Microscopic Protonation/Deprotonation Equilibria of the Anti‐Inflammatory Agent Piroxicam

The microscopic ionization behavior of piroxicam was investigated using two different approaches, i.e. , direct UV spectroscopy and an indirect analogue approach (deductive method). The best microscopic p K a values (p K a12 = 4.60, p K a21 = 5.40, p K a22 = 2.72, and p K a11 = 1.92) were obtained by the deductive method using as p K a22 the p K a of the enolic O ‐methylated piroxicam 2 . The results show remarkable electrostatic effects in the protonation/deprotonation equilibria, a marked increase in the acidity of the enolic function (2.68 p K a units) being caused by the pyridinium group. The electronic structure of piroxicam was studied based on 1 H‐NMR chemical shifts at various ionization states, indicating an extended electron conjugation through the molecule. The partition measurements in octan‐1‐ol/H 2 O of zwitterionic compound 3 (the pyridyl N ‐methyl derivative of piroxicam ( 1 )) suggest that the two opposite charges in zwitterionic piroxicam are indeed in a close intramolecular proximity.