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

Alex Avdeef

doi:10.5599/admet.3.2.193

Abstract

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 °C to 25 °C), it is suggested that the 0.6-0.7 log unit currently expected interlaboratory reproducibility can be reduced to less than 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.

Highlights

We focus on the shake-flask solubility measurement as a function of pH which is still the “gold standard” methodology in the minds of most experimentalists
We are energized to improve the accuracy of the prediction of intrinsic solubility from 2D structure, of sparingly-soluble ionizable drug-relevant molecules
Solubility measurements have been reported in a multiplicity of concentration units: mol/L, mM, μM, mol/kg, mole fraction, mass fraction, weight/mL, mg/100 mL, mg/dL, %w/v, g%mL, mg/mL%, mg%, “1 in 40 of water,” “soluble in 2 parts of water,” “3% soluble in water,” units of IU/mL, etc

Summary

Introduction

Since the mid-1990s there has been a heightened effort in drug discovery to predict drug-relevant aqueous solubility, described in at least a hundred publications (e.g., Huuskonen et al [1,2]; Abraham and Le [3]; Jorgensen and Duffy [4,5]; Bergström et al [6]; Hou et al [7]; Delaney [8]; Dearden [9]; Balakin et al [10]; Taskinen and Norinder [11]; Jain and Yalkowsky [12]; Shayanfar and Jouyban [13]; Wang and Hou [14]; Elder and Holm [15]; McDonagh et al [16]). Smaller databases of crystalline drug-like molecules have been published (Analytical Profiles of Drug Substances [22], McFarland et al [23]; Rytting et al [24]; Bergström et al [25]; Faller and Ertl [18]; Llinàs et al [26]; Hopfinger et al [27]). These smaller databases consist largely of intrinsic solubility values, S0 – i.e., the solubility of the neutral species

Methods

Results

Conclusion