The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship

Abstract

The aqueous solubility of liquids and solids, as log S(W), has been correlated with an amended solvation equation that incorporates a term in Sigma alpha(2)(H) x Sigma beta(2)(H), where the latter are the hydrogen bond acidity and basicity of the solutes, respectively. Application to a training set of 594 compounds led to a correlation equation with a standard deviation, SD, of 0.56 log units. For a test set of 65 compounds, the SD was 0.50 log units, and for a combined correlation equation for 659 compounds, the SD was 0.56 log units. The correlation equations enable the factors that influence aqueous solubility to be revealed. The hydrogen-bond propensity of a compound always leads to an increase in solubility, even though the Sigma alpha(2)(H) x Sigma beta(2)(H) term opposes solubility due to interactions in the liquid or solid. Increase in solute dipolarity/polarizability increases solubility, whereas an increase in solute excess molar refraction, and especially, volume decrease solubility. The solubility of Bronsted acids and bases is discussed, and corrections for the fraction of neutral species in the saturated solution are graphically presented.

Estimation of drug solubility in water, PEG 400 and their binary mixtures using the molecular structures of solutes

“…This should be advantageous for the prediction accuracy in comparison with models that are limited in terms of the range of the descriptors used. For example, Rytting et al (2004) used only molecular weight and volume, number of rotatable bonds, numbers of hydrogen bonding donor and acceptor groups, molecular density and radius of gyration, and Abraham et al (1999) employed only the five Abraham descriptors.…”

“…Moreover, electrostatic interactions can be formed intra-molecularly. Although there have been attempts to approximate the intra-molecular interactions for example by the use of product terms of hydrogen bonding acceptor and donor descriptors (Abraham and Le, 1999), the extent of such interactions can only be estimated by rigorous conformational analysis of the molecules.…”

IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Neat Organic Solvents and Organic Solvent Mixtures

“…The logarithm of the aqueous molar solubility of ibuprofen is log 10 c 1,W ¼ -3.76. 118,119 The McGowan volume of ibuprofen, V ¼ 1.7771, was calculated from the number of chemical bonds in the molecule and the individual atomic group volumes, AV i , given in Sec. 1.3.…”

Recent progress in the computational prediction of aqueous solubility and absorption

“…Yet another factor in solubility prediction that is often ignored is the role of the crystal form of a druglike solute (an early notable exception is that of Abraham and Le 55 ). An excellent recent review discusses the importance of solidstate properties on a range of developability considerations in drug discovery and development.…”