Thermodynamic Study on the Interaction of Ampicillin and Amoxicillin

Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

pubs.acs.org/jced

Thermodynamic Study on the Interaction of Ampicillin and Amoxicillin with Ca2+ in Aqueous Solution at Different Ionic Strengths and Temperatures Ottavia Giuffrè,*,† Sara Angowska,‡ Claudia Foti,† and Silvio Sammartano† †

J. Chem. Eng. Data Downloaded from pubs.acs.org by UNIV DE BARCELONA on 01/09/19. For personal use only.

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 Ca2+−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 Ca2+−ampicillin system and CaLH2 and CaLH for the Ca2+− 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. pL0.5 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 Ca2+ under different conditions of pH, ionic strength, and temperature. For example, pL0.5 = 1.82 and 2.88, for ampicillin and amoxicillin, respectively, were obtained under physiological conditions.

■

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 differences in concentration can cause significant changes in both intracellular 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 properties 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 techniques, potentiometry and spectrophotometry. The potentiometric 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

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 Mg2+-containing species to be more stable than Ca2+ 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 phosphorylation, of dioxygen release in photosynthesis, and of many © XXXX American Chemical Society

Received: November 15, 2018 Accepted: December 26, 2018

A

DOI: 10.1021/acs.jced.8b01081 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Figure 1. Ligands under study.

Table 1. Chemicals chemical name

symbol

(2S,5R,6R)-6-[[(2R)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid, ampicillin anhydrous (2S,5R,6R)-6-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid, amoxicillin trihydrate calcium chloride dihydrate sodium chloride sodium hydroxide hydrochloric acid potassium hydrogen phthalate sodium carbonate ehylenediamine tetraacetic acid disodium salt

different NaCl concentrations to model the dependence of the stability constants on the ionic strength by using a Debye− Hückel type equation, as already done for similar systems.18,19 The sequestering ability of Amp and Amox toward Ca2+ was evaluated under different conditions of pH, temperature, and ionic strength.

purity

source

Amp

analytical standard

Sigma-Aldrich

Amox

analytical standard

Sigma-Aldrich

CaCl2·2H2O NaCl NaOH HCl KHPHTH Na2CO3 EDTA

>99% ≥99.5% Std solution p.a. (fixanal) Std solution p.a. (fixanal) ≥99.5% ≥99.5% >99.5%

Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich

control of the titrant delivery and the electromotive force (emf) stability. The accuracy was estimated to be ±0.02 mL and ±0.20 mV for the readings of titrant volume and for the emf, respectively. Different experimental conditions were employed for the two systems. For the Ca2+−Amp system, CM = (1 to 4) mmol kg−1 and CL = (2 to 6) mmol kg−1 at metal/ligand ratios from 1:1 to 1:3. For the Amox containing systems, CM = (2 to 4) mmol kg−1 and CL = (3 to 4) mmol kg−1, with different metal/ ligand ratios (from 1:1 to 1:2). The solutions containing the ligand, the metal cation, and sodium chloride were titrated with standard solutions of sodium hydroxide in the pH range from 2.5 to 10.19 Titrations of hydrochloric acid solutions with standard sodium hydroxide were performed to obtain the formal electrode potential under the same experimental conditions of ionic strength and temperature of the corresponding measurement. The concentration scale of free hydrogen ion was employed (pH = −log[H+]). To avoid O2 and CO2, pure N2 was bubbled in the titration cells. The solutions were magnetically stirred during the titration. UV-Spectrophotometric Measurements. A Varian Cary 50 UV−vis spectrophotometer with an optic fiber probe was used to perform the UV spectrophotometric measurements. The software Cary WinUV from Varian (version 3.00) was employed. A thermostated cell with a volume of 25 mL was used, and a combined metrosensor glass electrode from Metrohm (602 Biotrode) was connected to a potentiometric system (described in the previous section and in other papers).18,19 In this way, data of A versus λ (nm) and emf (mV) versus the volume of titrant (mL) were recorded for each point of the titration.

