Linked experimental and modelling approaches for tablet property predictions

Jolliffe, Hikaru G. and Ojo, Ebenezer and Mendez Torrecillas, Carlota and Houson, Ian and Elkes, Richard and Reynolds, Gavin and Kong, Angela and Meehan, Elizabeth and Becker, Felipe Amado and Piccione, Patrick M. and Verma, Sudhir and Singaraju, Aditya and Halbert, Gavin and Robertson, John (2022) Linked experimental and modelling approaches for tablet property predictions. International Journal of Pharmaceutics, 626. 122116. ISSN 0378-5173 (

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Recent years have seen the advent of Quality-by-Design (QbD) as a philosophy to ensure the quality, safety, and efficiency of pharmaceutical production. The key pharmaceutical processing methodology of Direct Compression to produce tablets is also the focus of some research. The traditional Design-of-Experiments and purely experimental approach to achieve such quality and process development goals can have significant time and resource requirements. The present work evaluates potential for using combined modelling and experimental approach, which may reduce this burden by predicting the properties of multicomponent tablets from pure component compression and compaction model parameters. Additionally, it evaluates the use of extrapolation from binary tablet data to determine theoretical pure component model parameters for materials that cannot be compacted in the pure form. It was found that extrapolation using binary tablet data – where one known component can be compacted in pure form and the other is a challenging material which cannot be – is possible. Various mixing rules have been evaluated to assess which are suitable for multicomponent tablet property prediction, and in the present work linear averaging using pre-compression volume fractions has been found to be the most suitable for compression model parameters, while for compaction it has been found that averaging using a power law equation form produced the best agreement with experimental data. Different approaches for estimating component volume fractions have also been evaluated, and using estimations based on theoretical relative rates of compression of the pure components has been found to perform slightly better than using constant volume fractions (that assume a fully compressed mixture). The approach presented in this work (extrapolation of, where necessary, binary tablet data combined with mixing rules using volume fractions) provides a framework and path for predictions for multicomponent tablets without the need for any additional fitting based on the multicomponent formulation composition. It allows the knowledge space of the tablet to be rapidly evaluated, and key regions of interest to be identified for follow-up, targeted experiments that that could lead to an establishment of a design and control space and forgo a laborious initial Design-of-Experiments.