pKa-critical Interpretations of Solubility–pH Profiles: PG-300995 and NSC-639829 Case Studies

Two weak bases, PG-300995 (anti-HIV agent) and NSC-639829 (anti-tumor agent), whose log S – pH profiles had been previously published, but whose pKa values had not been reported, were analyzed using a method which can determine pKa values from log S – pH data. This “SpH-pKa” technique, although often practiced, can result in inaccurate pKa values, for a variety of reasons. The operational SpH-pKa values were compared to those predicted by MarvinSketch (ChemAxon), ADMET Predictor (Simulation Plus), and ACD/Percepta (ACD/Labs). The agreement for the sparingly-soluble PG-300995 was reasonably good. However, a substantial difference was found for the practically-insoluble NSC639829. To probe this further, the pKa of NSC-639829 was measured by an independent spectrophotometric cosolvent technique. The log S pH profile of NSC-639829 was then re-analyzed with the independently-measured pKa. It was found that the equilibrium model which best fit the solubility data is consistent with the presence of a monocationic NSC-639829 dimeric species below pH 4. This illustrates that an independently-determined accurate pKa is critical to mechanistic interpretations of solubility-pH data. Apparently, the Henderson-Hasselbalch equation holds for PG300995, but not NSC-639829.