Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations

Lead Research Organisation: University of Leicester
Department Name: Engineering

Abstract

Solid dose forms are the backbone of many manufacturing industries. In pharmaceutical therapeutics, tablets, capsules, dry powder inhalers and powders for re-suspension cover the vast majority of the £5.6Bn sales by this industry in the UK. Food (sales £67Bn) is the single largest industry of the UK manufacturing sector which totalled £365Bn sales in 2014 (Office of National Statistics). In all these manufacturing processes and in final use, the physical behaviour of the powder is at least as important as the chemistry. Stability, weight and content uniformity, manufacturing difficulties and variable performance are determined by decisions made during the formulation process Manufacturing problems are ubiquitous; the Rand report (by E.W. Merrow, 1981) examined powder processes and found on average 2 year over-runs to get to full productivity, and development costs 210% of estimates, due to incompatibility between powder behaviour and process design. In the intervening years, plant engineering techniques have developed, but the rationalisation of formulation decisions has never received more than cursory, empirical study.

This project proposes to develop a Virtual Formulation Laboratory (VFL), a software tool for prediction and optimisation of manufacturability and stability of advanced solids-based formulations. The team has established expertise in powder flow, mixing and compaction which will be brought together for the first time to link formulation variables with manufacturability predictions.

The OVERALL AIMS of the project are (a) to develop the science base for understanding of surfaces, particulate structures and bulk behaviour to address physical, chemical and mechanical stability during processing and storage and (b) to incorporate these into a software tool (VFL) which accounts for a wide range of material types, particle structures and blend systems to enable the formulator to test the effects of formulation changes in virtual space and check fortential problems covering the majority of manufacturing difficulties experienced in production plants.

The VISION for VFL is to be employed widely in the development process of every new formulated powder product in food, pharmaceuticals and fine chemicals within five years of the completion of this project.
VFL will consider four processes: powder flow, mixing, compaction and storage; and will predict four manufacturability problems: poor flow/flooding, segregation/heterogeneity, powder caking and strength/breakage of compacts These account for the majority of practical problems in the processing of solid particulate materials

The OVERALL OBJECTIVES of the project are: (a) to fill the gaps in formulation science to link molecule to manufacturability, which will be achieved through experimental characterisation and numerical modelling, and (b) establish methodologies to deal with new materials, so that the virtual lab could make predictions for formulations with new materials without extensive experimental characterisation or numerical modelling. This will be achieved through developing functional relationships based on the scientific outcomes of the above investigations, while identifying the limits and uncertainties of these relationships.

Planned Impact

A. Industry impact for improved process efficiency
Industry impact is a top priority of this project. Our partners have an outstanding impact track record, and this proposal has found an exceptionally strong pull from industry. Keys to maximising impact are (i) to make the toolkit easy to use, highly accessible and effective, and (ii) taking it to the beneficiaries pro-actively. The plans to achieve this are articulated below.

B. Accelerating the output up the TRL scale
Accessibility requires the software package to run on a popular platform, have a user-friendly Graphic User Interface, with strong expert support maintained over the foreseeable future, and multiple access routes to suit the needs of different companies. Without these features, such advanced science would be very difficult for practicing formulators and engineers in industry to use. The starting point is the Virtual Powder Blending Laboratory (DEFRA AFM276) (Bradley and Berry), which has a functional structure, an expandable, shareable database to enter and store the properties of materials characterised, and a user friendly interface, optimised with the DEFRA project partners. It will be used as a basis to build the output of this project into a usable toolkit, moving the basic science, of TRL2, up to a position of direct impact on manufacturing, TRL4 to 5.

C. Positive engagement of the industry partners during the programme
To facilitate this, an Industrial/Academic Advisory Board will be convened including all the contributors, to meet quarterly, advised by two consultants (high level research leaders in formulation). The board will steer the programme, provide the industry context and ensure relevance. Powder producers and users will take active roles in characterisation of their powders and processes and testing the toolkit as it evolves and will help pursue compatibility with their own tools. All will involve their personnel in training in use of the techniques. The participants will thus get a head start in exploiting the output.

