Macro Ionization Constants of Hydroxyzine, Cetirizine and an Analog

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Abstract
Thermodynamic dissociation constants of piperidine and piperazine compounds have been determined at 20°C by combining two experimental techniques. These compounds have chromophoric changes dependent upon the pH of the solution. Using spectrophotometric measurements and potentiometric titration data, all constants have been calculated. the values determined by means of both methods are in good agreement. Especially the two overlapping macroconstants of cetirizine have been computed using an adequate algorithm. Unexpectedly, pKal of [2-[4-[[4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid (CETIRIZINE) has been shown to be much lower than pKal of its analog ([2-[2-[4-(diphenylmethylene)-1-piperidinyl] ethoxy] ethoxy] acetic acid), probably because of an electronic effect : an intramolecular hydrogen bond between the carbonyl of the carboxylic acid group and the protonated nitrogen atom bearing the ethoxyacetic chain.