Hydrates in Solution - Interactions of drug compounds with water in pre-nucleation clusters

Lead Research Organisation: Durham University
Department Name: School for Medicine, Pharmacy and Health


One of the bottlenecks of a new pharmaceutical drug entity reaching the market is its formulation into a safe and effective medicine. This cost- and time-intensive process is furthermore complicated by the presence of multiple crystal forms, which will alter the stability, processability and solubility of the material. In order to help speed up the process of a drug getting onto market, this project aims to improve the efficiency of this by investigating the interaction of drug with water during crystallisation and relate this to the physical stability of the resulting water-containing crystal forms (hydrates). This knowledge will then help to predict the occurrence and stability of these pharmaceutical materials, which present an especially challenging class to deliver to the pharmacological target due to their low water solubility and, thus, bioavailability. Hydrates are generally avoided during formulation wherever possible.

The project will:
1. Investigate the molecular interactions between drug compounds and water molecules in solution,
2. Determine the stoichiometry and strength of these interactions,
3. Connect the strength of these interactions with the physical stability of their respective hydrated crystal form,
4. Propose rules to connect solute-water interactions in solution with occurrence and stability of resulting hydrate forms.

This proposal is part of an overarching project aiming to understand the influence of solution structure and solute aggregation before crystallisation on the resulting crystal form in order to predict and control crystallisation experiments.

The results of this project will further our fundamental understanding of crystallisation. This knowledge can be immediately implemented into the day-to-day business of formulation and manufacturing, e.g. in the pharmaceutical and fine-chemical industries. It will thus benefit the broader public by shortening development times and accelerating the process of new medications reaching the market.

Planned Impact

This project will benefit the PDRA by training in a highly translational skill-set as well as the analytical thinking necessary for a successful independent career in industry or academia. He/she will additionally benefit from the scientific network that will be established through this research and the dissemination of its results. Interactions with the PI and mentoring through established University process will provide them with further translational skills such as project management, team working and leadership.

Funding this project will enable the PI to establish the relevant collaborations and networks to become one of the leading scientists in her field. Through the interactions necessary to successfully complete the proposed research, opportunities for further research collaborations will be generated, which will furthermore lead to future larger grant applications with both RCUK and other funding bodies as well as industry.

The immediate impact of this project's results will be biggest in the pharmaceutical industry. It is anticipated that the findings of this project can be implemented directly into the day-to-day business of Pharmaceutical Research and Development, speeding up the process of new drugs being formulated and reaching the market. This will furthermore benefit the general public, firstly because they will have access to these medicines, and secondly because quicker development will lower the cost and risk for pharmaceutical industry, which will benefit the NHS and thus the tax payer.

Understanding the process of hydrate formation and having simple rules to predict these challenging materials will lead to the reduction of crystal form screening, significantly reducing the material and solvent wastage. This will help to develop more environmentally friendly industrial processes, an aim that the British Government is eager to support.

This research additionally strengthens the UK's position as world-leading in crystallisation and polymorphism research, which attracts an increasing number of researchers into the country. These highly educated academics benefit the general culture of the UK and its research structure by cross-fertilisation through different ideas and education standards.

Finally, funding this research will have economic benefits. By offering the results to UK industry first, e.g. AstraZeneca who have already expressed interest in this study, it can be shown that cutting-edge academic science is collaborating with industry. This will strengthen the UK as an economic market place, and further industry will seek to benefit from this kind of collaboration and may open sites in the UK. In the long run, this will benefit the UK's gross income and thus the general population.


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Edkins K (2019) The solid state of pharmaceuticals in CrystEngComm

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Jones CD (2019) Pre-nucleation aggregation based on solvent microheterogeneity. in Chemical communications (Cambridge, England)

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Najib MNM (2017) The Complex Solid-State Landscape of Sodium Diatrizoate Hydrates. in Chemistry (Weinheim an der Bergstrasse, Germany)

Related Projects

Project Reference Relationship Related To Start End Award Value
EP/P002870/1 01/12/2016 30/04/2017 £101,088
EP/P002870/2 Transfer EP/P002870/1 01/05/2017 31/01/2019 £74,692
Description During the research period of this grant, we have investigated the solution structure of multiple pharmaceuticals in terms of interaction with water. We have found that using FTIR and NMR spectroscopy, we can probe the self-aggregation, i.e. how likely two solute molecules will interact with each other and that we can correlate this data with information about the probability of crystalline hydrate formation in the solid state. This will have significant influence on pharmaceutical industry and we are currently seeking funding to accelerate impact from our findings.
In addition, we have found that solution aggregation is strongly influenced by solvent structure, such as microheterogeneity, and that this might be important for other fields using solvents showing micro-segregation. This finding has recently been accepted for publication in Chemical Communications.
Exploitation Route We are currently working on scientific publications to disseminate our findings. We will then present the outcomes at national and international conferences as well as industry workshops. We have also sought for further funding to accelerate impact by directly communicating with pharmaceutical industry on a one-to-one basis.
Sectors Agriculture, Food and Drink,Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

