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• Shake-flask and CheqSol methods provide valuable and complementary information. • CheqSol shows that glimepiride and pioglitazone are prone to supersaturation. • Shake-flask suggests the formation of aggregates of glimepiride and pioglitazone. • CheqSol does not identify the influence of aggregation equilibria on solubility. • Shake-flask points out the effect of buffering species in the solubility of salts. 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. Image, graphical abstract [ABSTRACT FROM AUTHOR]