Pressure-Induced Nucleation for the Continuous Manufacture of supramolecular assemblies

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci

Abstract

The organic solid state is at the centre of a number of key billion dollar industries from pharmaceuticals ($60 billion, 2009); pigments and dyes ($1.2 billion revenue, 2010), agrochemicals ($134 billion market, 2010), energetics (explosives and propellants; $0.5 billion revenue, 2012). Each of these industries suffers from attrition whereby the number of possible products that reach the marketplace is a fraction of those conceived and made in research labs. A stage at which materials are discarded is that of the physicochemical properties. A well-known example is in the pharmaceutical industry where it is estimated that it costs $1.6 billion to produce one drug compound which is due, in part, to the catastrophic attrition rates of drug products from bench to production line. Therefore if there was a method by which one could alter the physicochemical properties without changing the functionality of the molecules the cost for manufacture would decrease considerably.

Crystal Engineering or co-crystallisation is one method by which one can alter the properties of materials by forming supramolecular assemblies. These assemblies contain more than one chemical entity but can enhance stability, solubility, colour and flow properties through the addition of the second inert component. The inclusion of a second component impacts on the three-dimensional arrangement of molecules which in turn changes the physical properties of materials. The beauty of this method is that the functionality of the molecule in question is not changed i.e. a pharmaceutical product still possesses the correct molecular geometry to bind to receptors to affect a response; the solubility of a pigment may be enhanced without the loss of its colour. Another method by which one can alter the three-dimensional structure of a material hence its physical properties is via the application of high-pressure (pressures of >1atm). High pressure has proven to be an extremely effective method for changing the 3-D structure and industrial high pressure methods are already in use for pasteurising foodstuffs e.g. chicken, shellfish, orange juice etc. One of the key disadvantages is that new high pressure forms of single-component materials, e.g. paracetamol, are not stable under normal working conditions. By coupling the two areas of science together, crystal engineering and high pressure, we will be able to create materials that are stable under normal working conditions.

This proposal seeks to develop a novel manufacturing methodology by which we are able to form new materials at high pressure and feed these into an industrial scale process. This process of 'seeding' is used in industrial settings presently to ensure that a consistent product is formed from the crystallisation process, we will use this process to promote the growth of high-pressure materials under ambient conditions in both batch and continuous flow systems. The latter system would align our project to the outputs of the EPSRC Centre for Continuous Manufacture and Crystallisation. Furthermore, detailed analysis of the process and the resulting materials will be carried out so that improvements can be made in the process, such as the pressures and concentrations used, as well as the design of the assemblies themselves. The physical properties of the new materials will be investigated and will provide the feedback to improve upon the process.

Planned Impact

The intended beneficiaries of this research are the pharmaceutical and other chemical industries. In addition we will capitalise on our novel techniques and use 3D printing to engage a much wider audience of school children and the general public with this research.

It is estimated that it costs a pharmaceutical company in the region of $1.6 billion to produce one marketable drug compound. Part of this huge cost is due to the catastrophic attrition or 'drop-out' rates of drug products from bench to production line. In some areas of pharmaceutical production there are high levels of wastage in terms of cost, time and human effort. A key reason for attrition is when it is apparent that the experimental compound is unsuitable or unstable and therefore cannot be reproduced reliably in large enough quantities for commercial use. The fine-tuning of properties such as colour, stability, solubility, and flow could be the difference between whether a product is taken forward to manufacture or left the shelf.

This proposal seeks to scale-up and accelerate the production of groups of molecules under high-pressure conditions. This research develops a different route to the marketplace for poorly performing functional materials and re-uses them in supramolecular assemblies for enhanced properties. I have already demonstrated that other properties of materials can be altered, by the assembly of a co-crystal or supramolecular material that contains more than one molecular component, under ambient conditions.

The pharmaceutical industry is only one of a number of key billion dollar revenue industries supporting world economic growth, which have the same problem in that the number of possible products reaching the marketplace is a fraction of those conceived and made in research labs. These include pigments and dyes ($1.2 billion revenue, 2010), agrochemicals ($134 billion market, 2010), energetics explosives and propellants ($0.5 billion revenue, 2012). In the long term, any production improvements in attrition rates should transfer to other sectors where the modelling of crystalline compounds will help to identify stable physicochemical states, leading to significant cost savings and a faster route to market.

