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

Ian Houson; Humera Siddique; Magdalene W.S. Chong; Murray Robertson; Alice J. Turner; Alison Nordon; Amal Osman; Amparo Galindo; Andrew S. Dunn; Blair Johnston; Brahim  Benyahia; Cameron J. Brown; Chantal L. Mustoe; Chris J. Price; Chris D. Reilly; Claire S.  Adjiman; George Jackson; Elke Prasad; Gavin Halbert; Helen Feilden; Jan Sefcik; John McGinty; John Robertson; Kenneth Smith; Mais Al-Attili; Mark McGowan; Mariam Siddique; Momina Pathan; Nazer Rajoub; Niki Hamilton; Rachel Feeney; Scott Brown; Stephanie J. Urwin; Thomas  Bernet; Thomas Pickles; Wei Li; Alastair J. Florence

doi:10.1016/j.ijpharm.2025.126343

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

Ian Houson, Humera Siddique, Magdalene W.S. Chong, Murray Robertson, Alice J. Turner, Alison Nordon, Amal Osman, Amparo Galindo, Andrew S. Dunn, Blair Johnston, Brahim Benyahia, Cameron J. Brown, Chantal L. Mustoe, Chris J. Price, Chris D. Reilly, Claire S. Adjiman, George Jackson, Elke Prasad, Gavin Halbert, Helen FeildenJan Sefcik, John McGinty, John Robertson, Kenneth Smith, Mais Al-Attili, Mark McGowan, Mariam Siddique, Momina Pathan, Nazer Rajoub, Niki Hamilton, Rachel Feeney, Scott Brown, Stephanie J. Urwin, Thomas Bernet, Thomas Pickles, Wei Li, Alastair J. Florence^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	126343
Number of pages	15
Journal	International Journal of Pharmaceutics
Volume	686
Early online date	1 Nov 2025
DOIs	https://doi.org/10.1016/j.ijpharm.2025.126343
Publication status	E-pub ahead of print - 1 Nov 2025

Funding

This work was supported by the EPSRC Future Continuous Manufacturing and Advanced Crystallisation Research Hub (grant ref: EP/P006965/1) and the CMAC National Facility with contributions from Digital Medicines Manufacturing (DM2) Research Centre co-funded by the Made Smarter Innovation challenge at UK Research and Innovation (grant ref: EP/V062077/1). This work was supported by UKRI and the Scottish Funding council under the UK Research Partnership Investment Fund. The authors would like to acknowledge that this work was carried out in the CMAC National Facility, housed within the University of Strathclyde’s Technology and Innovation Centre, and funded with a UKRPIF (UK Research Partnership Institute Fund) capital award, SFC ref. H13054, from the Higher Education Funding Council for England (HEFCE).

Keywords

active pharmaceutical ingredients
crystallisation
digital design in pharmaceutical development

Access to Document

10.1016/j.ijpharm.2025.126343Licence: CC BY 4.0

Houson-etal-IJP-2025-Quality-by-digital-design-in-actionFinal published version, 2.18 MBLicence: CC BY 4.0

1 Finished
1 Active

Made Smarter Innovation: Digital Medicines Manufacturing Research Centre (DM2)
Florence, A. (Principal Investigator), Johnston, B. (Co-investigator), Markl, D. (Co-investigator) & Pierce, G. (Co-investigator)
EPSRC (Engineering and Physical Sciences Research Council)
1/09/21 → 31/03/26
Project: Research
Future Continuous Manufacturing and Advanced Crystallisation Research Hub (CMAC Hub)
Florence, A. (Principal Investigator), Brown, C. (Co-investigator), Halbert, G. (Co-investigator), Johnston, B. (Co-investigator), Markl, D. (Co-investigator), Nordon, A. (Co-investigator), Price, C. J. (Co-investigator), Sefcik, J. (Co-investigator) & Ter Horst, J. (Co-investigator)
EPSRC (Engineering and Physical Sciences Research Council)
1/01/17 → 30/09/24
Project: Research

Data for "Quality by Digital Design in Action: A Workflow for Crystallisation and Isolation"
Siddique, H. (Creator), Turner, A. (Creator), Houson, I. (Creator), Chong, M. (Creator), Robertson, M. (Creator), Nordon, A. (Creator), Dunn, A. S. (Creator), Osman, A. (Creator), Galindo, A. (Creator), Johnston, B. (Creator), Benyahia, B. (Creator), Brown, C. (Creator), Mustoe, C. (Creator), Price, C. J. (Creator), Reilly, C. (Creator), Adjiman, C. (Creator), Jackson, G. (Creator), Prasad, E. (Creator), Halbert, G. (Creator), Feilden, H. (Creator), Sefcik, J. (Creator), McGinty, J. (Creator), Robertson, J. (Creator), Smith, K. (Creator), Al-Attili, M. (Creator), McGowan, M. (Creator), Siddique, M. (Creator), Pathan, M. (Creator), Rajoub, N. (Creator), Hamilton, N. (Creator), Feeney, R. (Creator), Brown, S. A. (Creator), Urwin, S. (Creator), Bernet, T. (Creator), Pickles, T. (Creator), Li, W. (Creator) & Florence, A. (Creator), University of Strathclyde, 27 Jun 2025
DOI: 10.15129/68fec595-1444-459f-99ae-4de352cf01e3
Dataset

