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Microscopic Protonation/Deprotonation Equilibria of the Anti‐Inflammatory Agent Piroxicam
Author(s) -
TakácsNovák Krisztina,
Kökösi József,
Podányi Benjámin,
Noszál Béla,
Tsai RueyShiuan,
Lisa Giuseppe,
Carrupt PierreAlain,
Testa Bernard
Publication year - 1995
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19950780304
Subject(s) - chemistry , piroxicam , deprotonation , protonation , intramolecular force , pyridinium , ionization , medicinal chemistry , stereochemistry , molecule , computational chemistry , crystallography , organic chemistry , medicine , ion , alternative medicine , pathology
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.