■

EXPERIMENTAL SECTION Materials and Methods. The solutions of calcium chloride were prepared without further purification from the Sigma-Aldrich product. These solutions were standardized against standard solutions of EDTA. The solutions of sodium hydroxide and hydrochloric acid were prepared from concentrated ampules and were standardized against potassium hydrogen phthalate and sodium carbonate, respectively. Aqueous solutions of sodium chloride were prepared by weighing pure salt previously dried in an oven at T = 383.15 K. Solutions of Amp and Amox were prepared from the SigmaAldrich product and titrated by alkalimetry to check their purity (>99%).18 All chemicals used, symbols, purity, and source are reported in Table 1. All solutions were prepared daily using ultrapure water (conductivity 0, then eq 1 refers to protonation equilibria of the ligand. The processing of the experimental potentiometric data included various computational trials considering different speciation models for the Ca2+−Amp system. Some examples of these trials are shown in Table 2, together with ones referring to the Ca2+−Amox system. For the choice of the most reliable speciation model, several factors were taken into account, such as the simplicity of the model, the formation percentages of the formed species, the statistical parameters (namely, mean and standard deviation on the fit), and the variance ratio between the accepted model and the others.26,27 The best speciation model, at the different temperatures and ionic strengths employed, includes two species, namely, CaLH and CaL. The results obtained, in terms of the speciation model and the formation constant values of complex species at the different temperatures and ionic strengths, are shown in Table 3. The speciation diagram referring to the system Ca2+− Amp (T = 298.15 K and I = 0.15 mol kg−1 in NaCl) is reported

■

RESULTS AND DISCUSSION Ligand Protonation Constants and Calcium Hydrolysis Constants. The protonation constants of the ligands and the hydrolysis constants of Ca2+ were taken into account in the calculations for the determination of formation constants of Ca2+−Amp and −Amox complex species. The acid−base properties of Amp and Amox, including spectral properties in the UV region, were previously investigated.21 Table 1S shows C



Article

in Figure 2. The speciation diagrams at the different temperatures for this system are reported in Figure 1S. In

Figure 3. Molar absorbances of Ca2+−Amp complex species and Amp species at T = 298.15 K and I = 0.15 mol kg−1 in NaCl.

Table 5. Maximum Values of Molar Extinction Coefficients and Wavelengths Corresponding to the Individual Ca2+− Amp Species at T = 298.15 K and I = 0.15 mol kg−1 in NaCl Figure 2. Speciation diagram of the system Ca2+−Amp(L) (charges omitted for simplicity) at CM = 2 mmol kg−1 and CL = 4 mmol kg−1, I = 0.15 mol kg−1 in NaCl, and T = 298.15 K.

the wide pH range from 2 to 7, the main species is the CaLH, reaching formation percentages of ∼25%. In the alkaline pH range from 8 to 9, the CaL species predominates with formation percentages >20%. To confirm the speciation model as well as the formation constant values of the Ca2+−Amp species, spectrophotometric titrations were also performed, as already done for several other systems.28−32 With the spectrophotometry, it was possible to use lower ligand concentrations with respect to potentiometry. Spectrophotometric measurements confirmed the speciation model including the two species CaLH and CaL for the Ca2+−Amp system. The formation constant values of these species obtained from the spectrophotometric titrations are collected in Table 4. The comparison evidences the very

a

ligand Amp Amox

spectrophotometry 9.20 1.8 19.5 12.5

± ± ± ±

0.09 0.1 0.3 0.1

potentiometry 9.17 1.86 19.56 12.15

± ± ± ±

εmaxa,b

λc

CaLH CaL CaLH2

Amp

6478 ± 340 14 000 ± 750 10 197 ± 420 6838 ± 120 921 ± 32 12 501 ± 330 5 870 ± 93 1443 ± 32

202 202 207 231 274 207 231 274

Amox

In L mol−1 cm−1. b95% C.I. cIn nanometers

Formation of Ca2+−Amoxicillin Species. The elaboration of experimental potentiometric data allowed us to obtain a speciation model, with the best statistical fit, including the two species CaLH2 and CaLH. This model resulted in being identical to that obtained for the system containing Amox and the cation Mg2+.20 The analysis of the potentiometric data provided the results listed in Table 3 at T = (288.15 to 310.15) K and at I = (0.15 to 1) mol kg−1. From the comparison of the stability constants referring to the species containing Amox with Amp, it emerged that the former are a little more stable than the latter. As an example, referring to the partial reaction for CaLH species (Ca + LH = CaLH, charges omitted for simplicity), log K = 2.59 and 2.12 for Amox and Amp, respectively (I = 0.15 mol kg−1, T = 298.15 K). Figure 4 shows the speciation diagrams of the Ca2+−Amox system at different temperatures, evidencing high percentages of formation of both of the species. For example, in the pH range from 2 to 7, the CaLH2 species predominates, reaching a formation percentage of >70% at T = 310.15 K and I = 0.15 mol kg−1. In the pH range from 7.5 to 9, the main species is the CaLH one, with a maximum formation percentage of >50%. This underlines that at physiological pH, the CaLH2 and CaLH species coexist with equal amounts, reaching formation percentages of ∼35%. The spectra recorded at different pH values are shown in Figure 5. Amox-containing solutions absorb in the UV region from 220 to 310 nm, whereas Amp ones do not absorb (precisely in the range from 250 to 310 nm). This can be attributed to the auxochrome effect of the phenolic group

log βa,b species

ligand

CaLH

Table 4. Comparison between Experimental Formation Constants of Ca2+−Amp and −Amox Species Obtained by Spectrophotometry and Potentiometry at T = 298.15 K and I = 0.15 mol kg−1

