Quality by digital design in action : a workflow for crystallisation and isolation

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Houson, Ian and Siddique, Humera and Chong, Magdalene W.S. and Robertson, Murray and Turner, Alice J. and Nordon, Alison and Osman, Amal and Galindo, Amparo and Dunn, Andrew S. and Johnston, Blair and Benyahia, Brahim and Brown, Cameron J. and Mustoe, Chantal L. and Price, Chris J. and Reilly, Chris D. and Adjiman, Claire S. and Jackson, George and Prasad, Elke and Halbert, Gavin and Feilden, Helen and Sefcik, Jan and McGinty, John and Robertson, John and Smith, Kenneth and Al-Attili, Mais and McGowan, Mark and Siddique, Mariam and Pathan, Momina and Rajoub, Nazer and Hamilton, Niki and Feeney, Rachel and Brown, Scott and Urwin, Stephanie J. and Bernet, Thomas and Pickles, Thomas and Li, Wei and Florence, Alastair J. (2025) Quality by digital design in action : a workflow for crystallisation and isolation. International Journal of Pharmaceutics, 686. 126343. ISSN 1873-3476 (https://doi.org/10.1016/j.ijpharm.2025.126343)

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Abstract

This paper exemplifies a Quality by Digital Design (QbDD) workflow for the crystallisation and isolation of active pharmaceutical ingredients (APIs). QbDD uses a digital first approach to improve manufacturability and sustainability whilst assuring product quality within practical constraints. This study uses three exemplar compounds (ibuprofen, lamivudine, and AZD0837), each of which presents a different challenge for crystallisation; these include agglomeration, solid state form, and slow growth rates, respectively. These cases are used to evaluate the benefits of the QbDD approach and identify gaps for future research. Results of this work show that the QbDD workflow reduces the number of physical experiments by 28% and the API material usage by 52–65% when compared to comparable API development processes not using this approach. This approach provides a route to practically implement and exploit the benefits of digital tools and overcome digital skill shortages. By exploiting digital tools for process simulation and optimisation, the workflow improves efficiency, even in complex cases where multiple workflow iterations are required. This workflow, therefore, paves the way for more sustainable and cost-effective API production and it promotes future standardisation of digital design in pharmaceutical development.

ORCID iDs

Houson, Ian ORCID logoORCID: https://orcid.org/0009-0004-9836-6293, Siddique, Humera ORCID logoORCID: https://orcid.org/0000-0002-0770-7362, Chong, Magdalene W.S. ORCID logoORCID: https://orcid.org/0000-0002-0319-5769, Robertson, Murray ORCID logoORCID: https://orcid.org/0000-0001-9543-7667, Turner, Alice J. ORCID logoORCID: https://orcid.org/0000-0002-5323-9221, Nordon, Alison ORCID logoORCID: https://orcid.org/0000-0001-6553-8993, Osman, Amal, Galindo, Amparo, Dunn, Andrew S. ORCID logoORCID: https://orcid.org/0000-0002-8417-8468, Johnston, Blair ORCID logoORCID: https://orcid.org/0000-0001-9785-6822, Benyahia, Brahim, Brown, Cameron J. ORCID logoORCID: https://orcid.org/0000-0001-7091-1721, Mustoe, Chantal L. ORCID logoORCID: https://orcid.org/0000-0002-8404-2229, Price, Chris J. ORCID logoORCID: https://orcid.org/0000-0002-0790-6003, Reilly, Chris D., Adjiman, Claire S., Jackson, George, Prasad, Elke ORCID logoORCID: https://orcid.org/0000-0002-5412-9374, Halbert, Gavin, Feilden, Helen ORCID logoORCID: https://orcid.org/0009-0006-2122-3301, Sefcik, Jan ORCID logoORCID: https://orcid.org/0000-0002-7181-5122, McGinty, John ORCID logoORCID: https://orcid.org/0000-0002-8166-7266, Robertson, John ORCID logoORCID: https://orcid.org/0000-0002-2191-1319, Smith, Kenneth, Al-Attili, Mais ORCID logoORCID: https://orcid.org/0000-0002-1192-5020, McGowan, Mark, Siddique, Mariam ORCID logoORCID: https://orcid.org/0000-0002-3054-7192, Pathan, Momina, Rajoub, Nazer ORCID logoORCID: https://orcid.org/0000-0002-1373-3022, Hamilton, Niki ORCID logoORCID: https://orcid.org/0000-0002-5889-863X, Feeney, Rachel, Brown, Scott ORCID logoORCID: https://orcid.org/0000-0003-4908-7058, Urwin, Stephanie J. ORCID logoORCID: https://orcid.org/0000-0002-9092-0200, Bernet, Thomas, Pickles, Thomas ORCID logoORCID: https://orcid.org/0009-0006-3377-3124, Li, Wei and Florence, Alastair J. ORCID logoORCID: https://orcid.org/0000-0002-9706-8364;
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