The Importance of Understanding and Characterising the Physical & Chemical Properties of APIs in the Digital Design of Drug Products

Kevin J Roberts

Kevin J Roberts
Brotherton Professor of Chemical Engineering
University of Leeds

There is a growing interest in the prediction of the surface properties of active pharmaceutical ingredients in relation to their formulation downstream into practical dosage forms. In particular, it is well known [1, 2] that crystal surface properties of pharmaceutical ingredients can significantly impact on the physical chemical properties of these materials, and hence upon the critical quality attributes that impact on product performance, for both drug substance and drug product.

This talk will overview the application of synthonic modelling techniques [3, 4] using inter-molecular energy calculations with the atom-atom method. It will highlight how synthonic analysis can be applied to reveal the balance of intermolecular interactions between those of an intrinsic nature which stabilise the bulk structure and those of an extrinsic nature which, being surface-terminated, contribute to the surface energetic properties of the crystal particle.

The utility of these techniques will be illustrated through case studies based on recent research involving:

  • Understanding and optimising the particle morphology of lovastatin through a predictive solvent selection approach [5];
  • Characterising differences in the flow and compaction behaviour of two polymorphic forms of L-glutamic acid using X-ray computed tomography [6].
  • Predicting the surface properties of terbutalene sulphate and its adhesive/cohesive balance when formulated with excipients [7,8].

The integration of synthonic engineering tools within pharmaceutical R&D workflows will be highlighted and the potential extension of these techniques to the de novo design of drug products and the processes needed to manufacture them will be briefly overviewed and discussed.


I would like to gratefully acknowledge

  • INFORM2020 project supported by EPSRC (EP/N025075/1) in collaboration with: AstraZeneca, DFE Pharma, GSK, Intertec, Kindeva, Malvern Pananalytical, Nanopharm, Neutec and Zeiss together with the Universities of Hertfordshire, Cambridge & Manchester.
  • ADDoPT Digital Design project supported by Advanced Manufacturing Supply Chain Initiative (AMSCI 14060) in collaboration with: AstraZeneca, Britest, BMS, CCDC, GSK, Perceptive Engineering, Pfizer, PSE and STFC together with Cambridge & Strathclyde Universities.
  • Henry Moseley X-ray Imaging Facility at University of Manchester who provided X-CT beam time (EPSRC grants EP/F007906/1, EP/I02249X/1, EP/F028431/1 & EP/T02593X/1)


[1] Material science: solid form design and crystallisation process development, K J Roberts, R Docherty and S Taylor in Pharmaceutical Process Development: Current Chemical and Engineering Challenges, RSC Drug Discovery Series No. 9 ( ISBN978-1-84973—146-1), (Edited by J Blacker and M T Williams), The Royal Society of Chemistry, Cambridge, 2011, 286-313

[2] Engineering crystallography: from molecule to crystal to functional form, K J Roberts, R Docherty and R Tamura (Editors), Springer Advanced Study Institute (ASI) Series, ISBN 878-94-024-1118-8/1115-7/1117-1, 2017

[3] Synthonic engineering: from molecular and crystallographic structure to the rational design of pharmaceutical solid dosage forms, K J Roberts, R B Hammond, V Ramachandran and R Docherty, Chapter 7 in Computational Approaches in Pharmaceutical Solid State Chemistry (Edited by Y.A. Abramov), 2015 Wiley, Inc.

[4] “Particle Informatics”: advancing our understanding of particle properties through digital design, Mathew J. Bryant, Ian Rosbottom, Ian J Bruno, Robert Docherty, Colin M Edge, Robert B Hammond, Robert Peeling, Jonathan Pickering, Kevin J Roberts and Andrew G P Maloney, Crystal Growth and Design 19 (2019) 5258-5266

[5] Habit modification of the API lovastatin through a predictive solvent selection approach, T. D. Turner, L. E. Hatcher, C. C. Wilson, K. J. Roberts, Journal of Pharmaceutical Sciences 108 (2019) 1637-1922

[6] Measuring particle packing of glutamic acid through x-ray computed tomography to understand powder flow and consolidation behaviour, Thomas Turner, Parmesh Gajjar, Ioannis Fragkopoulos, James Carr, Thai Thu Hien Nguyen, Debbie Hooper, Fiona Clarke, Neil Dawson, Philip Withers and Kevin Roberts, Crystal Growth & Design 20 (2020) 4252–4263

[7] A Digital Workflow from Crystallographic Structure to Single Crystal Particle Attributes for Predicting the Formulation Properties of Terbutaline Sulphate, Thai T. H. Nguyen, Robert B. Hammond, Ioanna D. Styliari, Darragh Murnane and Kevin J. Roberts, CrystEngComm 22 (2020) 3347-3360

[8] From Particles to Powders: Digital Approaches to Understand Structure and Powder Flow of Inhaled Formulations, Parmesh Gajjar, Thai T. H. Nguyen, Ioanna Danai Styliari, Vivian W. Barron, Timothy L. Burnett, Xizhong Chen, Simon D. Connell, James A. Elliott, Robert Hammond, Faiz M. Mahdi, Kevin Roberts, Philip J. Withers and Darragh Murnane, Respiratory Drug Delivery (2021) in press