Predicting intrinsic aqueous solubility by a thermodynamic cycle

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).


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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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1021/mp7000878
ISSNs: 1543-8384 (print)
1543-8392 (electronic)
Keywords: adme, qspr, crystal, lattice energy, solvation, pharmacokinetics
Subjects: Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
Divisions : Faculty of Natural and Environmental Sciences > Chemistry > Computational Systems Chemistry
Faculty of Natural and Environmental Sciences > Chemistry > Organic Chemistry: Synthesis, Catalysis and Flow
ePrint ID: 343441
Accepted Date and Publication Date:
Date Deposited: 08 Oct 2012 12:36
Last Modified: 31 Mar 2016 14:35

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