pH-metric solubility assay

pH-metric solubility assay: Chasing Equilibrium Solubility method¹

This analytical tool is adequate for ionizable substances (acids and bases) and provides the following parameters:

  • Kinetic solubility (SK) of the neutral species
  • Intrinsic solubility (So) of the neutral species
  • pH-solubility profile according to Henderson-Hasselbalch equations
  • Extent and duration of supersaturation

The method is based on measuring the small pH changes in a solution where an ionizable compound precipitates or dissolves. Small amounts of 0.5 M HCl and 0.5 M KOH are added to force the compound to precipitate or dissolve, giving rise to a succession of positive and negative pH gradients. The equilibrium is situated where the gradient is zero.

The measurements are performed at 0.15 M ionic strength, controlled temperature (±0.2 oC) an in air-tight vessels with degassed reagents under argon atmosphere.

The assay can be performed at different mediums such as FaSSIF and FeSSIF biorelevant buffers (Fasted and Fed State Simulated Intestinal Fluids).

The knowledge of the pKa values of the compound is mandatory.

Instrumentation:

  • PCA200 titrator with D-PAS spectrometer (Sirius Analytical Instruments, East Sussex, UK) controlled from a computer running RefinementPro and CheqSol software.
  • pH electrode (Ag/AgCl, Sirius Analytical Instruments Ltd.).
  • Temperature probe to motorize the temperature during the course of the measurement

Required amount of substance: It depends on the compound solubility. Tentative values for a unique measurement are given in the following Table.

So (mol/L) mg/determination
log So < -5 5 -6
-5<log So < -4 10 – 25
-4<log So < -3 30 – 80
-3<log So < -2 40 – 100
-2<log So < -1 100 – 300
log So > -1 > 300

¹ Chasing Equilibrium: Measuring the Intrinsic Solubility of Weak Acids and Bases Martin Stuart* and Karl Box. Anal. Chem. 2005, 77, 983-990

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