Several procedures based on the shake-flask method and designed to require a minimum amount of drug for octanol-water partition coefficient determination have been established and developed. The procedures have been validated by a 28 substance set with a lipophilicity range from -2.0 to 4.5 (logD7.4). The experimental partition is carried out using aqueous phases buffered with phosphate (pH 7.4) and n-octanol saturated with buffered water and the analysis is performed by liquid chromatography. In order to have accurate results, four procedures and eight different ratios between phase volumes are proposed. Each procedure has been designed and optimized (for partition ratios) for a specific range of drug lipophilicity (low, regular and high lipophilicity) and solubility (high and low aqueous solubility). The procedures have been developed to minimize the measurement in the octanolic phase. Experimental logD7.4 values obtained from different procedures and partition ratios show a standard deviation lower than 0.3 and there is a nice agreement when these values are compared with the reference literature ones.

This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation), use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method), solubility type (water, buffer, intrinsic), temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pKa, equilibration time (stirring and sedimentation), separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.