CaLH CaL CaLH2 CaLH

species

0.01 0.04 0.02 0.02

a

Refer to reaction 1; charges are omitted for simplicity. b95% C.I.

good agreement between the results of the two techniques. The molar absorbances of complex species of the Ca2+−Amp system are shown in Figure 3. The maximum values of the molar extinction coefficients of the single species formed in the Ca2+−Amp system and the corresponding wavelengths at T = 298.15 K and I = 0.15 mol kg−1 in NaCl are collected in Table 5. D



Article

Figure 5. Experimental UV spectra of Ca2+−Amox solutions at different pH values, CM = CL = 0.1 mmol kg−1, T = 298.15 K, and I = 0.15 mol kg−1.

present in the Amox molecule. Figure 5 shows that with the increase in the pH, absorbance increases at λ = 207 and 274 nm and decreases at λ = 231 nm. The spectrophotometric results confirmed the speciation model for the Ca2+−Amox system, which includes the two CaLH2 and CaLH species. The formation constant values of these two species obtained from the spectrophotometric measurements are shown in Table 4. They fully confirm the potentiometric findings, evidencing a good agreement between the results obtained by the two techniques, especially for CaLH2 species. The molar absorbances of Ca2+−Amox species are shown in Figure 6. Table 5 reports the maximum values of ε of the Ca2+−Amox species and the corresponding wavelengths at T = 298.15 K and I = 0.15 mol kg−1 in NaCl.

Figure 6. Molar absorbances of Ca2+−Amox complex species and Amox species at T = 298.15 K and I = 0.15 mol kg−1 in NaCl.

Dependence on Ionic Strength and Temperature. The dependence on the ionic strength of the stability constants of the Ca2+−Amp and −Amox systems was analyzed by the following Debye−Hückel type equation33−37

Figure 4. Speciation diagrams of the system Ca2+−Amox(L) (charges omitted for simplicity) at CM = 2 mmol kg−1 and CL = 4 mmol kg−1, I = 0.15 mol kg−1 in NaCl, and (A) T = 288.15 K, (B) T = 298.15 K, and (C) T = 310.15 K. E


Journal of Chemical & Engineering Data log β = log Τ β − 0.51z*

I + CI 1 + 1.5 I

Article

(2)

where β and β are the stability constants at a given ionic strength and at infinite dilution, respectively, C is an empirical parameter, and z* = ∑(charge)reactants2 − ∑(charge)products2. The dependence on the temperature of the formation constants and the calculation of the enthalpy change values of the complexes was modeled by the van’t Hoff equation, as already done for other systems38 T

log βT = log βθ + ΔH °(1/θ − 1/T )R ln 10

(3)

where log βT is the stability constant at a specific temperature (expressed in Kelvin) and ionic strength and log βθ is the stability constant at T = 298.15 K, R = 8.314472 J K−1 mol−1 if ΔH0 is in kJ mol−1. The formation constants of Ca2+−Amp and −Amox species were recalculated by applying eqs 2 and 3, taking into account the dependence on ionic strength and temperature, to the experimental data obtained by both potentiometry and spectrophotometry. The speciation diagrams at different ionic strength in NaCl and T = 298.15 K for both the ligands are shown in Figures 7 and 8. The thermodynamic formation constants and the C parameter for the dependence on the ionic strength, on the basis of a Debye−Hückel type equation (eq 2), for Ca2+−Amp and −Amox species are listed in Table 6. For example, C values for MLH2 and MLH species referring to the Ca2+−Amox system are 1.5 and 1.2, respectively, at T = 298.15 K, resulting in almost identical Mg2+−Amp values (1.59 and 1.27 for MLH2 and MLH, respectively, under the same conditions).20 The enthalpy change values obtained by van’t Hoff equation are listed in Table 7 with ΔG0 and TΔS0 values. These results, in particular, for Ca2+−Amox species, are close to those Mg2+− Amox species.20 For example, for MLH2 and MLH species referring to Amox, ΔH0 = −59 and −42 kJ mol−1 for Ca2+ (at T = 298.15 K and I = 0.15 mol kg−1; see Table 7) and ΔH0 = −53.5 and −38.2 for Mg2+ (at T = 298.15 K and I = 0 mol kg−1).20 In Table 3S are reported partial thermodynamic parameters for both Ca2+−Amp and −Amox species, calculated according to the equations Ca + LHi = CaLHi and Ca + L = CaL (charges omitted for simplicity). Figure 9 shows the bar plots of these parameters, evidencing that they are small and the main contribution to the free energy is the entropic one (except for CaAmoxH species). Sequestering Ability. The efficacy of a ligand, which can be used as a sequestering agent toward metal cations, is a function not only of its binding ability but also of the speciation both of the ligand and the cations under certain conditions. In real multicomponent systems, such as biological fluids, many interfering cations and ligands are present, giving rise to many competing reactions with the metal cation and binding agents of interest and significantly influencing the sequestration process. For example, the knowledge of the ability of a specific ligand to sequester a toxic metal cation is crucial to assess its utilization as a detoxificant agent, as already described in several papers.39,40 The binding capacity of a ligand toward different cations cannot be defined only by the comparison of the stability constants and the percentages of formation of the species. It is significantly influenced by several parameters, such as ionic strength, pH, temperature, and reactions such as metal hydrolysis, ligand protonation, and other interactions.19

