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

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.

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.