We have detailed plans to engage the public and schools throughout the research project, through well-established links between the University of Strathclyde and the Glasgow Science Centre, and through the 3D printing labs on campus. The ethos of the University of Strathclyde is to take every opportunity to make our research accessible and interesting to a wide range of external audiences.

Publications

10 25 50
 
Title Cover art for article 
Description This artwork was related to our anti-solvent addition at extreme conditions and showed a glass ampoule breaking under load from diamonds with a background of the molecular structure of paracetamol 
Type Of Art Image 
Year Produced 2019 
Impact There are no notable impacts from the artwork. It will have reached the readership of CrystEngComm. 
URL https://pubs.rsc.org/en/journals/journalissues/ce#!issueid=ce021030&type=current&issnonline=1466-803...
 
Description We have observed a number of new findings. 1. We can obtain a new form of the drug hydrochlorothiazide at high pressure that is stable to ambient pressure. This is an encouraging result because it demonstrates that we are able to isolate materials form high pressure in larger volumes (gram scale). We have used this method to isolate new forms of p-aminobenzoic acid and recovered this to ambient pressure. This has culminated in a publication of the work in 2019. 2. We have been able to investigate how different types of intermolecular interactions respond to high pressure. Most high pressure studies have investigated pure compounds, our approach, using multi-component systems, has allowed us to investigate a greater variety of hydrogen bonding interactions. We have been awarded experimental time at Diamond Light Source to investigate these systems. In addition to this we have been allocated beamline time at ISIS Neutron and Muon Source to continue this study on more complex systems. 3. We have successfully demonstrated with proof-of-concept experiment that we are able to couple high pressure and anti-solvent crystallisation techniques to induce crystallisation at high pressure. This involves the introduction of a solvent that reduces the solubility of a compound in a solvent. By achieving this at pressure we are able to alter the saturation level in the solution inducing crystallisation. This has culminated in a publication and two conference presentations (Martin Ward and Iain Oswald) 4. The discovery of polymorphism through spray-drying of chlorpropamide. The application of spray-drying to invoke polymorphism is rare and we are collaborating with theoretical chemists and other experimentalists to produce a joint research article based on the polymorphism of chlorpropamide. 5. We have rationalised the crystallisation of trimesic acid solvates and provided an understanding of the energies in the crystal structure. 6. The discovery of a tenth form of Galunisertib in collaboration with Eli-Lilly and University of Edinburgh. This was part of a larger study into the polymorphism. Together with colleagues from University of Edinburgh we were able to isolate a high-pressure form of this drug.
Exploitation Route These achievements will (once published) be able to be used by many groups around the world in academia and industry. We plan to demonstrate the antisolvent crystallisation on a wide range of materials to show control over polymorph selection.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

URL https://pubs.rsc.org/en/content/articlelanding/2019/CE/C9CE00365G#!divAbstract
 
Description The projects that my team have been on have had an impact on the working practices of the Industrial collaborators involved. This is anecdotally noted from the collaborators however the methodologies will be employed in their internal discovery programs. Our pressure methodologies are being incorporated into the workflows of Future Manufacturing Research Hub CMAC for the discovery of crystalline forms. Our team is conducting screening work alongside our colleagues in CMAC.
First Year Of Impact 2018
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Pressure-dependent In-Situ Monitoring of Granular Materials
Amount £519,463 (GBP)
Funding ID EP/S02168X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2022
 
Description Quantifying the Dynamic Response in Metal-Organic Frameworks (MOFs): A Platform for Tuning Chemical Space in Porous Materials
Amount £423,306 (GBP)
Funding ID EP/T034114/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2020 
End 09/2023
 
Description scaled-up production of metastable solid forms using the KRAIC
Amount £893 (GBP)
Funding ID T090420MW 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 02/2020 
 
