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Jon Mole
Thomas Müller Jon Mole Karl Box


Chasing Equilibrium Solubility (CheqSol) – a novel approach for measuring the solubility of ionizable compounds

Jon Mole, Karl Box, Martin Stuart, Gabriela Cimpan, John Comer, Sirius Analytical Instruments Ltd, Riverside, Forest Row Business Park, Forest Row, East Sussex, RH18 5DW, UK

Purpose: To develop a new method for measuring solubility of ionizable drug molecules.

Methods: Chasing Equilibrium Solubility (CheqSol) [1] is a new pH-metric method for the measurement of solubility of ionizable drug molecules. Equilibrium and kinetic values are obtained in the same measurement. A small quantity of solid sample is dissolved in an aqueous solution by adjusting the pH such that the compound exists mainly in its ionized form. The sample is then titrated to a pH where the neutral species begin to precipitate. The concentration of sample at the point of initial precipitation, the kinetic solubility, is recorded.

The rate of change of pH is then monitored, whilst strong acid and strong base are added alternately to force the sample to fluctuate between a supersaturated and “subsaturated” state. By careful monitoring of the rate of pH change, the equilibrium conditions can be determined and an intrinsic solubility can be measured. This process is called chasing equilibrium.  While many samples chase equilibrium; some samples don’t, and the result is calculated differently.

Most samples can be analyzed in 20 to 60 minutes. The results are in excellent correlation with published values. Besides its speed and accuracy, this method confirms the result several times within the same experiment, and measures solubility in the presence of solid material without separation.

Results: Six CheqSol assays on nitrofurantoin produced a result of 112µg/mL with a CV=6%. Six parallel shake-flask experiments confirmed a result of 109µg/mL (CV=7%). Similarly, warfarin gave a CheqSol result of 5.30µg/mL (CV=4%, 6 assays) and shake-flask 5.25µg/mL CV=4%, 6 assays). Other comparative results will be presented.

Conclusion: CheqSol is a valid method for measuring solubility of ionizable compounds.

[1] Stuart, M. Box, K.  Chasing equilibrium: measuring the intrinsic solubility of weak acids and bases. Anal. Chem. 2005 (77(4)) pp 983-990

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Last modified: 28 April 2008