D. Communication with beneficiaries beyond the project participants
Around 20 open access papers in archival journals, 40 conference publications, then trade journal articles, and workshops with learned and trade bodies (IMechE, IChemE, SHAPA etc, in which many of the investigators hold positions of influence e.g. chairmen & committee members).
The toolkit will be incorporated in Wolfson Centre short courses on powder processing. Annually, about 20 courses reach 250 to 300 people involved in formulation and manufacturing of powder products, in 60 to 70 different companies. Leeds organises complementary short courses in powder science, which will also promote the toolkit and the science behind it. Britest, PSE and NFC will also lead activities in marketing and taking to users.

E. Contributing to the health of academic disciplines worldwide
The advances in modelling, surface energy characterisation etc will significantly push forwards the ability of the community to model the behaviour of powders. These will be promoted to the academic community through publications, short courses and workshops for researchers, international conferences (AAPS/AIChE, APS, PARTEC, APT, CHoPS, ICBMH), exhibitions (Powtech), learned body meetings e.g. IChemE, IMechE, EFCE, and industry bodies eg SHAPA.

F. Public communication and engagement
The PIs are active in public lectures through IOM3, schools visits, science festivals, House of Commons annual science event etc. Case studies from this project should form an excellent showcase for the direct impact of research on efficiency and competitiveness of UK manufacturing.
 
Description The concepts of Surface Stress, Surface tension and SFE are sometimes confused in the literature and applications. The equivalence of these concepts is true only for interfaces involving liquids, while for interfaces with solids, extra care should be taken when these quantities are calculated within molecular simulations or measured in experiments, as different methods of calculation or measurement lead to different results.
Exploitation Route New framework for the calculation of Surface Free Energy (SFE) and surface stress in solids and liquids. Verification of the Shuttleworth equation. Calculation of the SFE for organic crystals (mannitol).
Sectors Agriculture, Food and Drink,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description EPSRC Industrial CASE (iCase) studentship award at Imperial College
Amount £108,580 (GBP)
Funding ID Voucher No. 16000114 
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 10/2017 
End 03/2021
 
Description PhD Studentship (Part-time) at Imperial College
Amount £50,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 08/2017 
End 07/2022
 
Description VC Scholarship Scheme at the University of Greenwich
Amount £120,000 (GBP)
Organisation University of Greenwich 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
Title Novel Cellular Automaton model for assessing size segregation in fuel handling (University of Greenwich) 
Description A von Neumann automaton approach to model free surface segregation effects in handling of biomass fuel 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? No  
Impact Anticipated impact will be to allow optimisation of storage reclaim strategy to minimise variation in dust content in wood pellet fuel in order to minimise explosion and health risks. 
 
Title Virtual Powder Blending Lab (University of Greenwich) 
Description Further development and enhancement of a data base of bulk flow properties and particle properties built up from historical test data, that use an averaging technique to predict the flow properties of a blended powder. 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? No  
Impact Anticipated impact will be to assist the optimisation of the flow properties of blended materials. 
 
Description Dr Koichiro Ogata: Analysis of FT4 specific flow energy for cohesive mixtures 
Organisation National Institute of Technology, Oita College
PI Contribution Training, development of contact model, material characterisation and providing test materials
Collaborator Contribution Analysis of FT4 specific flow energy by DEM simulations for binary mixtures
Impact Chemical Engineering and Mechanical Engineering
Start Year 2017
 
Description Dr Sadegh Nadimi: Effect of surface roughness on inter-particle friction 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Training, material characterisation, providing test materials, development of a technique for measuring the effective friction coefficient
Collaborator Contribution Providing an insight on the effect of particle roughness for adhesive contact
Impact Chemical Engineering and Mechanical Engineering
Start Year 2018
 
