Potentiometric CheqSol and standardized shake-flask solubility methods are complimentary tools in physicochemical profiling

The solubility of three drugs (glimepiride, pioglitazone, sibutramine) with different acid/base properties and expected supersaturation behavior was examined in detail using the shake-flask (SF) and potentiometric (CheqSol) methods. Both uncharged (free) species and hydrochloride salts were used as starting materials. On the one hand, the SF method provided information about the thermodynamic solubility at any pH value, including the counterion-dependent solubility of ionic species. Additionally, this method easily allowed the identification of the solid phase in equilibrated solutions by powder X-ray diffraction, and the detection and quantification of aggregation and complexation reactions. On the other hand, CheqSol method permitted the measurement of the equilibrium solubility of neutral species, the observation of changes in solid forms, and the extent and duration of supersaturation (kinetic solubility) for 'chaser' compounds. The combined information from both methods gave an accurate picture of the solubility behavior of the studied drugs.