Predictive relationships in the water solubility of salts of a nonsteroidal anti-inflammatory drug

Abstract

A number of metal and amine salts of the nonsteroidal anti-inflammatory drug 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen) (1) were synthesized, and the water solubilities of these materials were investigated. The solubility of flurbiprofen versus pH is in excellent agreement with the theoretical profile which assumes an intrinsic solubility of 5.0 X 10(-5) M for the free acid and a pKa of 4.22. The solubility determination of 1:1 amine salts of slightly soluble carboxylic acids is complicated by possible precipitation of the free acid when the salt is dissolved in water. The lower than expected apparent salt solubility seen when this phenomenon occurs is referred to as the "stoichiometric solubility." A theoretical treatment delineating three distinct regions in the phase solubility diagram for the tromethamine salt of flurbiprofen illustrates the care which must be taken in characterizing the system for salt solubility determinations. A multiple linear regression analysis was carried out to determine the relationship between the log Ksp of six amine salts and their melting points and cation hydrophilicities. While a strong dependence of Ksp on melting point was found, there was not a significant correlation between Ksp and amine cation hydrophilicity.