Utilization of a kinetic isotope effect to decrease decomposition of ceftriaxone in a mixture of D2O/H2O

Jasprica, Ivona; Horvat, Petar; Zrnc, Katarina; Bonney, Karl J.; Bjornstad, Vidar; Hok, Lucija; Vianello, Robert; Bregović, Nikola; Požar, Josip; Leko, Katarina; Tomišić, Vladislav; Meštrović, Ernest (2023) Utilization of a kinetic isotope effect to decrease decomposition of ceftriaxone in a mixture of D2O/H2O. European Journal of Pharmaceutical Sciences, 187 . ISSN 09280987

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Abstract

The discovery of cephalosporin and demonstration of its improved stability in aqueous solution, as well as enhanced in vitro activity against penicillin-resistant organisms, were major breakthroughs in the development of β-lactam antibiotics. Although cephalosporins are more stable with respect to hydrolytic degradation than penicillins, they still experience a variety of chemical transformations. The present study offers an insight into the rates and mechanisms of ceftriaxone degradation at the therapeutic concentration in water, a mixture of water and deuterium oxide, and deuterium oxide itself at the neutral pH. Specific ceftriaxone degradation products were observed in aged samples (including a previously unreported dimer-type species), and by comparing the degradation rates in H2O and D2O, the observation of a kinetic isotope effect provided some valuable insight as to the nature of the initial ceftriaxone degradation. The effect of protium to deuterium isotope change on the degradation kinetics of ceftriaxone was evaluated using the method of initial rates based on HPLC analysis as well as by quantitative 1H NMR spectroscopy. Moreover, computational analysis was utilized to get a molecular insight into chemical processes governing the ceftriaxone degradation and to rationalize the stabilizing effect of replacing H2O with D2O.

Item Type:	Article
Uncontrolled Keywords:	beta-lactams; Ceftriaxone; D2O kinetic isotope effect; Molecular dynamics simulations; Quantum-chemical calculations
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Chemistry BIOMEDICINE AND HEALTHCARE > Pharmacy
Divisions:	Division of Organic Chemistry and Biochemistry
Depositing User:	Josipa Karadžole
Date Deposited:	15 Apr 2026 10:51
URI:	http://fulir.irb.hr/id/eprint/11717
DOI:	10.1016/j.ejps.2023.106461

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