Description Dr Wenguang Nan: Analysis of elutriation segregation and powder flowability 
Organisation Nanjing Tech University
Country China 
Sector Academic/University 
PI Contribution Training, material characterisation, providing test materials, developing the test rig and analysis of segregation experimentally
Collaborator Contribution Providing an insight on the effect of immersing/ permeating air on flowability and segregation
Impact Chemical Engineering and Mechanical Engineering
Start Year 2018
 
Title LAMMPS package for cleaving model calculations (University of Leicester) 
Description Molecular Dynamics software: LAMMPS package for cleaving model calculations. 
Type Of Technology Software 
Year Produced 2017 
Impact The package is included in the LAMMPS distribution and is going to be available to the public. 
 
Title MATLAB model for surface energy deconvolution (Imperial College London) 
Description MATLAB software: Boltzmann probability distribution model to simulate the adsorption of gaseous probes for deconvolution of surface energy data 
Type Of Technology Software 
Year Produced 2018 
Impact Method implementation 
 
Description Application of DEM for Particle Flow, Mixing, Separation, and Segregation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Application of DEM for Particle Flow, Mixing, Separation, and Segregation. Characterisation Advances in Particle Engineering (University of Cape Town, Nov 2018)
Year(s) Of Engagement Activity 2018
 
Description Application of DEM for particle flow, mixing, separation and segregation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Application of DEM for particle flow, mixing, separation and segregation. Characterisation Advances in Particle Engineering (University of Cape Town, Nov 2018).
Year(s) Of Engagement Activity 2018
 
Description Contact Mechanics: Deformation, Damping, and Adhesion 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Contact Mechanics: Deformation, Damping, and Adhesion, Short Course: Modelling of Particulate Systems using Distinct Element Method (University of Leeds September 2018)
Year(s) Of Engagement Activity 2018
 
Description Department of Mathematics, University of Leicester. "Surface Properties in Liquid and Solids: Theory and Computations" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Department of Mathematics, University of Leicester. "Surface Properties in Liquid and Solids: Theory and Computations"
Year(s) Of Engagement Activity 2019
 
Description Dr. Ben Edmans - Invited to give seminar at Brunel University, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Explored potential for future collaboration on fracture of particles
Year(s) Of Engagement Activity 2018
 
Description Dr. I.C. Sinka - organises a conference at Leicester: Future Formulation III with the RSC Formulation Science and Technology Group, Royal Society of Chemistry 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 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 opportunity to hear about the exciting progress being made towards the future of formulation.  During the 3rd Future "Future Formulation2 meeting will offer the researchers will get the opportunity to update on their individual projects and through interactive session provide further details and give you the opportunity to contribute to the development of the projects.
Year(s) Of Engagement Activity 2019
URL https://www.formulation.org.uk/ff3
 
Description Dr. I.C. Sinka talks at: Future formulation II. "Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk at: Future formulation II. Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations. Organised by The Formulation Science and Technology group (FSTG) of the Royal Society of Chemistry at the University of Nottingham.
Year(s) Of Engagement Activity 2018
 
Description Dr. I.C. Sinka: Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations. Talk at Manufacturing Classification System Working Group Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations. Manufacturing Classification System Working Group Meeting (online). 28 September 2017.
Year(s) Of Engagement Activity 2017
 
Description East Midlands Materials Society meeting - Dr. I.C. Sinka: Materials Selection for Powder Products, 15 November 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited talk: I.C. Sinka: Materials Selection for Powder Products.
Year(s) Of Engagement Activity 2017
 
Description Jamming during Particle Spreading in Additive Manufacturing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Jamming during Particle Spreading in Additive Manufacturing (Hewlett-Packard, Sep 2018)
Year(s) Of Engagement Activity 2018
 
Description Jamming during Particle Spreading in Additive Manufacturing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Jamming during Particle Spreading in Additive Manufacturing, DEM Powder Calibration Meeting (DEM Solutions, June 2018)
Year(s) Of Engagement Activity 2018
 
