Determination of acid dissociation constants of poorly water-soluble nicotinic ligands by means of electrophoretic and potentiometric techniques

Objectives: Acid-base dissociations constants of a series of poorly water-soluble nicotinic ligands designed as anti-inflammatory agents were determined in order to characterize the pharmacokinetic profile of this kind of ligands. Methods: pKas values were assessed by means of potentiometric and electrophoretic methods and investigated by computational protocols. Results: Both electrophoretic and potentiometric measurements produced reliable results. However, with the electrophoretic technique only an average value for close pKas was found, whereas the potentiometric method allowed determination of each pKa value in water-cosolvent mixtures. A theoretical treatment with various prediction programs - i.e. ADME Boxes v. 4.1, ACD/pKa DB and ACD/pKa GALAS - led in most cases to values which were not in accordance with the experimental ones. Conclusion: Electrophoretic and potentiometric techniques showed complementary features. Indeed, with capillary electrophoresis, the problem associated with the low water solubility of the studied samples could be easily overcome, although this technique did not allow to measuring all dissociation constants. In contrast, application of the potentiometric method afforded all the theoretical pKa values, although we had to perform the titrations in watercosolvent mixtures, a less precise, more laborious and time-consuming approach.