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 pK a values had not been reported, were analyzed using a method which can determine pK a values from log S – pH data. This “S pH -pK a ” technique, although often practiced, can result in inaccurate pK a values, for a variety of reasons. The operational S pH -pK a 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 NSC-639829. To probe this further, the pK a 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 pK a . 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 pK a is critical to mechanistic interpretations of solubility-pH data. Apparently, the Henderson-Hasselbalch equation holds for PG-300995, but not NSC-639829.