Description Jamming during Particle Spreading in Additive Manufacturing 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Jamming during Particle Spreading in Additive Manufacturing, DEM Powder Calibration Meeting (DEM Solutions, June 2018)
Year(s) Of Engagement Activity 2018
 
Description Joint organiser Dr. Jerry Heng, Imperial College: UK Particle Technology Forum (PTF) 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Joint organisation of the annual Particle Technology Forum (PTF) meeting, an IChemE's Particle Technology Subject Interest Group (PTSIG) forum, by Imperial College London along with UCL.
Year(s) Of Engagement Activity 2018
 
Description Mechanical properties of particles 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Mechanical properties of particles. Characterisation Advances in Particle Engineering (University of Cape Town, Nov 2018).
Year(s) Of Engagement Activity 2018
 
Description Participation by Dr Vikram Karde, a PDRA on this project, in a conference on Design of Crystalline Products: IG/CCG Joint Autumn Meeting, 2017 at Cambridge. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Participation by Dr Vikram Karde, a PDRA on this project, in a conference on Design of Crystalline Products: IG/CCG Joint Autumn Meeting, 2017 at Cambridge.
Year(s) Of Engagement Activity 2017
 
Description Participation by Dr Vikram Karde, a PDRA on this project, in the 4th David Grant Symposium 2018 organised by the University of Minnesota, College of Pharmacy at Minneapolis, MN on the current topics of importance in pharmaceutical drug product development. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Participation by Dr Vikram Karde, a PDRA on this project, in the 4th David Grant Symposium, 2018 organised by the University of Minnesota, College of Pharmacy at Minneapolis, MN.
Year(s) Of Engagement Activity 2018
 
Description Particle Shape and Structure Characterisation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Particle Shape and Structure Characterisation, Characterisation Advances in Particle Engineering (University of Cape Town, Nov 2018)
Year(s) Of Engagement Activity 2018
 
Description Prediction of Flowability of Powder Mixtures at High Strain Rate Conditions by DEM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Prediction of Flowability of Powder Mixtures at High Strain Rate Conditions by DEM, (HP, Barcelona, Sep 2018)
Year(s) Of Engagement Activity 2018
 
Description Professor MSA Bradley: Powders in the Ceramic AM Process 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Applications for Ceramics, in 3D printing / additive manufacturing, Special interest group
Year(s) Of Engagement Activity 2018
URL https://ktn-uk.co.uk/events/applications-for-ceramics-in-3d-printingadditive-manufacturing-special-i...
 
Description Sampling and sample preparation for particle characterisation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Sampling and sample preparation for particle characterisation. Characterisation Advances in Particle Engineering (University of Cape Town, Nov 2018)
Year(s) Of Engagement Activity 2018
 
Description Shape Consideration in Discrete Element Modelling 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Shape Consideration in Discrete Element Modelling, Short Course: Modelling of Particulate Systems using Distinct Element Method (University of Leeds Sep 2018).
Year(s) Of Engagement Activity 2018
 
Description Shape Consideration in Discrete Element Modelling 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Shape Consideration in Discrete Element Modelling (HP, Barcelona, Sep 2018)
Year(s) Of Engagement Activity 2018
 
Description Short Course: Modelling of Particulate Systems using Discrete Element Method (DEM). 5 - 6 September, University of Leeds, Leeds UK. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Short Course: Modelling of Particulate Systems using Discrete Element Method (DEM). 5 - 6 September, University of Leeds, Leeds UK.
Year(s) Of Engagement Activity 2018
 
Description Workshop: Discrete Element Method: Challenges and Trends. 7 September 2018, University of Leeds, Leeds UK. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Organised Workshop: Discrete Element Method: Challenges and Trends. 7 September 2018, University of Leeds, Leeds UK.
Year(s) Of Engagement Activity 2018