Thermodynamic Study on the Interaction of Ampicillin and Amoxicillin with Ca 2+ in Aqueous Solution at Different Ionic Strengths and Temperatures Ottavia Giuffre ̀ ,* ,† Sara Angowska, ‡ Claudia Foti, † and Silvio Sammartano † † Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy ‡ Department of Pharmaceutical Chemistry, Poznań University of Medical Sciences, ul. Grunwaldzka 6, 60-780 Poznań , Poland * S Supporting Information ABSTRACT: A potentiometric and UV spectrophotometric study on Ca 2+ -ampicillin and -amoxicillin systems in NaCl aqueous solution is reported. The potentiometric investigation was carried out at different ionic strengths, I = (0.15 to 1) mol kg -1 , and temperatures, T = (288.15 to 310.15) K. The most reliable speciation models include two species, namely, CaLH and CaL for the Ca 2+ -ampicillin system and CaLH 2 and CaLH for the Ca 2+ - amoxicillin system. The spectrophotometric results obtained for both of the systems are fully consistent with potentiometric ones, confirming the formation as well as the stability of the complex species. The dependence of formation constants of the species on ionic strength over the range I = (0.15 to 1) mol kg -1 in NaCl and on temperature over the range T = (288.15 to 310.15) K is also reported. pL 0.5 empirical parameter (i.e., the concentration of ligand required to bind 50% of the metal cation present in the trace) was employed to evaluate the ability of both of the ligands to sequester Ca 2+ under different conditions of pH, ionic strength, and temperature. For example, pL 0.5 = 1.82 and 2.88, for ampicillin and amoxicillin, respectively, were obtained under physiological conditions. ■ INTRODUCTION Penicillins are a very important class among β-lactamic antibiotics for their considerable activity against bacteria, assuming an essential biological role in the treatment of several diseases. 1,2 In recent years, the chemistry of this antibiotic class has aroused significant interest in relation to its biological activities. 3,4 It has been known that all β-lactamic antibiotics interact in in vivo systems with several metal cations, forming metal complex species, 1 and their bioavailability can be enhanced or reduced owing to the interaction with metal cations. 5-10 Therefore, it is crucial to assess the chemical interaction of penicillins with some important metal cations having biological roles in the human body. 11 The assessment of the interactions between penicillins and a biologically relevant metal cation, such as calcium, is of crucial importance for understanding the in vivo mode of action of these ligands. 12 Among them, ampicillin and amoxicillin are semisynthetic derivatives of penicillin, active as broad-spectrum antibiotics. 13 In general, the stability of complex species depends on the ionic potential of the metal ion (z/r) as well as steric hindrance, covalence, and other specific factors. 14 In particular, for alkaline-earth metals, the order of stability based on ionic radii of metal cations causes the Mg 2+ -containing species to be more stable than Ca 2+ species. 14 Some inversions of order occur, for example, with very small anions depending on the type of ligands used. 14 The role of calcium in metabolism includes the control of dehydrogenases in oxidative phosphor- ylation, of dioxygen release in photosynthesis, and of many kinase reactions. 14 The effective free calcium concentration in the cell is in the range 10 -6 to 10 -8 mol kg -1 , and in the sarcoplasme it is close to 10 -3 mol kg -1 . 15 Only free calcium results effective in the regulation of the cellular processes. 16 The total extracellular calcium is 2.5 mmol kg -1 ; ∼50% is present as free ion, 40% is complexed by plasma proteins, and 10% is bound to citrate and phosphate. 16 The main donor groups to the calcium cation from proteins are carbonyl and carboxylate centers. 15 The rigid control of plasma free calcium is very important because even small di fferences in concentration can cause significant changes in both intra- cellular free calcium as well as the skeletal site, with unavoidable consequences on bone health. 16,17 This paper is part of larger research on the ampicillin (Amp) and amoxicillin (Amox) acid-base and complexation proper- ties with different metal cations in aqueous solution. 18-21 Ligands under study are reported in Figure 1. In this study, the experimental measurements were performed by two techni- ques, potentiometry and spectrophotometry. The potentio- metric investigations were carried out at different ionic strengths in the range I = (0.15 to 1) mol kg -1 in NaCl and at different temperatures, T = (288.15 to 310.15) K. The UV spectrophotometric titrations were carried out at T = 298.15 K and I = 0.15 mol kg -1 in NaCl. This study was performed at Received: November 15, 2018 Accepted: December 26, 2018 Article pubs.acs.org/jced Cite This: J. Chem. Eng. Data XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.jced.8b01081 J. Chem. Eng. Data XXXX, XXX, XXX-XXX J. Chem. Eng. Data Downloaded from pubs.acs.org by UNIV DE BARCELONA on 01/09/19. For personal use only.