Cite this

Houson, I., Siddique, H., Chong, M. W. S., Robertson, M., Turner, A. J., Nordon, A., Osman, A., Galindo, A., Dunn, A. S., Johnston, B., Benyahia, B., Brown, C. J., Mustoe, C. L., Price, C. J., Reilly, C. D., Adjiman, C. S., Jackson, G., Prasad, E., Halbert, G., ... Florence, A. J. (2025). Quality by digital design in action: a workflow for crystallisation and isolation. International Journal of Pharmaceutics, 686, Article 126343. Advance online publication. https://doi.org/10.1016/j.ijpharm.2025.126343

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title = "Quality by digital design in action: a workflow for crystallisation and isolation",

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.",

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author = "Ian Houson and Humera Siddique and Chong, \{Magdalene W.S.\} and Murray Robertson and Turner, \{Alice J.\} and Alison Nordon and Amal Osman and Amparo Galindo and Dunn, \{Andrew S.\} and Blair Johnston and Brahim Benyahia and Brown, \{Cameron J.\} and Mustoe, \{Chantal L.\} and Price, \{Chris J.\} and Reilly, \{Chris D.\} and Adjiman, \{Claire S.\} and George Jackson and Elke Prasad and Gavin Halbert and Helen Feilden and Jan Sefcik and John McGinty and John Robertson and Kenneth Smith and Mais Al-Attili and Mark McGowan and Mariam Siddique and Momina Pathan and Nazer Rajoub and Niki Hamilton and Rachel Feeney and Scott Brown and Urwin, \{Stephanie J.\} and Thomas Bernet and Thomas Pickles and Wei Li and Florence, \{Alastair J.\}",

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month = nov,

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doi = "10.1016/j.ijpharm.2025.126343",

language = "English",

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Houson, I, Siddique, H , Chong, MWS, Robertson, M, Turner, AJ, Nordon, A , Osman, A, Galindo, A, Dunn, AS, Johnston, B, Benyahia, B, Brown, CJ , Mustoe, CL, Price, CJ, Reilly, CD, Adjiman, CS, Jackson, G, Prasad, E , Halbert, G , Feilden, H , Sefcik, J, McGinty, J, Robertson, J, Smith, K, Al-Attili, M , McGowan, M , Siddique, M, Pathan, M, Rajoub, N, Hamilton, N , Feeney, R , Brown, S, Urwin, SJ, Bernet, T, Pickles, T, Li, W & Florence, AJ 2025, 'Quality by digital design in action: a workflow for crystallisation and isolation', International Journal of Pharmaceutics, vol. 686, 126343. https://doi.org/10.1016/j.ijpharm.2025.126343

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T2 - a workflow for crystallisation and isolation

AU - Houson, Ian

AU - Siddique, Humera

AU - Chong, Magdalene W.S.

AU - Robertson, Murray

AU - Turner, Alice J.

AU - Nordon, Alison

AU - Osman, Amal

AU - Galindo, Amparo

AU - Dunn, Andrew S.

AU - Johnston, Blair

AU - Benyahia, Brahim

AU - Brown, Cameron J.

AU - Mustoe, Chantal L.

AU - Price, Chris J.

AU - Reilly, Chris D.

AU - Adjiman, Claire S.

AU - Jackson, George

AU - Prasad, Elke

AU - Halbert, Gavin

AU - Feilden, Helen

AU - Sefcik, Jan

AU - McGinty, John

AU - Robertson, John

AU - Smith, Kenneth

AU - Al-Attili, Mais

AU - McGowan, Mark

AU - Siddique, Mariam

AU - Pathan, Momina

AU - Rajoub, Nazer

AU - Hamilton, Niki

AU - Feeney, Rachel

AU - Brown, Scott

AU - Urwin, Stephanie J.

AU - Bernet, Thomas

AU - Pickles, Thomas

AU - Li, Wei

AU - Florence, Alastair J.

PY - 2025/11/1

Y1 - 2025/11/1

N2 - 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.

AB - 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.

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KW - crystallisation

KW - digital design in pharmaceutical development

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DO - 10.1016/j.ijpharm.2025.126343

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VL - 686

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

M1 - 126343

ER -

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

Abstract

Funding

Keywords

Access to Document

Fingerprint

Projects

Made Smarter Innovation: Digital Medicines Manufacturing Research Centre (DM2)

Future Continuous Manufacturing and Advanced Crystallisation Research Hub (CMAC Hub)

Datasets

Data for "Quality by Digital Design in Action: A Workflow for Crystallisation and Isolation"

Cite this