On the hydrolytic behavior of tinidazole, metronidazole, and ornidazole.
Using two UV-spectrophotometric methods, the hydrolysis of tinidazole was studied at pH 1.00-8.45 at 80 degrees C. The reaction followed apparent first-order kinetics throughout the studied range. No kinetic salt effect was detected, indicating that at least one of the reacting partners forming the transition state has a charge of 0. The reaction rate macro constants M(1)-M(4) were calculated to be 3.35 x 10(-2) M(-1) h(-1), 1.45 x 10(-2) h(-1), 3.76 x 10(-6) M h(-1), and 2.85 x 10(-11) M(2) h(-1), respectively. At pH >or= 7, the uncharged tinidazole was decomposed by the hydroxide ion; the reaction was found out to involve a proton transfer from the ethylsulfonylethyl side chain. At around pH 4.5, the degradation of the uncharged tinidazole was due to the solvent. In more acidic conditions, the reaction mechanism could not be fully resolved. The alkaline hydrolysis of metronidazole was studied on the basis of literature data. A general reaction mechanism was proposed, but an unequivocal explanation for the inflection point in the pH rate profile at pH 6 could not be found. The implications of the proposed reaction mechanism for the hydrolytic behavior of ornidazole were discussed.
Salo
Jukka-Pekka K
JP
Division of Pharmaceutical Chemistry, Department of Pharmacy, P.O. Box 56, Viikinkaari 5 E, FIN-00014, University of Helsinki, Helsinki, Finland. jpsalo@cc.helsinki.fi
Yli-Kauhaluoma
Jari
J
Salomies
Hannele
H
D000994:Antitrichomonal Agents / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008795:Metronidazole / Q000737:chemistry*; D009950:Ornidazole / Q000737:chemistry*; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014011:Tinidazole / Q000737:chemistry*
D000994:Antitrichomonal Agents; D012997:Solvents; D014011:Tinidazole; D008795:Metronidazole; D009950:Ornidazole