Figure 7. Speciation diagrams of the system Ca2+−Amp(L) (charges omitted for simplicity) at CM = 2 mmol kg−1 and CL = 4 mmol kg−1, T = 298.15 K in NaCl, and (A) I = 0.15 mol kg−1, (B) I = 0.5 mol kg−1, and (C) I = 1 mol kg−1. F



Article

Table 6. Thermodynamic Parameters of Ca2+−Amp and − Amox Species at T = 298.15 K and I = 0 mol kg−1

a

species

ligand

CaLH CaL CaLH2 CaLH

Amp Amox

log βTa,b 9.30 2.14 20.05 12.99

± ± ± ±

C

0.01 0.03 0.08 0.08

0.74 1.40 1.5 1.2

± ± ± ±

0.02 0.04 0.1 0.1

Refer to reaction 1; charges are omitted for simplicity. b95% C.I.

Table 7. Thermodynamic Parameters of Ca2+−Amp and −Amox Species at T = 298.15 K and I = 0.15 mol kg−1 species

ligand

−ΔG0a,b

CaLH CaL CaLH2 CaLH

Amp

52.3 10.6 111.6 69.4

Amox

ΔH0a,b,c −41 3 −59 −42

± ± ± ±

2 5 8 7

TΔS0a,b 11 13 53 27

Refer to reaction 1; charges are omitted for simplicity. bIn kJ mol−1. 95% C.I.

a c

Accordingly, this research group proposed an empirical parameter, pL0.5, which takes into account the factors cited above for the purpose of quantitatively assessing the binding capacity of a ligand toward a metal cation. pL0.5 is the ligand concentration (as cologarithm), under the investigated conditions, able to bind 50% of the metal cation present in trace. To calculate pL0.5 parameter, a Boltzmann-type equation with asymptotes of 0 for pL → 0 and 1 for pL → ∞ is employed41−43 1 χ= (4) 1 + 10(pL − pL0.5) where χ is the sum of molar fractions of the species and pL represents the cologarithm of the total concentration of the ligand. Calculated values of pL0.5 referring to Ca2+−Amp and −Amox systems under different conditions of pH, temperature, and ionic strength are listed in Table 8. At pH 7.4, T = 310.15 K, and I = 0.15 mol kg−1, the calculated values are pL0.5 = 1.82 and 2.88 for Amp and Amox, respectively. Under these conditions, Amox displays a higher ability to sequester Ca2+ with respect to Amp, as shown in Table 8 and Figure 10. This trend was also observed with Mg2+, although the difference in terms of sequestering ability between Amp and Amox is much smaller than that toward Ca2+. In more detail, for Mg2+ at pH 7.4, T = 310.15 K, and I = 0.15 mol kg−1, the values are pL0.5 = 2.52 and 2.78 for Amp and Amox, respectively. Another comparison that can be made is with Zn2+; under the same conditions, pL0.5 = 3.16 and 2.88 for Amp and Amox, respectively. Another peculiarity to underline is that the Amox shows an almost equal sequestering capacity toward Ca2+, Mg2+, and Zn2+. Literature Comparisons. The main stability constant databases do not report thermodynamic data regarding complexes formed by Ca2+ and Amp.44−46 In the literature, there is only one paper on the complexation of Amp and Amox with different metal cations including Ca2+, Mg2+, Zn2+, Cu2+, and others at T = 293.15 K and unspecified ionic strength.47 It reports formation constant values of different orders of magnitude higher than literature values (for Mg2+, Zn2+, Cu2+) and the values in this paper (for Ca2+). For example, for Amp, referring to ML species, log K = 6.431, 6.312, 5.963, and 6.832 for Ca2+, Mg2+, Zn2+, and Cu2+, respectively. This

