. The second meeting has just been held in Nottingham to once again share and highlight progress, the third meeting in planned to be held in Liecester in May 2019.
Ricky Wildman welcomed everyone to the Advanced Manufacturing Building on the University of Nottingham's Jubbilee Campus, the home of the Centre for Additive Manufacture. Simon Gibbon then introduced the meeting with the background of the UK's recognition nearly a decade ago of the importance of formulation to the UK economy as having been the driving force for both the FFCP grants and CPI's National Formulation Centre (NFC). Simon had envisioned the meeting as way of allowing far greater visibility of the cohort of projects as they progressed, rather than once they completed or through individual research presentations, this idea has been enthusiastically embraced by all the investigators and recognised by the EPSRC as an innovative approach to dissemination. Many of the attendees as Future Formulation II would not normally meet as few meetings cover both 3D printing and inhaled pharmaceuticals, so these meeting create some unique chances for knowledge exchange.
Professor Colin Bain (Durham University) introduced "Drying Droplets" (Evaporative drying of droplets and the formation of microsctured and functional particles and films) a collaboration between Durham, Leeds and Bristol with the support of a growing industry club, which aims through a predictive understanding of droplet drying be able to control the microstructure of the particles and the thin films formed. The project is logically building up control of microstructure through understanding of the drying of isolated drops, mechanisms of droplet interaction, this leads into processes such a spray drying and the coalescence with preceeds film formation. Progress in the project was highlighted by Jack Goodall, one of the PhD students, who is studying particle migration in drying droplets. Jack has started from the extensive literature on processes such as the coffee ring effect and the tears of wine, being governed by convective flow and Marangoni stresses. Jack's experiments have shown that droplet drying is far richer than suggested by these two well understood examples, once you start to think about complex products. So in the presence of mixed liquids Marangoni forces are overcome by chemophoresis with particles moving against Marangoni forces. Viscosity has a kinetic effect as could be expected and in complex products may well freeze in a final form that is not the thermodynamic solution in solution. Perhaps surprisingly Jack found only a weak dependence on particle size for the effects he has observed. While Jack's work has shown the physical complexity introduced by complex multi-component formulations, it has also emphasised the predictability of the structure evolution on evaporation based on the physical properties of the components. I could imagine this work being turned into a digital simulator which would allow formulation parameters to be tuned in silico for the optimum product structure before a laboratory is visited.
Dr Jin Sun (University of Edinburgh) introduced "Predictive formulation of high-solid content complex dispersions" a joint project with the University of Strathclyde supported by a range of different companies. To control the flow of complex dispersions they have taken the approach to reduce the systems down to their fundamental physics, understand this fully, then introduce engineer details and finally consider the industrial scale challenge. Realistic models have been created to adjust the onset of stress and understand the role of attractive interactions. The role of particle properties in controlling rheometric flows has studied to build up understanding for example that introdcution of friction eliminate rolling and adhesion stops sliding of particles, these are reflected in the rheometry. Previously the fluctuations and instabilities seen in real system has been poorly understood, models are now able to largely predict the observed behaviour, especially now new measurement systems have been constructed to accurately measure these subtle behaviours. Many processes involve elongational flow, so this has been considered for extrusion of pastes etc.. Systems have also been designed where the interaction of the particles will dominate the rheology of suspending fluid, entirely changing the yield-stress behaviour. Dr John Royer (University of Edinburgh) has used well characterised model systems and then introduced addtional complexity through changes in shape, roughness, interactions. Through this approach he is able to connect paritlce properties to observed rheology, understand the effect of salt on flow and confirm this through direct force measurements of particles. Mark Haw (University of Strathclyde) described the pragmatic statistical approach they are taking to understand jamming and clogging, the findings are very promising as fluctuations seen are statistically well-defined making them predictable and complex geometry flows can be understood. The next steps are explain how microscale interaction grows into bulk scale fluctuations and see if desired behaviour can be engineered through the use of certain geometries. Mark also described who the project is being taken into school with "Sludge engineering", bringing on the next generation of sludge engineers.
Dr Csaba Sinka (University of Leicester) introduced "Virtual Formulation Laboratory (VFL for prediction and optimisation of manufacturability of advanced solids based formulations) a collaboration between Leicester, Leeds, Greenwich and Imperial College. The idea of VFL is to be able to predict manufacturability from measured powder parameters, specifically VFL will focus on flow/arching, flooding, mixing/segregation, storage/caking and compaction/breakage. Dr Ben Edmans described the work on compaction where the aim is to link across size scale from single particle properties to contact mechanics to contact law parameters to micro-mechanical theory to bulk powder properties. A contact law for compressible particles has been developed, which has been used to understand a material model contact law and mechanism. The work has shown that the choice of model has a profound impact on the way in which the force is transmitted and thus the failure mechanism of the compact. For spherical particle systems particle properties micromechanical modelling has been used to calculate compact strength. The work is now moving to link particle properties with compact strength for real powder systems by developing an analytical homogenisation framework.
