Potentiometric titration method has been used to define stoichiometries and stability constants of ternary complexes of Cu(II) with duloxetine (D) and some selected amino acids (L). The protonation constants of the ligands and the stability constants of the binary and ternary complexes of Cu(II) with the ligands were calculated from the potentiometric data using the HYPERQUAD program. The formation constants of the complexes formed in aqueous solutions and their concentration distributions as a function of pH were evaluated at 25°C and ionic strength 0.10 mol·L−1 NaNO3. Respective stabilities of ternary complexes have been determined compared with the corresponding binary complexes in terms of
Drugs are naturally occurring or synthetic, which contain oxygen or sulfur or nitrogen atoms in their functional groups. They form complexes with metal ions either initially or after metabolic changes in the body to form stable five- or six-membered rings. The ever-increasing importance of ternary complexes especially those involving ligands containing functional groups identical with those present in enzymes, namely, -COOH, - NH2, and -CONH, is obvious from the application of such complexes in many analytical and biological reactions [
Duloxetine is the most recent serotonin and norepinephrine reuptake inhibitor (SSNRI) drug introduced for the therapy of depression [
Chemical structure of duloxetine (D).
All chemicals used in this study were of the highest purity available and were used without any further purification. Duloxetine (D) and amino acids (glycine (Gly), alanine (Ala),
Potentiometric titration was done at 25 ± 0.1°C through double-walled glass vessel (Griffin pH J-300-010G Digital pH meter was used). Electrode systems were calibrated via concentration scale, where pH must be unstated as of −log [H+] through the course of study. Ionic strength remained constant (0.1 mol·L−1), and this constant pH was achieved through NaNO3 solution (40 ml used in each titration).
Equilibrium reaction in the system was determined, which may be presented as generic expression:
This is being defined as follows:
Formation constant was calculated through the HYPERQUAD computer program [
Speciation was calculated via the HYSS program [
The duloxetine drug (D) (2.23 g; 7.53 mmol) was dissolved in 20 mL of ethanol, and then 1.68 g (7.53 mmol) of Cu(NO3)2·2H2O dissolved in 20 mL of ethanol was added dropwise, and the reaction mixture was stirred and heated at 50°C for 3 h. The solvent was allowed to evaporate slowly to produce a solid. The resultant product was collected by filtration and washed with ethanol and diethylether to get the pure complex.
Brown; yield, solid 83%; m.p.: >300°C; % found (calculated) [C18H20ClCuNO2S (M.Wt. = 413.4)]: C = 52.21 (52.30), H = 4.73 (4.88), N = 3.26 (3.39), Cl = 8.27 (8.57), S = 7.57 (7.75), and Cu = 15.32 (15.37);
An appropriate amount of Cu(NO3)2·2H2O (1.68 g, 7.53 mmol) is dissolved in hot ethanol (20 mL), which was further mixed with a boiling ethanolic solution (20 mL) of duloxetine drug (D) (2.23 g, 7.53 mmol) followed by addition of glycine (Gly) (0.57 g, 7.53 mmol). The mixture was heated on a water bath for about 3 h and filtered. The filtrate was left to stand overnight, yielding shining deep brown crystals of the complex, which were filtered off. The resultant product was collected by filtration and washed with ethanol and diethylether to get the pure complex.
Deep brown; yield, solid 85%; m.p.: >300°C; % found (calculated) [C20H22CuN2O3S (M.Wt. = 434.0)]: C = 55.29 (55.35), H = 4.93 (5.11), N = 6.37 (6.45), S = 7.24 (7.39), and Cu = 14.58 (14.64);
Potentiometric titration data were used for protonation coefficients (log10
The protonation constants of the ligands at 25°C and 0.10 mol·L−1 ionic strength.