Figure 8. Speciation diagrams of the system Ca2+−Amox(L) (charges omitted for simplicity) at CM = 2 mmol kg−1 and CL = 4 mmol kg−1 at (A) I = 0.15 mol kg−1, (B) I = 0.5 mol kg−1, and (C) I = 1 mol kg−1. G



Article

Table 8. pL0.5 values of Amp and Amox towards Ca2+ at Different pH Values, Ionic Strengths in NaCl, and Temperatures ligand

T/K

I/mol kg−1

pH

pL0.5

Amp

298.15 298.15 298.15 298.15 298.15 288.15 310.15 298.15 298.15 298.15 298.15 298.15 288.15 310.15

0.15 0.15 0.15 0.5 1 0.15 0.15 0.15 0.15 0.15 0.5 1 0.15 0.15

5.0 7.4 8.0 7.4 7.4 7.4 7.4 5.0 7.4 8.0 7.4 7.4 7.4 7.4

2.12 1.96 1.89 2.19 2.63 1.90 1.82 2.69 2.63 2.59 2.85 3.20 2.97 2.88

Amox

Figure 10. Sum of the fractions of Ca2+−Amp and -Amox species versus pL at pH 7.4, T = 310.15 K, and I = 0.15 mol kg−1 in NaCl.

Table 9. Formation Constant Values of Amp and Amox Species with Different Metal Cations at T = 298.15 K and I = 0.15 mol kg−1

Figure 9. Bar plots of −ΔG0 (pink), ΔH0 (green), and TΔS0 (violet) referring to the (A) Ca2+−Amp(L) system and (B) Ca2+−Amox(L) system at T = 298.15 K and I = 0.15 mol kg−1 in NaCl (according to the reactions Ca + LHi = CaLHi and Ca + L = CaL; charges are omitted for simplicity).

cation

log KMLHa

log KMLb

references

1.86 2.86 2.96 5.39 log KMLHa

this paper 20 18 19 references

2.59 2.63 2.78

this paper 20 18

Amp

significant discrepancy may also be partly due to the speciation model that provides a single ML species for all metal cation− Amp systems. As far as we know, similar to Ca2+−Amp, in the main databases reporting formation constant values and in the literature there are no thermodynamic data on Ca2+−Amox species.44−46 There is only one paper dealing with the Ca2+− Amox interaction, where a speciation model and the formation constants attributed to species having a certain stoichiometry have not been determined.48 Because of the lack of data in the literature on Ca2+ complexes with Amp and Amox, for comparison purposes, in Table 9 are listed the formation constant values regarding the complex species of these ligands with other divalent cations, such as Mg2+, Zn2+, and Cu2+.18−20 Despite the different nature of these cations, the comparison highlights that Zn2+ has very similar formation constant values as Ca2+ and Mg2+, mainly for MLH species for both of the ligands. As expected, the Cu2+−

Ca2+ Mg2+ Zn2+ Cu2+ cation

2.12 2.54 2.62 2.38 log KMLH2c

Ca2+ Mg2+ Zn2+

2.69 2.25 2.57

Amox

a

According to the reaction M + LH = MLH (charges are omitted for simplicity). bAccording to the reaction M + L = ML (charges are omitted for simplicity). cAccording to the reaction M + LH2 = MLH2 (charges are omitted for simplicity).

Amp (ML) species shows a higher stability with respect to Ca2+, Mg2+, and Zn2+ species; instead, the MLH species has comparable stability for all four cations. H



■

■

CONCLUSIONS The speciation models and the formation constants of the Ca 2+ −Amp and −Amox systems were determined by potentiometry at T = 298.15 K and I = (0.15 to 1) mol kg−1 (in NaCl) and T = (288.15 to 310.15) K and I = 0.15 mol kg−1 (in NaCl). The spectrophotometric titrations at T = 298.15 K and I = 0.15 mol kg−1 fully confirmed the potentiometric findings. The thermodynamic constants of the species and the parameters for the dependence on ionic strength and the enthalpy changes at T = 298.15 K were also obtained. Knowledge of the stability constant values, the speciation model, and the sequestering capacity is of relevant interest. All of the interactions occurring in a system are taken into account by the sequestering capacity of the ligands, defined by pL0.5 empirical parameter. For example, under the physiological conditions of pH, ionic strength, and temperature, the sequestering capacity of Amox toward Ca2+ is higher than a logarithmic unit with respect to Amp, whereas for the MLH common species the difference in terms of the formation constant value is less significant (∼0.5 for the reaction M + LH = MLH; see Table 9). It is just one of the many possible examples that confirm the strong necessity to calculate the sequestering ability taking into account all of the possible interactions in solution as well as the crucial importance of speciation studies. The results here obtained in terms of the quantification of the interactions between Ca2+, a cation of biological relevance, and two ligands of considerable pharmacological importance, such as Amp and Amox, are useful to rationalize and predict the bioavailability of this metal cation and to evaluate the mechanism of action exerted by these ligands.