Title Anti-solvent Addition at high pressure 
Description This method was developed by the team to initiate crystallisation through anti-solvent under high pressure. This was possible due to the large volume press that we have at the University. 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? Yes  
Impact We have been able to isolate high-pressure forms of paracetamol and recover them to ambient pressure 
 
Title An investigation of the crystallisation of CO2/N2O mixtures over a range of pressure and temperature conditions 
Description This dataset contains a series of Bruker format frames in .sfrm format that can be read by APEX 2/3 software that were obtained for the characterisation of CO2/N2O binary crystal by single crystal X-ray diffraction. The Compressiondatasets.zip contains 5 datasets for the binary crystal on compression. Comp01 is at 2.0GPa, Comp02 at 2.3 Gpa; Comp03 at 2.6 GPa; Comp04 at 4 GPa; Comp06 5.2 GPa. Comp05 is not present due to an aborted run (power cut). The compound codes for the low temperature datasets are self explanatory composition appended with temperature at which the dataset was collected. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The dataset provides evidence that carbon dioxide and nitrous oxide behave in a very similar way in the solid state and that solids can be formed using a range of different concentrations of each. This dataset demonstrated the ability of a newly developed gas cell at Diamond Light Source for wider research programs that it was originally developed. 
URL https://pure.strath.ac.uk/portal/en/datasets/an-investigation-of-the-crystallisation-of-co2n2o-mixtu...
 
Title Data for: "Anti-solvent addition at extreme conditions" 
Description Data associated with preparation of paper. Details of the data are included in the pdf summary provided. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact This dataset serves to demonstrate the new techniques of anti-solvent addition at high-pressure. This is a novel method that has been developed in the group. We are in the process of developing this further using other test systems 
 
Title Data for: "Hidden solvates and transient forms of trimesic acid" 
Description Dataset associated with the study of solvation of trimesic acid. "Pure_upload" contains the data pertinant to the submitted article i.e. new phases of trimesic acid solvates. "other" contains additional single crystal data collected during screening of other samples from which no further new phases were obtained. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact This dataset contributes to the knowledge around the crystallisation of Trimesic acid, a common material used in co-crystallisation. We demonstrate the effect of solvent size on the rigid hydrogen-bonded structure. 
URL https://pureportal.strath.ac.uk/en/datasets/9ef4e1e1-9eb9-4738-8ae9-165a7e80ebc2
 
Title Data for: "Mannitol Crystallization at Sub-Zero Temperatures: Time/Temperature-Resolved Synchrotron X-ray Diffraction Study and the Phase Diagram." 
Description The description of the data are found in the word document "Data_structure". The folders are arranged in the w%solutions and into SAXS and WAXS data (small and Wide angle X-ray scattering). The reduced data have .dat extension (xy format). these can be opened in any data manipulation package. For some for some of the data there are missing image files and unfortunately these cannot be recovered by the ESRF. These image files are .edf and .ehf files. To view these proprietary software from ID02 at ESRF is used. The data are split into three .zip files. Two files are the raw images for 5% mannitol solution. The third file are all the reduced data for the different concentrations 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Information derived from this dataset provides evidence of the impact of cooling on aqueous mannitol systems. We note that the rate of cooling can substantially impact on the crystallisation outcome and that two-step crystallisation can be observed under certain conditions. This work is directly useful to freeze-dried samples and the way in which they should be handled. 
URL https://pureportal.strath.ac.uk/en/datasets/296f22e1-f89d-44c3-a176-dbaa2c0a69ea
 
Title Data for: "Pressure-induced polymorphism of caprolactam: a neutron diffraction study" 
Description Data contained herein for characterization of the two new phases of caprolactam including single-crystal X-ray and neutron-powder diffraction. The single crystal diffraction images are in their native format (.sfrm, Bruker format). Neutron diffraction data files in readily accessible .DAT format that can be viewed using a text editor application. We have used TOPAS academic for refinement but GSAS or any other powder diffraction software should cope with the data. The refined peak shape parameters from Cerium oxide and Silicon have been used and their data is present in the dataset also. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact The dataset provides information on the transient forms of Caprolactam and demonstrates that kinetics of compression are an important factor in the isolation of new phases. 
 