System |
|
|
|
---|---|---|---|
Duloxetine (D) | 9.34 (0.01) | ||
Glycine (Gly) | 9.61 (0.02) | 2.48 (0.02) | |
Alanine (Ala) | 9.80 (0.01) | 2.82 (0.03) | |
Valine (Val) | 9.68 (0.00) | 2.50 (0.01) | |
Proline (Pro) | 10.65 (0.009) | 2.53 (0.01) | |
|
9.20 (0.01) | 2.61 (0.03) | |
S-Methylcysteine (Met) | 8.65 (0.02) | ||
Threonine (Thr) | 9.06 (0.009) | 2.01 (0.03) | |
Ornithine (Orn) | 10.58 (0.03) | 8.99 (0.04) | 1.55 (0.05) |
Lysine (Lys) | 10.44 (0.01) | 9.22 (0.02) | |
Histidine (Hisd) | 9.48 (0.01) | 6.28 (0.01) | 2.16 (0.04) |
Histamine (Hist) | 9.88 (0.03) | 6.06 (0.05) | |
Imidazole (Imz) | 7.06 (0.01) |
Standard deviations are given in parentheses.
Stability coefficients of Cu(II) complexes of the binary system at 25°C and 0.10 mol·L−1 ionic strength.
Systems |
|
|
|
|
log |
---|---|---|---|---|---|
Cu(II)-D | 1 | 1 | 0 | 0 | 8.07 (0.003) |
1 | 2 | 0 | 0 | 12.65 (0.01) | |
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Cu(II)-Gly | 1 | 0 | 1 | 0 | 8.15 (0.02) |
1 | 0 | 2 | 0 | 14.89 (0.04) | |
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Cu(II)-Ala | 1 | 0 | 1 | 0 | 8.13 (0.03) |
1 | 0 | 2 | 0 | 14.77 (0.05) | |
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Cu(II)-Val | 1 | 0 | 1 | 0 | 8.11 (0.02) |
1 | 0 | 2 | 0 | 14.73 (0.03) | |
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CuII-Prol | 1 | 0 | 1 | 0 | 8.60 (0.03) |
1 | 0 | 2 | 0 | 15.97 (0.05) | |
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Cu(II)-Phe | 1 | 0 | 1 | 0 | 8.35 (0.02) |
1 | 0 | 2 | 0 | 14.25 (0.03) | |
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Cu(II)-Met | 1 | 0 | 1 | 0 | 8.10 (0.01) |
1 | 0 | 2 | 0 | 14.81 (0.02) | |
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Cu(II)-Thr | 1 | 0 | 1 | 0 | 8.34 (0.02) |
1 | 0 | 2 | 0 | 14.80 (0.04) | |
1 | 0 | 1 | −1 | 1.06 (0.01) | |
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Cu(II)-Orn | 1 | 0 | 1 | 0 | 11.85 (0.04) |
1 | 0 | 2 | 0 | 15.95 (0.07) | |
1 | 0 | 1 | 1 | 19.69 (0.03) | |
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Cu(II)-Lys | 1 | 0 | 1 | 0 | 11.83 (0.02) |
1 | 0 | 2 | 0 | 15.12 (0.03) | |
1 | 0 | 1 | 1 | 19.44 (0.02) | |
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Cu(II)-Hisd | 1 | 0 | 1 | 0 | 10.65 (0.01) |
1 | 0 | 2 | 0 | 18.68 (0.03) | |
1 | 0 | 1 | 1 | 18.39 (0.02) | |
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Cu(II)-Hist | 1 | 0 | 1 | 0 | 9.39 (0.02) |
1 | 0 | 2 | 0 | 15.12 (0.05) | |
1 | 0 | 1 | 1 | 17.34 (0.02) | |
|
|||||
Cu(II)-Imz | 1 | 0 | 1 | 0 | 4.23 (0.01) |
1 | 0 | 2 | 0 | 7.57 (0.02) |
Note:
Duloxetine (D) contains as a minimum one site which may reversibly dissociate a proton (a hydrogen ion) to form negative-charged anion. Duloxetine may discharge one proton from the amine group. The
Titration of duloxetine was done in presence and absence of the Cu(II) ion. Titration curves of the Cu(D) complex are depressed from the free D curve, representing Cu(II) complex formation through protons displacement. Formation constant was measured by fitting potentiometric data based on probable composition models. The selected model with finest statistical fit was determined to consist of Cu(D) (duloxetine) (1100) and Cu(D)2 (1200) complexes (Table
The concentration distribution diagram of Cu(II)-D systems is provided in Figure
Concentration distribution of various species as a function of pH in the Cu-D binary system.
