Suggested Improvements for Measurement of Equilibrium Solubility-pH of Ionizable Drugs

The accurate prediction of solubility of drug-like molecules is difficult, and perhaps a satisfactory general model is not yet available. The most cited challenge to good prediction has been the lack of enough high-quality and drug-relevant solubility data that adequately cover the chemical space of drugs. This review addresses data quality in solubility measurement. Specifically, the gold standard shake-flask and related methods used to measure equilibrium solubility of ionizable drug-like compounds as a function of pH were reviewed. Over 800 publications were examined. Many factors affecting the quality of the measurement were recognized, and a number of suggestions are offered to improve the experimental methodology. Some of the suggestions focus on improving methods for future measurements, and some refer to improvements in data mining, i.e., to ways of extracting more reliable information from existing data. By normalizing data for pH (i.e., deriving intrinsic solubility, S-0) and for temperature (by transforming measurements performed in the range 20 - 40 degrees C to 25 degrees C), it is suggested that the 0.6-0.7 log unit currently expected interlaboratory reproducibility can be reduced to near 0.15. It is the aim of the review that the improvements in data quality would lead to better predictions of drug solubility using in silico methods.