■

REFERENCES

(1) Di Stefano, R.; Scopelliti, M.; Pellerito, C.; Fiore, T.; Vitturi, R.; Colomba, M. S.; Gianguzza, P.; Stocco, G. C.; Consiglio, M.; Pellerito, L. Organometallic complexes with biological molecules. XVII. Triorganotin(IV) complexes with amoxicillin and ampicillin. J. Inorg. Biochem. 2002, 89, 279−292. (2) Bravo, A.; Anacona, J. R. Synthesis and characterization of metal complexes with ampicillin. J. Coord. Chem. 1998, 44, 173−182. (3) El-Gamel, N. E. A. Metal chelates of Ampicillin versus Amoxcillin: Synthesis, structural investigation and biological studies. J. Coord. Chem. 2010, 63, 534−543. (4) Hamelink, J. M.; Rudolph, E. S. J.; van der Wielen, L. A. M.; Vera, J. H. Activity coefficients of antibiotics in aqueous NaCl solutions at 298.2 K. Biophys. Chem. 2002, 95, 97−108. (5) Imran, M.; Iqbal, J.; Mehmood, T.; Latif, S. Synthesis, characterization and in vitro screening of amoxicillin and its complexes with Ag(I), Cu(II), Co(II), Zn(II) and Ni(II). J. Biol. Sci. 2006, 6, 946−949. (6) Gutiérez Navarro, P.; El Bekkouri, A.; Rodriguez Reinoso, E. Spectrofluorimetric study of the degradation of [small alpha]-amino [small beta]-lactam antibiotics catalysed by metal ions in methanol. Analyst 1998, 123, 2263−2266. (7) Navarro, P. G.; Blazquez, I. H.; Osso, B. Q.; Martinez de las Parras, P. J.; Puentedura, M. I. M.; Garcia, A. A. M. Penicillin degradation catalysed by Zn(II) ions in methanol. Int. J. Biol. Macromol. 2003, 33, 159−166. (8) Marquez Garcia, A.; Gutiérrez Navarro, P.; Martinez de las Parras, P. J. Degradation of ampicillin in the presence of cadmium(II) ions. Talanta 1998, 46, 101−109. (9) Sher, A.; Veber, M.; Marolt-Gomiscek, M.; Gomiscek, S. Complexation of copper(II) ions with ampicillin I: Spectroscopic and electrochemical investigation of interactions under equilibrium conditions. Int. J. Pharm. 1993, 90, 181−186. (10) Shoukry, M. M. Potentiometric studies of binary and ternary complexes of amoxycillin. Talanta 1992, 39, 1625−1628. (11) Zayed, M. A.; Abdallah, S. M. Synthesis and structure investigation of the antibiotic amoxicillin complexes of d-block elements. Spectrochim. Acta, Part A 2005, 61, 2231−2238. (12) Kupka, T. β-Lactam antibiotics. Spectroscopy and molecular orbital (MO) calculations: Part I: IR studies of complexation in penicillin-transition metal ion systems and semi-empirical PM3 calculations on simple model compounds. Spectrochim. Acta, Part A 1997, 53, 2649−2658. (13) Proctor, P.; Gensmantel, N. P.; Page, M. I. The chemical reactivity of penicillins and other [small beta]-lactam antibiotics. J. Chem. Soc., Perkin Trans. 2 1982, 2, 1185−1192. (14) Frausto da Silva, J. J. R.; Williams, R. J. P. The Principles of the Uptake and Chemical Speciation of the Elements in Biology. In The Biological Chemistry of the Elements: The Inorganic Chemistry of Life; Oxford University Press: 2001; Chapter 2, pp 29−82. (15) Frausto da Silva, J. J. R.; Williams, R. J. P. Calcium: Controls and Triggers. In The Biological Chemistry of the Elements: The Inorganic Chemistry of Life; Oxford University Press: 2001; Chapter 10, pp 278−314. (16) Peterlik, M.; Stoeppler, M. Calcium. In Elements and Their Compounds in the Environment; Merian, E., Anke, M., Ihnat, M., Stoeppler, M., Eds.; WILEY-VCH: Weinheim, Germany, 2004; Vol. 2, Chapter 2.3, pp 599−618. (17) Whedon, G. D. Recent Advances in Management of Osteoporosis. In Phosphate and Mineral in Health and Disease; Massry, S. G., Ritz, E., Jahn, H., Eds.; Advances in Experimental Medicine and Biology 128; Springer: Boston, 1980; pp 600−613. (18) Cardiano, P.; Cigala, R. M.; Crea, F.; De Stefano, C.; Giuffrè, O.; Sammartano, S.; Vianelli, G. Potentiometric, UV and 1H NMR study on the interaction of penicillin derivatives with Zn(II) in aqueous solution. Biophys. Chem. 2017, 223, 1−10. (19) Cardiano, P.; Crea, F.; Foti, C.; Giuffrè, O.; Sammartano, S. Potentiometric, UV and 1H NMR study on the interaction of Cu2+