Multiple equilibrium studies by pH-metric measurements in ternary copper(II) complexes with duloxetine (D) as the primary ligand and amino acids (L) as secondary ligands exhibited occurrence of [Cu(D)(L)], [Cu(D)(LH)], and [Cu(D)(LH-1)] ternary complex species. Stability coefficients of amino acid complexes are greater compared to those of the corresponding monodentate imidazole complex, reflecting that amino acids possibly organizes with Cu(D) as the bidentate ligand through amino and carboxylate groups, despite of the monodentate ligand. Constancy of the ternary complex containing glycine is advanced compared to those containing alanine. It is recommended that steric interference, initiated by manifestation of the methyl group on the carbon-containing amino group (alanine),is liable for low stability of its ternary complexes.
Value of the stability constant of the histidine complex was found higher as compared to
Formation coefficients of ternary complexes in Cu(II)-D-amino acids systems at 25°C and 0.10 mol·L−1 ionic strength.
System |
|
|
|
|
log10 |
|
|
|
%R.S.b |
---|---|---|---|---|---|---|---|---|---|
Cu(II)-D-Gly | 1 | 1 | 1 | 0 | 17.32 (0.01) | 9.25 | 9.17 | 1.1 | 13.50 |
Cu(II)-D-Ala | 1 | 1 | 1 | 0 | 17.12 (0.02) | 8.95 | 8.89 | 0.82 | 10.09 |
Cu(II)-D-Val | 1 | 1 | 1 | 0 | 17.05 (0.01) | 8.98 | 8.94 | 0.87 | 10.73 |
Cu(II)-D-Pro | 1 | 1 | 1 | 0 | 17.61 (0.01) | 9.54 | 9.01 | 0.04 | 10.93 |
Cu(II)-D-Phe | 1 | 1 | 1 | 0 | 16.75 (0.02) | 8.68 | 8.40 | 0.33 | 3.95 |
Cu(II)-D-Met | 1 | 1 | 1 | 0 | 17.96 (0.02) | 9.89 | 9.86 | 1.79 | 22.10 |
Cu(II)-D-Thr | 1 | 1 | 1 | 0 | 17.56 (0.02) | 9.49 | 9.22 | 1.15 | 13.64 |
1 | 1 | 1 | −1 | 2.62 (0.02) | |||||
Cu(II)-D-Orn | 1 | 1 | 1 | 0 | 20.30 (0.01) | 12.23 | 8.45 | 0.38 | 3.21 |
1 | 1 | 1 | 1 | 25.45 (0.01) | |||||
Cu(II)-D-Lys | 1 | 1 | 1 | 0 | 20.76 (0.03) | 12.69 | 8.93 | 0.86 | 7.27 |
1 | 1 | 1 | 1 | 24.88 (0.01) | |||||
Cu(II)-D-Hisd | 1 | 1 | 1 | 0 | 21.30 (0.01) | 13.23 | 10.55 | 2.58 | 24.22 |
1 | 1 | 1 | 1 | 26.01 (0.01) | |||||
Cu(II)-D-Hist | 1 | 1 | 1 | 0 | 20.90 (0.04) | 12.83 | 11.51 | 3.44 | 36.63 |
1 | 1 | 1 | 1 | 25.11 (0.02) | |||||
Cu(II)-D-Imz | 1 | 1 | 1 | 0 | 13.34 (0.002) | 5.27 | 9.11 | 1.04 | 24.59 |
Note:
Ornithine and lysine can bind to the Cu(II) ion as
Concentration distribution of various species as a function of pH in the Cu-D: the ornithine ternary system.
