pKa values in solubility determination using the Henderson- Hasselbalch equation

Alex Avdeef [1] and Samuel Yalkowsky [2] have independently studied the solubility and ionization properties of an investigational drug (NSC-639829). In the study conducted by Avdeef and coworkers, the pKa value derived from Henderson-Hasselbalch (HH) equation was 4.70, which was different from the value of 3.76 as determined experimentally by the Yasuda-Shedlovsky plot using the pKa values obtained from co-solvent UV titrations. The authors then invoked an ionization-precipitation-aggregation model by assuming the formation of a positively charged dimer to generate the theoretical solubility-pH profile. In their implementation, the pKa was fixed at 3.76, while the S0, and the aggregation equilibrium constant were treated as adjustable parameters. To this end, the authors obtained a reasonably good fit between the model and the experiment. The S0 value as determined using this approach appeared to be in line with the previously reported value [2].