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

Abstract

This commentary compares 233 CheqSol intrinsic solubility values (log S₀) reported in the Wiki-pS₀ database for 145 different druglike molecules to the 838 log S₀ values determined mostly by the saturation shake-flask (SSF) method for 124 of the molecules from the CheqSol set. The range of log S₀ spans from -1.0 to -10.6 (log molar units), averaging at -3.8. The correlation plot between the two methods indicates r² = 0.96, RMSE = 0.34 log unit, and a slight bias of -0.07 log unit. The average interlaboratory standard deviation (SD_i) is slightly better for the CheqSol set than that of the SSF set: SD_i^CS = 0.15 and SD_i^SSF = 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_i of both methods be about ~0.15 log unit. The multi-lab averaged log S₀ (and the corresponding SD_i) values could be helpful additions to existing training-set molecules used to predict the intrinsic solubility of drugs and druglike molecules.