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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 id orcid.org/0000-0002-3139-5442 ; n - ADME Research, 1732 First Avenue, #102, New York, NY 10128 , USA


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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

https://hrcak.srce.hr/140677

Publication date:

1.7.2015.

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