In addition to the Cu(D)(L) complex threonine forms the Cu(D)(LH-1) species, which is formed via induced ionization of the
In order to characterize the stability of the mixed ligand [Cu(D)L], complexes with respect to the corresponding binary analogues can be expressed quantitatively in terms of
Values of
Another parameter, which is percent relative stabilization (%R.S.) for quantifying the stability of a ternary complex, may be defined as follows:
The values of %R.S. have been calculated (Table
Complexes of Cu(II) have been synthesized according to Scheme
Schematic syntheses of [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes.
The measurements of conductivity for complexes were registered in the experimental part. From the results recorded, it was found that the molar conductance value of [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] chelate was 12.4 and 10.3 Ω−1·mol−1·cm2, respectively, which referred to the nonionic nature of both complexes [
From the result of IR spectra (Figure
IR spectra of duloxetine drug and [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes.
The mass spectra of [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes are presented in Figure
Mass spectra of (a) [Cu(D)Cl(H2O)] complex and (b) [Cu(D)(Gly)] complex.
The EPR spectra of [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes were recorded on the powder sample at room temperature (Figures
EPR spectra of complex [Cu(D)Cl(H2O)] (a) and complex [Cu(D)(Gly)] (b).
Thermal behaviors of [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes were investigated by TG/DTG/DTA/DSC techniques. The thermogravimetric analysis for the complexes was carried out within temperature ranging from room temperature to 735.9°C for [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes. The TG/DTG curves of both complexes are given in Figure
TGA/DTA/DTG spectra of complex [Cu(D)Cl(H2O)] (a) and complex [Cu(D)(Gly)] (b).
Coats–Redfern of a relationship [
Kinetic parameters evaluated by Coats–Redfern equation.
Compound | Stage | Decomposition range (°C) |
|
|
Δ |
Δ |
Δ |
---|---|---|---|---|---|---|---|
[Cu(D)(H2O)Cl] | 1st | 463 | 86.88 × 107 | 112.21 | 109.64 | −0.033 | 154 |
2nd | 546 | 11.23 × 107 | 144.33 | 140.67 | −0.068 | 187 | |
3rd | 632 | 97.22 × 109 | 177.21 | 172.98 | −0.094 | 247 | |
|
|||||||
[Cu(D)(Gly)] | 1st | 459 | 6.45 × 109 | 36.74 | 76.08 | −0.032 | 158 |
2nd | 562 | 7.25 × 1010 | 83.41 | 92.15 | −0.073 | 195 | |
3rd | 633 | 8.12 × 106 | 122.22 | 123.45 | −0.095 | 192 |
The observed magnetic moments for [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes are generally diagnostic of the coordination geometry about the metal ion. Room temperature magnetic moment of the [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes is at 1.78 and 1.82 B.M., respectively, and these values are in tune with a high spin configuration and suggest square planar geometry for [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes [
UV-Vis spectra of (a) [Cu(D)Cl(H2O)] complex and (b) [Cu(D)(Gly)] complex.
X-ray powder diffractograms of the [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes have been given in Figure
X-Ray powder diffraction patterns of (a) [Cu(D)Cl(H2O)] complex and (b) [Cu(D)(Gly)] complex.
