Kevin Roberts
School of Chemical & Process Engineering, University of Leeds LS2 9JT, UK
email: k.j.roberts@leeds.ac.uk

In solution phase crystallisation processes, understanding and controlling the transition pathway associated with the assembly of molecules from their solvated state, into three-dimensional, ordered crystalline-solids, represents a significant grand challenge for the physical-chemical sciences. Crystallisation can be sub-divided into three-dimensional nucleation and two-dimensional, surface-mediated, crystal growth stages. Understanding and controlling the various physico-chemical aspects associated with these two stages is important mindful of their impact upon the critical quality attributes of the resulting product crystals. In particular, the nucleation stage directs the crystal size distribution, crystallinity and polymorphic form whilst the crystal growth stage directs crystal purity, morphology, surface properties and inter-particle properties. This paper presents an integrated multi-technique examination of the crystallisation behaviour of the two polymorphic forms of para amino benzoic acid (PABA) encompassing both computational modelling and experimental studies comprising:

• Examination of the molecular conformational stability and energetics using DFT QM modelling.
• Determination of the bulk crystal chemistry and lattice energies using inter-molecular (intrinsic synthons) crystallographic modelling.
• Modelling solution state molecular cluster energetics and propensities using synthonic, DFT/statistical mechanics and molecular dynamics techniques.
• Studies of solubility, crystallisability, nucleation kinetics and mechanism as a function of solvent using gravimetric, optical turbidimetric and SAXS methods.
• Characterisation of crystal morphology and surface chemistry using inter-molecular (extrinsic synthons) modelling in relation to observed crystal habits.
• Assessment of surface-specific single crystal growth kinetics, growth mechanism and interfacial stability.

The industrial relevance of the research in terms of the evolving Industry 4.0 agenda for the digital design of drug products and the processes for their manufacture will be highlighted.

Acknowledgements: The talk presents a summary of a wide ranging collaborative research project with: Robert Hammond, Xiaojun Lai, Caiyun Ma, Jonathan Pickering, Ian Rosbottom, Tom Turner and Guangyi Xi at the University of Leeds. I also gratefully acknowledge them and also the associated funding support from UK Research and Innovation through Molecules, clusters and crystals: A multi-scale approach to understanding kinetic pathways in crystal nucleation from solution (EPSRC Critical Mass Grant EP/I014446/1) and ADDoPT: Advanced digital design of pharmaceutical therapeutics” (Advanced Manufacturing Supply Chain Initiative Grant No. 14060).