Title Data for: "Quantitative Investigation of Particle Formation of a Model Pharmaceutical Formulation using Single Droplet Evaporation Experiments and X-Ray Tomography" 
Description "This is a collection of data and methodologies used in the following publication. Public access to the dataset is currently under embargo, as data forms part of ongoing PhD research. Expressions of interest can be made via the contact email: researchdataproject@strath.ac.uk Title: Quantitative Investigation of Particle Formation of a Model Pharmaceutical Formulation using Single Droplet Evaporation Experiments and X-Ray Tomography Authors: Frederik J. S. Doerr, Iain D. H. Oswald, Alastair J. Florence Accepted Date: 18/09/2018 DOI: 10.1016/j.apt.2018.09.027 Abstract: The implementation of a particle design platform that can be applied to novel pharmaceutical systems using acoustic levitation (SAL) and X-ray tomography (XRT) is discussed. Acoustic levitation was employed to provide a container-less particle design environment for single droplet evaporation experiments. Dried particles were subject to further visual and quantitative structural analysis using X-ray tomography to assess the three-dimensional volume space. The workflow of the combined SAL-XRT platform has been applied to investigate the impact of increasing HPMC K100LV concentrations on the evaporation, drying and final particle morphology of particles from a model pharmaceutical formulation containing metformin and D-mannitol. The morphology and internal structure of the formulated particles after drying are dominated by a crystalline core of D-mannitol partially suppressed with increasing HPMC K100LVadditions. The final structure can be correlated to the observed evaporation kinetics. The characterisation of formulated metformin hydrochloride particles with increasing polymer content demonstrated the importance of an early-stage quantitative assessment of formulation related particle properties. The ability to study the evolution of solid phase formation and its influence on the final particle morphology can enable the selection of formulation and process parameter that deliver the desired particle structure and consequent performance by design." 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact
 
Title Data for: "Structural investigation and compression of a co-crystal of indomethacin and saccharin." 
Description The single crystal diffracion data for the compression of indomethacin:saccharin in Bruker format (.sfrm). These can be read with Bruker apex3 software or in CrysalisPro. Reduced data are in the work folders. These files can normally be read using a text editor (Notepad or Notepad++) . Metadata.xls provides the respective namse and pressure for each dataset. Files generated for the Gaussian calcaution are included. .gjf files can be read by Gaussian or GaussView software. An .opju file consolidates the output vales from gaussian (fits them to a Morse curve) and can be read by Origin. Raman data are also provided but these have not been used in the publication but are present for completeness. These can be read in any graphical package (Origin, excel) but .l6s are proprietary for Horiba Labspec software. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact This dataset provides evidence that the size of two molecules in a co-crystal may impact on the compression of hydrogen bonds. 
 
Title Data for: "The effect of chirality on the compression of 2-(2-Oxo-1-pyrrolidinyl) butyramide: A Tale of Two Crystals" article 
Description Data for characterization of S-enantiomer (levetiracetam) and racemic compound (etiracetam) of 2-(2-Oxo-1-pyrrolidinyl) butyramide by increasing pressure. The data was collected through single-crystal X-ray diffraction and Raman Spectroscopy. The single-crystal X-ray diffraction images are in the format .sfrm (Bruker program) and can be read in APEX software. The PIXEL data has been generated using Gaussian software (.gjf files) and PIXEL (.mlc, .pri files); the latter can be viewed in a text editor. The Raman spectroscopy data are in the .l6S format (LabSpec 6 program) and also .txt format that can be viewed using any data analysis software. The modification of single-crystal X-ray file names from the original names to those represented in the article is explained in .xlsx files visible in the main folder. The naming used in the PIXEL calculation follows those represented in the article. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
URL https://pureportal.strath.ac.uk/en/datasets/29ade4d6-6603-4a70-a807-0c8889751f07
 
Title Data for: "The impact of paracetamol impurities on face properties: investigating the surface of single crystals using TOF-SIMS" 
Description "AFM, TOF-SIMS, LC-TOF, optical microscope, raman microscopy, single crystal x-ray, SEM, solubility and UV-vis spectrometery data of paracetamol and 4-nitrophenol single crystals and on face impurities " 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact
 