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.8b01081. Table 1S. Protonation constants of Amp and Amox at different temperatures and ionic strength in NaCl. Table 2S. Hydrolysis constants of CaOH+ species at different temperatures and ionic strength in NaCl. Table 3S. Thermodynamic parameters of Ca2+−Amp and −Amox species at T = 298.15 K and I = 0.15 mol kg−1. Figure 1S. Speciation diagrams of the system Ca2+−Amp(L) (charges omitted for simplicity) at CM = 2 mmol kg−1 and CL = 4 mmol kg−1, I = 0.15 mol kg−1 in NaCl, and T = 288.15 K, T = 298.15 K, and T = 310.15 K (PDF)

■

Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: ogiuff[email protected]. ORCID

Ottavia Giuffrè: 0000-0002-8486-8733 Funding

O.G. and C.F. thank MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca) for financial support (cofunded PRIN project with Prot. 2015MP34H3). Notes

The authors declare no competing financial interest. I



Article

with ampicillin and amoxicillin in aqueous solution. Biophys. Chem. 2017, 224, 59−66. (20) Cigala, R. M.; Crea, F.; De Stefano, C.; Sammartano, S.; Vianelli, G. Thermodynamic Parameters for the Interaction of Amoxicillin andAmpicillin with Magnesium in NaCl Aqueous Solution, at Different Ionic Strengths and Temperatures. J. Chem. Eng. Data 2017, 62, 1018−1027. (21) Crea, F.; Cucinotta, D.; De Stefano, C.; Milea, D.; Sammartano, S.; Vianelli, G. Modelling solubility, acid−base properties and activity coefficients of amoxicillin, ampicillin and (+)6-aminopenicillanic acid, in NaCl(aq) at different ionic strengths and temperatures. Eur. J. Pharm. Sci. 2012, 47, 661−677. (22) De Stefano, C.; Sammartano, S.; Mineo, P.; Rigano, C. Computer Tools for the Speciation of Natural Fluids. In Marine Chemistry - An Environmental Analytical Chemistry Approach; Gianguzza, A., Pelizzetti, E., Sammartano, S., Eds.; Kluwer Academic Publishers: Amsterdam, 1997; pp 71−83. (23) Alderighi, L.; Gans, P.; Ienco, A.; Peters, D.; Sabatini, A.; Vacca, A. Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species. Coord. Chem. Rev. 1999, 184, 311−318. (24) Gans, P.; Sabatini, A.; Vacca, A. Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs. Talanta 1996, 43, 1739−1753. (25) Gans, P.; Sabatini, A.; Vacca, A. Determination of equilibrium constants from spectrophometric data obtained from solutions of known pH: THE PROGRAM pHab. Ann. Chim. (Rome, Italy) 1999, 89, 45−49. (26) Furia, E.; Napoli, A.; Tagarelli, A.; Sindona, G. Speciation of 2hydroxybenzoic acid with Calcium(II), Magnesium(II), and Nickel(II) Cations in self-medium. J. Chem. Eng. Data 2013, 58, 1349− 1353. (27) Filella, M.; May, P. M. Reflections on the calculation and publication of potentiometrically-determined formation constants. Talanta 2005, 65, 1221−1225. (28) Cardiano, P.; De Stefano, C.; Giuffrè, O.; Sammartano, S. Thermodynamic and spectroscopic study for the interaction of dimethyltin(IV) with L-cysteine in aqueous solution. Biophys. Chem. 2008, 133, 19−27. (29) Falcone, G.; Giuffrè, O.; Sammartano, S. Acid-base and UV properties of some aminophenol ligands and their complexing ability towards Zn2+ in aqueous solution. J. Mol. Liq. 2011, 159, 146−151. (30) De Stefano, C.; Foti, C.; Giuffrè, O.; Sammartano, S. Acid-base and UV behaviour of 3-(3,4-dihydroxyphenyl)-propenoic acid (caffeic acid) and complexing ability towards different divalent metal cations in aqueous solution. J. Mol. Liq. 2014, 195, 9−16. (31) Beneduci, A.; Furia, E.; Russo, N.; Marino, T. Complexation behaviour of caffeic, ferulic and p-coumaric acids towards aluminium cation: a combined experimental and theoretical approach. New J. Chem. 2017, 41, 5182−5190. (32) Cardiano, P.; Giacobello, F.; Giuffrè, O.; Sammartano, S. Thermodynamic and spectroscopic study of Al3+ interaction with glycine, L-cysteine and tranexamic acid in aqueous solution. Biophys. Chem. 2017, 230, 10−19. (33) Cardiano, P.; Giacobello, F.; Giuffrè, O.; Sammartano, S. Thermodynamic and spectroscopic study on Al3+-polycarboxylate interaction in aqueous solution. J. Mol. Liq. 2017, 232, 45−54. (34) Cardiano, P.; Giacobello, F.; Giuffrè, O.; Sammartano, S. Thermodynamics of Al3+-thiocarboxylate interaction in aqueous solution. J. Mol. Liq. 2016, 222, 614−621. (35) Foti, C.; Giuffrè, O.; Sammartano, S. Thermodynamics of HEDPA protonation in different media and complex formation with Mg2+ and Ca2+. J. Chem. Thermodyn. 2013, 66, 151−160. (36) Cardiano, P.; Giuffrè, O.; Pellerito, L.; Pettignano, A.; Sammartano, S.; Scopelliti, M. Thermodynamic and spectroscopic study of the binding of dimethyltin(IV) by citrate at 25°C. Appl. Organomet. Chem. 2006, 20, 425−435. (37) Crea, F.; Crea, P.; De Stefano, C.; Giuffrè, O.; Pettignano, A.; Sammartano, S. Thermodynamic Parameters for the Protonation of

