Chromatographic determination of aqueous dissociation constants of some water-insoluble nonsteroidal antiinflammatory drugs.

The purpose of this work is to propose a new, useful, and easy chromatographic method to determine accurately the aqueous dissociation constant of drugs sparingly soluble in water. The method uses the rigorous intersolvental pH scale, (w)(s)pH, i.e., the pH measurements are made in the mobile phase after mixing the aqueous buffer with methanol by a combined glass electrode previously standardised with common aqueous buffers. The measured pK allows the determination of the drug's pK(a) in the mobile phase, (w)(s)pK(a), which can be easily converted in the aqueous pK(a), (w)(w)pK(a), by means of previously established equations. A series of nonsteroidal carboxylic acids with antiinflammatory properties were selected to test the method because their aqueous pK(a) values, (w)(w)pK(a), had been previously evaluated from different approaches that gave consistent results. The comparison of the aqueous pK(a) values obtained by means of the proposed procedure with those of literature allows the accurate evaluation of this new methodology. The results obtained show very good precision and accuracy. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 991-999, 2002