Title Discovery of delta polymorph of para-aminobenzoic acid 
Description High pressure study to investigate the polymorphism of para-aminobenzoic acid. Investigation discovered previously unreported polymorph of para-aminobenzoic acid designated the delta-polymorph. Data contained herein for characterization of the new delta polymorph including spectroscopy and single-crystal structure resolution. All data files converted to readily accessible format (.txt and .csv) with the exception of single crystal diffraction images that remain in their native format (.sfrm, Bruker format) - important header information required for image processing part of each image file. Neutron diffraction data files in readily accessible .DAT format that can be viewed using a text editor application. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact
 
Title Rapid continuous antisolvent crystallization of multi-component systems 
Description Contains single crystal datasets for the three solid solutions presented in the paper that were collected and can be opened in Rigaku Crysalis software. Powder diffraction data are also included from both Diamond Light Source and in house diffractometer. The former are ASCII and the latter are in .raw format that can be read into many powder diffraction software 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Unknown 
 
Description Control of eutectic composition by cocrystallisation as a separation technique 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution SB visited the lab of Tom Leyssens for three months to investigate how co-crystallisation can change the eutectic composition in racemic and chiral systems. SB is the main experimenter on the project and Myself and Joop ter Horst at Strathclyde are the supervisors of the project.
Collaborator Contribution Tom Leyssens and his group hosted SB and helped to initiate the work. SB accomplished a large body of experiments under the supervision of Tom whilst out on placement.
Impact There are no outputs, as yet, but we are still collecting data at Strathclyde to augment the work SB did at Louvain.
Start Year 2017
 
Description Crystal to tablet 
Organisation Cambridge Crystallographic Data Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration is a studenship with the CCDC. We are providing the experimental evidence for changes to structure as a function of pressure.
Collaborator Contribution The CCDC is providing the tools for the analysis of the crystal structures. We have been granted access to modules that are in development within their CSD Materials software package.
Impact Non at present
Start Year 2020
 
Description Scaled-up production of metastable solid forms using the KRAIC 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration initiated by MRW to build on the work of this grant. This work is facilitated by a travel grant awarded by the Directed Assembly Network, and due to COVID restrictions this has not yet been fulfilled. Seed materials for scale up work will be produced by MRW and provided to collaborators in Nottingham (Karen Robertson)
Collaborator Contribution Our collaborators have developed the KRAIC platform that will be used in this work. With seed material provided by our group, the KRAIC will be used to perform scale up using a seeded crystallization strategy.
Impact This is a multidiscplinary project with metastable phases produced using high pressure crystallization techniques (chemistry, crystallography), the produced materials will then be used to initate a seeded crystallization using the KRAIC platform (chemical engineering).
Start Year 2020
 
Description Harry Potter event at Waterstones 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Event was based on the pharmacology/chemistry of the potions in Harry Potter and the real world applications of pharmaceutical products and to inspire young people to take pharmacology/chemistry at University. I was providing a view point from the perspective of the pharmaceutical product and how the structure is found through Crystallography. A particular positive is that one person has changed their application to Chemistry.
Year(s) Of Engagement Activity 2020
URL https://www.waterstones.com/events/harry-potter-spells-and-potions-night-for-13-to-18-year-olds/glas...
 
Description Im a scientist, get me out of here 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Panel member during a online chats hosted by 'I'm a scientist, get me out of here'. Each chat involves a few scientists and allows a class of school children to ask questions during a ~40 minute session per chat. Each chat on average has 20-25 children taking part. Great feedback has ben received from teachers following the events that has led to participating students having greater engagement in science topics. During chats between 2020-2021 I have taken part in ~ 50 chat sessions that have involved schools from all over the UK.
Year(s) Of Engagement Activity 2020,2021
URL https://purple21.imascientist.org.uk/
 
Description Scottish Scientific Advisory Board Launch of 'Scotland's Science Landscape Short Report' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Together with Centre for Continuous Manufacturing and advanced Crystallization (CMAC) team we were publicizing the work of the centre and how it impacts on industry and the manufacturing of fine products
Year(s) Of Engagement Activity 2019