Description We are currently working with Syngenta to implement our findings and method of hydrate prediction into their industrial workstream.
First Year Of Impact 2020
Sector Agriculture, Food and Drink
Impact Types Economic

Description ISIS neutron facility - call Spring 2018
Amount £60,000 (GBP)
Funding ID RB1820476 
Organisation ISIS Neutron Source Facility 
Sector Learned Society
Country United Kingdom
Start 06/2018 
End 05/2019
Description ISIS: RB1700032
Amount £60,000 (GBP)
Funding ID RB1700032 
Organisation Science and Technologies Facilities Council (STFC) 
Department ISIS Neutron and Muon Source
Sector Academic/University
Country United Kingdom
Start 12/2017 
End 12/2017
Description Neutron beamtime call Autumn 2018
Amount £105,000 (GBP)
Funding ID RB1910405 
Organisation ISIS Neutron Source Facility 
Sector Learned Society
Country United Kingdom
Start 01/2019 
End 12/2020
Description STFC
Amount £81,690 (GBP)
Funding ID RB1810604 
Organisation Science and Technologies Facilities Council (STFC) 
Department ISIS Neutron and Muon Source
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 03/2018
Description Hydrate formation in pharmaceutical compounds 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Researcher exchange - PhD student of the group was sent to Macclesfield site of AZ to perform experiments. In addition, AZ is partner on an Impact Acceleration fund including a 6 month position of a PostDoc. The Researcher has been to AZ several times to perform experiments on AZ compounds.
Collaborator Contribution Support with equipment, perform measurements, support with mentoring, supply of compounds
Impact Two publications are currently drafted based on the results from the exchange. Impact Acceleration funding has been awarded for this collaboration, a further publication is in the draft stage.
Start Year 2018
Description Interaction of pharmaceutical fragments with biologically relevant solvent 
Organisation Rhodes University
Department Pharmacy Faculty
Country South Africa 
Sector Academic/University 
PI Contribution Measurements of a novel pharmaceutical fragment to gauge its interaction with water and DMF as biomimetic
Collaborator Contribution synthesis and initial characterisation of the fragment
Impact This collaboration is between medicinal chemistry and physical pharmaceutics, so multi-disciplinary. No outputs have been made yet.
Start Year 2017
Description Pre-nucleation aggregates in amorphous pharmaceuticals 
Organisation Science and Technologies Facilities Council (STFC)
Department ISIS Neutron and Muon Source
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration through a PhD student jointly supervised by ISIS and a multi-disciplinary team of Queen's Pharmacy and Chemistry Department. This partnership is currently advertising for the PhD position. We have written and revised the project application.
Collaborator Contribution The partner institution will host the candidate for longer periods of time to train them in neutron scattering and help with the modelling of experimental data. Additional training courses are planned
Impact none yet
Start Year 2017
Description Pre-nucleation aggregation in pharmaceutical compounds - Pfizer 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Knowledge exchange
Collaborator Contribution Measurements of samples, input into follow-up funding application
Impact Publication: Chemistry - A European Journal 23 (68), 17339-17347 EPSRC fellowship application - unsuccessful
Start Year 2017
Description Prediction of hydrate forming ability of Agrochemicals 
Organisation Syngenta International AG
Department Syngenta Ltd (Bracknell)
Country United Kingdom 
Sector Private 
PI Contribution Materials transfer agreement in place including 10 agrochemicals of interest to the partner. Two compounds have been investigated using our method of hydrate predicion to generate preliminary data. I have been visiting Syngenta to establish the collaboration and have been in touch with them several times by skype conference.
Collaborator Contribution Materials transfer agreement including ten agrochemicals to be shipped free of charge. Discussion time to elucidate research areas interesting for Syngenta and how my group can fit into this.
Impact no outcomes as of yet.
Start Year 2020
Description Crystallography meeting for Chemical and Industrial Crystallographers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Invited talk at the annual Autumn meeting bringing together academia and industry. Discussion afterwards with a delegate from Syngenta that has resulted in an active collaboration manifested by an MTA and application for further funding to implement our method into their day-to-day workstream.
Year(s) Of Engagement Activity 2019
Description Neutron Scattering Group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact This was the meeting of the Neutron Scattering Group of the Faraday Division, which brings together academics, third sector scientists and industry. New connections to industry and central facilities were made, which will further our research and future grant applications.
Year(s) Of Engagement Activity 2018
URL https://www.events.iop.org/e/neutrons-and-global-challenges-ii-health-and-healthcare-58c47b398f55462...