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Predicting intrinsic aqueous solubility by a thermodynamic cycle

Predicting intrinsic aqueous solubility by a thermodynamic cycle
Predicting intrinsic aqueous solubility by a thermodynamic cycle
We report methods to predict the intrinsic aqueous solubility of crystalline organic molecules from two different thermodynamic cycles. We find that direct computation of solubility, via ab initio calculation of thermodynamic quantities at an affordable level of theory, cannot deliver the required accuracy. Therefore, we have turned to a mixture of direct computation and informatics, using the calculated thermodynamic properties, along with a few other key descriptors, in regression models. The prediction of log intrinsic solubility (referred to mol/L) by a three-variable linear regression equation gave r2 = 0.77 and RMSE = 0.71 for an external test set comprising drug molecules. The model includes a calculated crystal lattice energy which provides a computational method to account for the interactions in the solid state. We suggest that it is not necessary to know the polymorphic form prior to prediction. Furthermore, the method developed here may be applicable to other solid-state systems such as salts or cocrystals.

adme, qspr, crystal, lattice energy, solvation, pharmacokinetics
1543-8384
266-279
Palmer, David S.
9a2d8d93-2137-456a-9566-91e46aaf3b17
Llinàs, Antonio
a919c773-7bb1-46b0-938d-2f4d7733c235
Morao, Iñaki
4f2da31b-0c88-4e1f-acfc-554aefd3c8c0
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Goodman, Jonathan M.
e5b4c6ee-935c-41d4-8389-5a8f7361a956
Glen, Robert C.
de828a9d-5506-421b-979d-4cb89b06f107
Mitchell, John B.O.
ca8def10-fbbb-4d69-af8d-21ea782d2491
Palmer, David S.
9a2d8d93-2137-456a-9566-91e46aaf3b17
Llinàs, Antonio
a919c773-7bb1-46b0-938d-2f4d7733c235
Morao, Iñaki
4f2da31b-0c88-4e1f-acfc-554aefd3c8c0
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Goodman, Jonathan M.
e5b4c6ee-935c-41d4-8389-5a8f7361a956
Glen, Robert C.
de828a9d-5506-421b-979d-4cb89b06f107
Mitchell, John B.O.
ca8def10-fbbb-4d69-af8d-21ea782d2491

Palmer, David S., Llinàs, Antonio, Morao, Iñaki, Day, Graeme M., Goodman, Jonathan M., Glen, Robert C. and Mitchell, John B.O. (2008) Predicting intrinsic aqueous solubility by a thermodynamic cycle. Molecular Pharmaceutics, 5 (2), 266-279. (doi:10.1021/mp7000878).

Record type: Article

Abstract

We report methods to predict the intrinsic aqueous solubility of crystalline organic molecules from two different thermodynamic cycles. We find that direct computation of solubility, via ab initio calculation of thermodynamic quantities at an affordable level of theory, cannot deliver the required accuracy. Therefore, we have turned to a mixture of direct computation and informatics, using the calculated thermodynamic properties, along with a few other key descriptors, in regression models. The prediction of log intrinsic solubility (referred to mol/L) by a three-variable linear regression equation gave r2 = 0.77 and RMSE = 0.71 for an external test set comprising drug molecules. The model includes a calculated crystal lattice energy which provides a computational method to account for the interactions in the solid state. We suggest that it is not necessary to know the polymorphic form prior to prediction. Furthermore, the method developed here may be applicable to other solid-state systems such as salts or cocrystals.

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More information

Published date: 2008
Keywords: adme, qspr, crystal, lattice energy, solvation, pharmacokinetics
Organisations: Organic Chemistry: Synthesis, Catalysis and Flow, Computational Systems Chemistry

Identifiers

Local EPrints ID: 343441
URI: http://eprints.soton.ac.uk/id/eprint/343441
ISSN: 1543-8384
PURE UUID: 4b503c5f-5801-4454-894e-1f741e7a4cfc
ORCID for Graeme M. Day: ORCID iD orcid.org/0000-0001-8396-2771

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Date deposited: 08 Oct 2012 12:36
Last modified: 15 Mar 2024 03:44

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Contributors

Author: David S. Palmer
Author: Antonio Llinàs
Author: Iñaki Morao
Author: Graeme M. Day ORCID iD
Author: Jonathan M. Goodman
Author: Robert C. Glen
Author: John B.O. Mitchell

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