ADMET and DMPK, Vol. 3 No. 2, 2015.
Original scientific paper
https://doi.org/10.5599/admet.3.2.182
pKa-critical Interpretations of Solubility–pH Profiles: PG-300995 and NSC-639829 Case Studies
George Butcher
; Sirius Analytical Ltd., Forest Row, West Sussex RH18 5DW, UK
John Comer
; Sirius Analytical Ltd., Forest Row, West Sussex RH18 5DW, UK
Alex Avdeef
orcid.org/0000-0002-3139-5442
; n - ADME Research, 1732 First Avenue, #102, New York, NY 10128 , USA
Abstract
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.
Keywords
sparingly-soluble; solubility as a function of pH; solubility equations; shake-flask solubility; aggregation
Hrčak ID:
140677
URI
Publication date:
1.7.2015.
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