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In Silico Screening for Solid Dispersions: The Trouble with Solubility Parameters and ?FH

Turpin, Eleanor R.; Taresco, Vincenzo; Al-Hachami, Wathiq A.; Booth, Jonathan; Treacher, Kevin; Tomasi, Simone; Alexander, Cameron; Burley, Jonathan; Laughton, Charles A.; Garnett, Martin C.


Eleanor R. Turpin

Wathiq A. Al-Hachami

Jonathan Booth

Kevin Treacher

Simone Tomasi

Professor of Computational Pharmaceutical Science

Martin C. Garnett


© Copyright 2018 American Chemical Society. The problem of predicting small molecule-polymer compatibility is relevant to many areas of chemistry and pharmaceutical science but particularly drug delivery. Computational methods based on Hildebrand and Hansen solubility parameters, and the estimation of the Flory-Huggins parameter, χ, have proliferated across the literature. Focusing on the need to develop amorphous solid dispersions to improve the bioavailability of poorly soluble drug candidates, an innovative, high-throughput 2D printing method has been employed to rapidly assess the compatibility of 54 drug-polymer pairings (nine drug compounds in six polymers). In this study, the first systematic assessment of the in silico methods for this application, neither the solubility parameter approach nor the calculated χ, correctly predicted drug-polymer compatibility. The theoretical limitations of the solubility parameter approach are discussed and used to explain why this approach is fundamentally unsuitable for predicting polymer-drug interactions. Examination of the original sources describing the method for calculating χ shows that only the enthalpic contributions to the term have been included, and the corrective entropic term is absent. The development and application of new in silico techniques, that consider all parts of the free energy of mixing, are needed in order to usefully predict small molecule-polymer compatibility and to realize the ambition of a drug-polymer screening method.


Turpin, E. R., Taresco, V., Al-Hachami, W. A., Booth, J., Treacher, K., Tomasi, S., …Garnett, M. C. (2018). In Silico Screening for Solid Dispersions: The Trouble with Solubility Parameters and χFH. Molecular Pharmaceutics, 15(10), 4654-4667.

Journal Article Type Article
Acceptance Date Aug 24, 2018
Online Publication Date Aug 24, 2018
Publication Date Oct 1, 2018
Deposit Date Mar 30, 2020
Journal Molecular Pharmaceutics
Print ISSN 1543-8384
Electronic ISSN 1543-8392
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 15
Issue 10
Pages 4654-4667
Keywords Molecular Medicine; Drug Discovery; Pharmaceutical Science
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