Prediction of Structure and Stability of Amorphous Pharmaceuticals

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Focus on structure and stability prediction of amorphous active pharmaceutical ingredient and microcrystalline amorphous systems. It will screen a range of APIs, formulate as amorphous materials and determine their solid-state structure in order to populate a new data repository for amorphous pharmaceuticals. It will subsequently use data-driven approaches to determine an Amorphous Stability Index.The API molecule library will cover size, structural complexity and biopharmaceutical properties plus data from select mc-A systems. Materials will be related with measured and calculated molecular data including data mined from literature. Automated, small scale thermal methods will be used to prepare amorphous sample libraries with other methods as needed. Process conditions will be controlled and recorded and the resultant samples tested in Standardised sample preparation and data collection/reduction approaches will optimise measurement data quality. Metadata requirements for key material, process, equipment, and modelling information will give context for future comparative studies. XRPD, DSC will provide primary characterisation of all samples with analysis of local, bulk and surface structure using X-ray pair distribution function, spectroscopy, thermal, tomography, microscopy and AFM with key physical properties complement molecular data from above. Calculated outputs from molecular will also be captured. Accelerated stability studies will assess time to onset of crystallisation for each sample under relevant conditions giving response data to train the ASI.The AMDb will be used to train and benchmark ML models to develop the ASI. This digital development guide for amorphous stability will allow users to predict resistance to crystallisation for given molecules, rapidly indicating the need for alternative stabilisation strategies.PDF has been used to fingerprint nanocrystallinity4 and amorphous changes during storage. We will use advanced scattering and modelling to investigate the relationship between molecular structure, intermolecular packing and stability in selected APIs. New structure refinement methods allow fits of MD derived models to experimental PDF enabling model refinement. International facilities for ssNMR, synchrotron and neutron for time-resolved studies will be used when required.Deliverables:-Comprehensive, FAIR structural and physicochemical data describing amorphous API and mc-A;-Unique APDb structure-property database for amorphous solids;-Validated ML based ASI to predict amorphous behaviour based on molecular structure;-Predictive developability model to select properties of formulated systems based on ASI.In delivering the fundamental understanding and new tools for investigating amorphous state, DDMAP will create opportunities for novel materials, products and manufacturing. Pharma is the UK's largest manufacturing export sector. However, the UK and European industries face serious challenges to maintain their competitive position in the global economy and COVID-19 has only served to throw a spotlight on the challenge facing us. The "Pharmaceutical strategy for Europe" 2020 aims to "make sure that patients across Europe have new medicines and therapies in their countries quickly and under all circumstances and that there are fewer shortages of medicines". This should be ensured while at a same time delivering solutions allowing for personalised medicine, combating falsified products, and reducing the environmental footprint of related manufacturing. We address this by enabling the greater exploitation of processes such as HME and additive manufacturing coupled with predictive, digital design methodologies for pharmaceuticals through our research. We also deliver a talented cohort of trained PDRA and doctoral students skilled in state-of-the-art science and with highly developed multidisciplinary and collaborative abilities, primed to be the future leaders in this exciting area.