PH‐metric Solubility. 1. Solubility‐pH Profiles from Bjerrum Plots. Gibbs Buffer and pKa in the Solid State

Abstract

If measurements of solubility were not so laborious, slow, and consuming of sample, solubility-pH profiles would be used more often at the initial stages of drug discovery to screen out molecules with problematic pharmacokinetic profiles. An automated potentiometric titration method for solubility measurements, which addresses some of the shortcomings of the traditional methods, is described. A simple graphical procedure for estimating solubility constants, based on Bjerrum difference plots, is developed, and the relationships between titration data and solubility-pH profiles for mono- and diprotic ionizable substances are explored, drawing on generalized mass-balance based simulation methods. One useful derived equation (valid in a solution where part of the sample precipitates early in the titration) is: log So = log (C/2) - |ΔpKa| where C is the sample concentration, So is the intrinsic solubility of the unchanged substance, and ΔpKa = pKappa - pKa, the difference between the apparent pKa determined under conditions of precipitation and the true pKa, measured in the absence of the solid phase. The relationship holds in both aqueous and cosolvent solutions (e.g. dimethylsulphoxide-water). The properties of the state where an unchanged substance (e.g. HX) coprecipitates with its ionized form (e.g. X− salt) were explored. A super buffer, termed the Gibbs buffer, was formed and characterized by an ionization constant, pK(s)a, of the substance in the solid state. It was shown that pK(s)a - pKa = log SHX - log SX, where SHX and SX refer to the solubility constants of HX and X species. Flurbiprofen (acid), benzydamine (base), and buprenorphine (ampholye) were used to illustrate the experimental procedure. Our initial studies indicate that these new methods will meet many of the needs of not only discovery-stage researchers but also of preformulation and development scientists, traditionally concerned with solubility measurements.