High Throughput Method to Characterize Acid-Base Properties of Insoluble Drug Candidates in Water

CASTELLS, C.B.; ACQUAVIVA, A.; ACQUAVIVA, A.; BENITO, D.E.; GAGLIARDI, L.G.; BENITO, D.E.; GAGLIARDI, L.G.; CASTELLS, C.B.

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018 vol. 154 p. 404 - 412

0731-7085

In drug design experimental characterization of acidic groups in candidate molecules is one of the more importantsteps prior to the in-vivo studies. Potentiometry combined with Yasuda-Shedlovsky extrapolation isone of the more important strategy to study drug candidates with low solubility in water, although, it requiresa large number of sequences to determine pKa values at different solvent-mixture compositions to, finally,obtain the pKa in water ( ) by extrapolation. We have recently proposed a method which requires onlytwo sequences of additions to study the effect of organic solvent content in liquid chromatography mobilephases on the acidity of the buffer compounds usually dissolved in it along wide ranges of compositions. Inthis work we propose to apply this method to study thermodynamic of drug candidates with low solubilitiesin pure water. Using methanol/water solvent mixtures we study six pharmaceutical drugs at 25°C. Fourof them: ibuprofen, salicylic acid, atenolol and labetalol, were chosen as members of carboxylic, amine andphenol families, respectively. Since these compounds have known values, they were used to validate theprocedure, the accuracy of Yasuda-Shedlovsky and other empirical models to fit the behaviors, and to obtainby extrapolation. Finally, the method is applied to determine unknown thermodynamic values oftwo pharmaceutical drugs: atorvastatin calcium and the two dissociation constants of ethambutol. The procedureproved to be simple, very fast and accurate in all of the studied cases.