Poly(allylamine) in concentrated LiCl(aq) and NaCl(aq). J. Chem. Eng. Data 2004, 49, 658−663. (38) Bretti, C.; Cigala, R. M.; Giuffrè, O.; Lando, G.; Sammartano, S. Modeling solubility and acid-base properties of some polar side chain amino acids in NaCl and (CH3)4NCl aqueous solutions at different ionic strengths and temperatures. Fluid Phase Equilib. 2018, 459, 51− 64. (39) Cardiano, P.; Falcone, G.; Foti, C.; Giuffrè, O.; Napoli, A. Binding ability of glutathione towards alkyltin(IV) compounds in aqueous solution. J. Inorg. Biochem. 2013, 129, 84−93. (40) Cardiano, P.; Falcone, G.; Foti, C.; Giuffrè, O.; Sammartano, S. Methylmercury(II)-sulphur containing ligand interactions: a potentiometric, calorimetric and 1H-NMR study in aqueous solution. New J. Chem. 2011, 35, 800−806. (41) Cardiano, P.; Foti, C.; Giacobello, F.; Giuffrè, O.; Sammartano, S. Study of Al3+ interaction with AMP, ADP and ATP in aqueous solution. Biophys. Chem. 2018, 234, 42−50. (42) Aiello, D.; Cardiano, P.; Cigala, R. M.; Gans, P.; Giacobello, F.; Giuffrè, O.; Napoli, A.; Sammartano, S. Sequestering Ability of Oligophosphate Ligands toward Al3+ in Aqueous Solution. J. Chem. Eng. Data 2017, 62, 3981−3990. (43) Gianguzza, A.; Giuffrè, O.; Piazzese, D.; Sammartano, S. Aqueous solution chemistry of alkyltin(IV) compounds for speciation studies in biological fluids and natural waters. Coord. Chem. Rev. 2012, 256, 222−239. (44) May, P. M.; Murray, K. Database of chemical reactions designed to achieve thermodynamic consistency automatically. J. Chem. Eng. Data 2001, 46, 1035−1040. (45) Pettit, L. D.; Powell, K. J. IUPAC Stability Constants Database; IUPAC: 2001. (46) Martell, A. E.; Smith, R. M.; Motekaitis, R. J. NIST Critically Selected Stability Constants of Metal Complexes Database; National Institute of Standard Technology: Gaithersburg, MD, 2004. (47) Orabi, A. S. Physicochemical Properties of Ampicillin and Amoxicillin as Biologically Active Ligands with Some Alkali Earth, Transition Metal, and Lanthanide Ions in Aqueous and Mixed Solvents at 20, 30, and 40°C. J. Solution Chem. 2005, 34, 95−111. (48) Sultana, N.; Nath, A. K.; Islam, M. M.; Das, J. In vitro interaction of Amoxicillin with Calcium Chloride (Fused) at pH 2.4 and pH 7.4. J. Appl. Pharm. Sci. 2015, 5, 98−101.

J


Thermodynamic Study on the Interaction of Ampicillin and Amoxicillin

Recommend Documents