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

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ADMET and DMPK, Vol.3 No.2 July 2015. -

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 NSC-639829. 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 PG-300995, but not NSC-639829.

sparingly-soluble; solubility as a function of pH; solubility equations; shake-flask solubility; aggregation

Autor: George Butcher - ; Sirius Analytical Ltd., Forest Row, West Sussex RH18 5DW, UK John Comer - ; Sirius Analytical Ltd., Forest Row



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