Multi-lab intrinsic solubility measurement reproducibility in CheqSol and shake-flask methods.

This commentary compares 233 CheqSol intrinsic solubility values (log S) reported in the Wiki-pS database for 145 different druglike molecules to the 838 log S values determined mostly by the saturation shake-flask (SSF) method for 124 of the molecules from the CheqSol set. The range of log S spans from -1.0 to -10.6 (log molar units), averaging at -3.8. The correlation plot between the two methods indicates r = 0.96, RMSE = 0.34 log unit, and a slight bias of -0.07 log unit. The average interlaboratory standard deviation (SD) is slightly better for the CheqSol set than that of the SSF set: SD = 0.15 and SD = 0.24. The intralaboratory errors reported in the CheqSol method (0.05 log) need to be multiplied by a factor of 3 to match the expected interlaboratory errors for the method. The scale factor, in part, relates to the hidden systematic errors in the single-lab values. It is expected that improved standardizations in the 'gold standard' SSF method, as suggested in the recent 'white paper' on solubility measurement methodology, should make the SD of both methods be about ~0.15 log unit. The multi-lab averaged log S (and the corresponding SD) values could be helpful additions to existing training-set molecules used to predict the intrinsic solubility of drugs and druglike molecules.