Predicting Intrinsic Aqueous Solubility by a Thermodynamic Cycle

DS Palmer, A Llinas, I Morao, GM Day, JM Goodman, RC Glen, John B. O. Mitchell

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)266-279
Number of pages14
JournalMolecular Pharmaceutics
Volume5
Issue number2
DOIs
Publication statusPublished - 7 Apr 2008

Keywords

  • ADME
  • QSPR
  • crystal
  • lattice energy
  • solvation
  • pharmacokinetics
  • MOLECULAR-CRYSTAL STRUCTURES
  • CONTINUUM DIELECTRIC THEORY
  • DISTRIBUTED MULTIPOLE
  • DRUG SOLUBILITY
  • LATTICE ENERGY
  • MELTING-POINT
  • SOLVATION
  • MODELS
  • SUBLIMATION
  • DISSOLUTION

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