Dr Robin Curtis (The University of Manchester) introduced Enabling rapid liguq and freeze-dried formulation design for the manufacture and delivery of novel biopharmaceuticals a collaboration between UCL and Manchester. Biopharmecuticals create new formulation challenges as efficacy will be lost if the protein structure/form is not maintained, so this project is being guided by computational methods to both look at protein variants and predict formulation excipients which will gaurantee protein stabilisation. Protein aggregation is complex to study, so it is planed to study unfolding temperature and colloidal stability variations as a surogate for aggregation. The project will develop high-throughput automation to build-up a database of protein:excipient combinations, molecular informatics and modelling to predict and new analytical techniques for more sensitive assessment of degradation. Dr Jordan Bye described the work within the project looking at the effect of polyvalent excipients on protein-protein interactions. Protein-protein interactions and their interaction with solutes are not well understood but govern protein aggregation / phase behaviour / crystllisation / purification, so an understanding of protein-solute interactions could provide a new formulation design rule for more stable delivery forms. The work has looked at the role of two polyphosphate polyvalent anions in controlling precipitation of lysozyme, where the binding of the polyvalent ions will provide an additional control of preciption when compared to the screening provided by monovalent ions, also potentially able to crosslink proteins with a single polyvalent ion being bound to two proteins. All this shows the importance of charge in controlling protein aggregation, and how the use of excipients allows the behaviour of an already registered protein to be tuned, without a need to modify the registration. The work so far has demonstrated that polyvalent ions are effective at reducing aggregate growth rates for a negatively charged protein. Future work will discover whether this effect is seen in other proteins and whether polyvalent anions can drive phase separation leading to new forms of more stable storage.
Professor Darragh Murnane (University of Hertfordshire) introduced INFORM 2020 - Molecules to manufacture (Formulation and process engineering of inhaled particle therapies) a collaboration with Leeds, Cambridge, Bath and Manchester. The project is based on a computational pharamaceutical engineering approach. Good progress has been made on the specific hypothesis that incorporation powder microstructure and cohesion into computational models will improve understanding and engineering of formulation processing and performance. Using lactose as a probe material the work has shown good agreement between CFD predicted and actual emission rates, however the presence of fine particles gave poorer agreement which will be addressed by the incorporation of microstructure and cohesive forces into the model. Dr Thai Thu Hien Nguyen from Leeds has been working on hypothesis 1 Computational engineering provides an in silico modelling approach to calculate particle surface energy and inter-particulate forces predictive of agglomeration in molecular, ionic and solvated crystals, by validating the synthonic modelling of saltes and hydrates. A number of excipients have been studied, with intermolecular packing, lattice energy and crystal morphologies being calculated. This allows cohesive energy predictions from a systematic grid search, providing guidance for likely aggregate formation. Dr Ioanna Danai Styliari from Hertfordshire has been working closely with Dr Parmesh Gajjar from Manchester on hypothesis 3 - Understanding powder microstructure combined with measurements of agglomerate forces will enable the rational design of formulations achieving uniform aerosolization, by using a wide range of imaging techniques to understand size and crystal effects. Bulk particle sizing which is widely used to study powders does not correlate well with observed inhalation properties. This work is using micro-ct (x-ray computer tomography) which provides not only the ability to see the full 3D microstrcuture of powder agglomerates, but also allows differences in density and porosity to be examined. The work has concentrated on looking at a range of different lactoses to understand the role of fines and different crystal structures on the formation of agglomerates.
Professor Panagiota Angeli (University College London) introduced Complex ORAL health products (CORAL): Characterisation, modelling and manufacturing challenges involving Chemical Engineering, Mechanical Engineering and Mathematics at UCL. The aim of the project is to connect manufacuring to fundamental local and bulk rheology through constitutive equations and a continuum description such that scale-up can be achieved rapidly based on the results of a rheological charaterisation. Oral products are by nature highly viscous and have traditionally been made by batch processes, so Dr W Weheliye described work on batch mixing in a stirred tank of non-Newtonian fluids using particle image velocimetry, combined with dye as a tracer it is possible to capture the flow under these conditions, then by comparison with CFD it is possible to validate the models based purely on input of the rheological measurements. In future modelling of the impeller torque will provide further validation of the model. Continuous mixing potentially provides a range of manufacturing advantages and so S Migliozzi described the process whereby initial liquid mixing is followed by gelation and then addition of the solid particles. The study has shown that the gelation process is accelerated by increasing temperature and increases in glycerol content, producing a series of operating maps showing the degree of gelation as a function of processing time. The use of a visualization section on the continuous mixer allows the fluid flow within the continuous mixed to be seen with suitable tracer materials and the flow patterns to be compared to CFD caclulations to validate models which will be used to enable scale-up.
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