The microscopic ionization behavior of piroxicam was investigated using two different approaches, ie., direct UV spectroscopy and an indirect analogue approach (deductive method). The best microscopic pK, values (pK,,, = 4.60, pK,,, = 5.40, pKa2, = 2.72, and pK,,, = 1.92) were obtained by the deductive method using as pK,,, the pK, of the enolic 0-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 pK, units) being caused by the pyridinium group. The electronic structure of piroxicam was studied based on 'H-NMR chemical shifts at various ionization states, indicating an extended electron conjugation through the molecule. The partition measurements in octan-l-ol/H,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. Introduction. -Oxicams ( = 4-hydroxy-1,2-benzothiazine-3-carboxamides) are a class of long-lasting non-steroidal anti-inflammatory drugs (NSAIDs), which act by inhibiting enzymes involved in the biosynthesis of prostaglandins [I] [2]. To date, piroxicam ( = 4-hydroxy-2-methyl-N-(pyridin-2-y1)-2H-1,2-benzothiazine-3-carboxamide 1,ldioxide; 1, see Fig. I ) and tenoxicain are among the top-ten NSAIDs on the market [3].
Of particular chemical interest among the oxicams are those bearing a weakly basic pyridyl group, resulting in compounds of a zwitterionic nature such as piroxicam, tenoxicam, and lornoxicam. For these zwitterionic oxicams, the acidity of the enolic function Piroxicam 2 3 ") Trivial numbering. The planar conformation shown is defined as EZE (for the sake of simplicity; nof according to the definition of (€)-and (2)-notation for isomerism around double bonds) referring to the bonds C(8)-C(9), C(9)-N( 10). and N(1O)-C(1 l), respectively.