X-ray powder diffraction data of [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes.
|
2 |
2 |
|
|
|
---|---|---|---|---|---|
|
|||||
10.4422 | 8.546 | 8.499 | 0 | 0 | 1 |
9.2689 | 9.432 | 9.582 | −2 | 0 | 1 |
8.4586 | 10.404 | 10.969 | 1 | 1 | 0 |
5.7841 | 16.902 | 16.8563 | 2 | 0 | 1 |
4.3596 | 19.299 | 19.458 | 2 | 1 | 0 |
4.2228 | 21.574 | 21.741 | −2 | 1 | 2 |
3.7538 | 25.328 | 25.526 | −5 | 0 | 3 |
3.2916 | 28.558 | 28.876 | −6 | 0 | 3 |
2.7878 | 33.163 | 33.383 | −1 | 2 | 1 |
2.9987 | 34.480 | 34.782 | 0 | 0 | 4 |
2.6327 | 36.819 | 36.465 | 2 | 1 | 3 |
2.4331 | 37.167 | 37.159 | −8 | 0 | 2 |
2.3248 | 41.807 | 41.748 | −8 | 1 | 4 |
2.1888 | 43.645 | 43.479 | −6 | 2 | 3 |
2.1472 | 44.661 | 44.236 | −2 | 2 | 4 |
|
|||||
|
|||||
9.8564 | 10.258 | 10.003 | 2 | 0 | 0 |
9.2583 | 11.458 | 11.256 | 0 | 0 | 1 |
7.1586 | 13.324 | 13.258 | −2 | 0 | 1 |
6.2435 | 15.696 | 15.638 | 1 | 1 | 0 |
5.5686 | 17.252 | 17.583 | −3 | 0 | 1 |
4.8517 | 19.918 | 19.899 | 1 | 1 | 1 |
4.2315 | 24.256 | 24.800 | 4 | 1 | 0 |
3.9898 | 25.633 | 25.385 | −4 | 1 | 1 |
3.8465 | 27.363 | 27.159 | −4 | 0 | 2 |
3.7258 | 34.208 | 34.851 | 7 | 0 | 0 |
3.6369 | 36.998 | 37.021 | 1 | 1 | 3 |
3.3458 | 38.995 | 39.433 | 2 | 2 | 2 |
3.1589 | 43.869 | 43.869 | −2 | 2 | 3 |
3.0258 | 44.287 | 44.889 | −8 | 1 | 2 |
The nature of the ligand seems to bear key structural factors for the morphology of the agglomerates. Figure
SEM image of (a) [Cu(D)Cl(H2O)] complex and (b) [Cu(D)(Gly)] complex.
The molecular modeling calculations for [Cu(D)Cl(H2O)] and [Cu(D)(Gly)] complexes were carried out using a Material Studio program that allows for rapid structure building, geometry optimization, and molecular display. Molecular mechanics calculate the steric energy, which partition into stretching, bending, torsion, and nonbonded interactions for the molecules, and give a stable structure with least strain energy. Energy minimization was repeated several times to find the global minimum. The computational strategy in this study is to determine the minimum strain energy for [Cu(D)(H2O)Cl] and [Cu(D)(Gly)] complexes, and the energy minimization values for square planar and without restricting the structure are almost equal, i.e., 4.93 and 32.87 kcal/mol, respectively. This supports square planar geometry for [Cu(D)(H2O)Cl] and [Cu(D)(Gly)] complexes. Some important calculated bond length for the [Cu(Dul)(H2O)Cl] complex is Cu_N, 1.814 Å; Cu_Owater, 1.793 Å and 1.773 Å; Cu_S, 2.814 Å; and Cu_Cl, 2.145 Å; and for [Cu(D)(Gly)] complex is Cu_N, 1.842 Å and 1.838 Å; Cu_O, 1.783 Å; and Cu_S, 2.834 Å [
Molecular modeling of [Cu(D)(H2O)Cl].
Molecular modeling of [Cu(D)(Gly)].
In summary, in our study, we have determined the stability constants of binary and ternary complexes of Cu(II) with duloxetine drug and some selected amino acids (L) at 25°C and ionic strength 0.10 mol·L−1 NaNO3. The complexes stability constants (log10
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
This research project was supported by a grant from the Research Center of the Female Scientific and Medical Colleges, Deanship of Scientific Research, King Saud University.