Application of the Henderson-Hasselbalch equation to solubility determination: NSC-639829 Case Study

A number of publications which challenge the applicability of the Henderson-Hasselbalch equation to saturated solutions have appeared in the last few years (Avdeef [1-3], Butcher et al. [4], and Volgyi et al. [5]). In the most recent of these, Butcher et al. [4] suggested “the Henderson-Hasselbalch equation may not always be an accurate predictor of the pH dependence of solubility.” They claimed that the pKa of 4.70 determined by Jain et al. [6] for NSC-639829 is incorrect and that the value of 3.76, which they obtained by extrapolation of spectrophotometrically determined pKa values in 22, 30, and 41 percent methanol-water solutions, is the correct value. We believe that 4.70 is the correct value and that there are several serious flaws in their analysis. These are described below

The Estimation of Selected Physicochemical Properties of Organic Compounds

Thermodynamic relationships are used to predict several physicochemical properties of organic compounds. As described in chapter one, the UPPER model (Unified Physicochemical Property Estimation Relationships) has been used to predict nine essential physicochemical properties of pure compounds. It was developed almost 25 years ago and has been validated by the Yalkowsky group for almost 2000 aliphatic, aromatic, and polyhalogenated hydrocarbons. UPPER is based on a group of additive and nonadditive descriptors along with a series of well-accepted thermodynamic relationships. In this model, the two-dimensional chemical structure is the only input needed. Chapter (1) extends the applicability of UPPER to hydrogen bonding and non-hydrogen bonding aromatic compounds with several functional groups such as alcohol, aldehyde, ketone, carboxylic acid, carbonate, carbamate, amine, amide, nitrile as well as aceto, and nitro compounds. The total data set includes almost 3000 compounds. Aside from the enthalpies and entropies of melting and boiling, no training set is used for the calculation of the properties. The results show that UPPER enables a reasonable estimation of all the considered properties. Chapter (2) uses modification of the van't Hoff equation to predict the solubility of organic compounds in dry octanol as explained in chapter two. The equation represents a linear relationship between the logarithm of the solubility of a solute in octanol to its melting temperature. More than 620 experimentally measured octanol solubilities, collected from the literature, are used to validate the equation without using any regression or fitting. The average absolute error of the prediction is 0.66 log units. Chapter (3) compares the use of a statistic based model for the prediction of aqueous solubility to the existing general solubility equation (GSE).Release after 19-Jul-201