Taste masking medicines for children through crystal engineering

Unacceptable palatability is a major obstacle in the development of medicines for infants and toddlers, as it often impedes patient adherence. The masking of bad taste is therefore widely recognized by regulatory authorities as a key aspect in modern paediatric drug development. and legislation in Europe and USA is currently requiring and rewarding the development of palatable paediatric medicines. The proposed PhD research project aims to develop a crystal-engineering approach to bitter-taste masking of drug molecules commonly used in paediatric oral formulations (e.g. flucloxacillin and prednisone). The approach relies on the construction of multi-component crystals involving a bitter-tasting drug and a taste-masking agent, whereby the molecules are held together by hydrogen bonds. The taste-masking agent is either a pharmaceutically acceptable compound taste blocker, or a molecule that hydrogen-bonds with the drug in a fashion that prohibits any interaction between the drug and the taste receptors. The formation of the described multi-component crystals (i.e. cocrystals) can be achieved fast (<1h), with the use of minimal amounts of solvents (or even without) and in large quantities (>1kg) without the use of specialised equipment. The taste of the cocrystals will be assessed in vivo, including using the Brief Access Taste Aversion model. Moreover, pharmaceutical studies will assess if cocrystals could enhance material properties (e.g. tabletability) in relation with handling, manufacturability and potentially clinical performance ensuring that the outcomes of this research are fully translational.

The research programme will explore the use of crystal engineering tactics in paediatric drug formulation, and aim to develop pharmaceutical cocrystals for palatable medicines. The research programme will involve the following:
- Selection of active pharmaceutical ingredients (APIs) relevant to paediatric health care and identify a set of suitable cocrystal formers using data base surveys and cheminformatics
- Completion of cocrystal screens for each API and finish the solid-state characterisation of the prepared cocrystals
- Evaluation pharmacokinetic properties of relevant cocrystals and assess their taste using the rat brief-access taste aversion (BATA) model
- Develop structure-property relationships that will enable development of guidelines for the design of palatable cocrystal using principles of crystal engineering.

Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.

Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.

Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.

Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.