Removal of Toxic heavy metal ions by the formation of complex with Theophylline (Therapy drug): Thermodynamic and kinetic study

 

Huda N. Al-Ani

Department of Chemistry, College of Science, University of Baghdad, Jadiriya, Baghdad, Iraq.

 

ABSTRACT:

Chelation therapy drug is an established treatment for heavy metal toxicity. Chelation therapy agents that remove toxic metal ions such as Lead, Nickel, Zinc, iron and copper from the body by removing them from intracellular or extracellular spaces. The present study create all the experiment were performed at different temperature (303, 308, 313, 318, 323)°K. The UV-Vis measurements were carried out for the metal-drug complex by Spectrophotometric method. The absorption Spectrum of the mixture of drug and Nickel ion shows a batho chromic (red) shift in ʎmax, the absorbance change caused by complex arrangement between the Nickel ion and drug. The stoichiometry of the formed complex was investigated by the method of continuous variation and it was found (1:1), In the present work we investigate the stability constant of therapy drug with Ni(II) ion using water at (298K, 303, 308K, 313, 318)°K, We employed to determine (Ni(II) - ligand) complex stability constant (logK) values. It is observed that Ni (II) ion forms 1:1 complex. The thermodynamic parameter ∆G^o, ∆H^o and ∆S^o were calculated from values of stability constant at different temperatures. The formations of (Ni(II) –drug) complex were found to be spontaneous and indothermic in nature. Chemical kinetics show, the Complication of drug with Ni ion was found to follow the second order reaction.

 

 

 

INTRODUCTION:

Pollution by heavy metals is a serious threat to aquatic ecosystems because some of these metals are potentially toxic, even at very low concentrations. Additionally, heavy metals are not biodegradable and tend to accumulate in living organisms, and they can cause severe problems to both human health and wildlife¹. Metal Toxicity is the toxic effect of certain metals in certain forms and doses on life. Toxic metals are individual metals and metal compounds that negatively affect people's health². The toxicity of heavy metals released by a series of productive activities is widely recognized. Nickel ion is metallic compound which is known as transitional metallic in periodic table³, Nickel (Π) is important oxidation state in biochemistry, it is form many complexes.

 

It is considered as essentials elements in the body because it is helping the body to absorbiron, and prevent anemia through building strong skeletal by strengthening bones, it is found in DNA, RNA means found in every cell in human body. Nickel is found in plants (peas, beans) and fish, it is help in breaking down glucose which help improvised energy for daily requirement’s⁴. Chelation therapy is a medical procedure that involves the administration of chelating agents to eliminate heavy metals from the body. Chelation therapy has long history of use in clinical toxicology and remains in use for some very specific medical treatments⁵. Chelating agents are organic or inorganic compounds able of binding metal ions to form complex ring called ‘chelates’. nts possess “ligand” binding atoms that form either two covalent linkages or one covalent and one co-ordinate or two co-ordinate linkages in the case of bi-dentate chelates. Mainly atoms like S, N and O function as ligand atoms. Bidenate or multidentate ligands form ring structures that include the metal ion and the two-ligand atoms attached to the metal⁶. Chelating agents are of great importance in the treatment of intoxications and overload with metals. Chemical principles for chelation therapy in general which is the aim of chelation treatment is to remove toxic metal ions from the vulnerable sites in the critical organs. This requires that the chemical affinity of the complexing agent for the metal ions is higher than the affinity of the metal ions for the sensitive biological molecules⁷. Therefore, chemical assessment of the stability constants of the metal-complex formed may give an indication of a chelating agent’s efficacy. For the present investigation, we selected Theophylline drug having molecular formula C₇H₈O₂N₄. H₂O, in simple cases to form a (1:1) complex between Nickel (II) ion and Theophylline 1, 3-dimethylxanthine (BDH) drug, Figure (1) show the Chemical structure of Theophylline⁸. Drugs have various functional groups present in its structure show (Figure.1), which can bind to metal ions present in human body⁹. Metal complex of drug are found to be more potent than parent drug¹⁰. Chemistry of drugs attracts many researchers because of its application in medicinal study. Metal Complexes are widely used in various fields, such as biological processes pharmaceuticals, separation techniques, analytical processes¹¹.

 

 

Figure 1: Chemical structure of Theophylline 1, 3-dimethylxanthine (BDH) drug.

 

Many researchers¹² use medicinal drug as a ligand, but very few were investigated thermodynamic stability constant and thermodynamic parameters of the formed complex at different temperature range by appliance of UV-Visible spectroscopic method. The detail study of complex under identical set of experimental condition¹³. Therefore, we decide to study the effect of temperature on thermodynamic parameters ∆G°, ∆H° and ∆S° of (Ni- drug) complex¹⁴. The Aims of the present work was Optimizing of all the chemical and physical conditions for the complexation¹⁵, Determining λmax and the absorbance for the drug and the complex, Determining the stoichiometric ratio of the formed complex by the Job method, Determining the equilibrium constant and the other thermodynamic parameters (ΔH°, ΔG° and ΔS°) for the complexation and Conducting kinetic studies for the rate constants and the reaction order determinations^16,17.

 

MATERIALS AND METHODS:

The ligand Theophylline drug (10^-4M) was prepared by dissolving 0.00198g in 100ml volumetric flask using distilled water as a solvent.

 

Nickel nitrate solution:

A stock solution of Ni (II) ion (10^-4M) was prepared by dissolving 0.003g in 100ml volumetric flask using distilled water as a solvent.

 

All spectra measurements were recorded with the UV-Vis Spectra photometer: UV-1800, by 1cm path length a quartz cell. The absorption spectra were taken with the UV-Vis spectrophotometer by a quartz cell of 1cm path length of Theophylline 1, 3-dimethylxanthine and Nickel ion (Π) was calculated in a wavelength (282–310nm). Theophylline 1, 3-dimethylxanthine and Nickel ion (Π) were purchased from HIMEDIA and MERCK. A series of solution different in concentration ranging from (1x 10^-4-5x10^-5) M were prepared by dilution from their stock solutions of drug, and the absorption spectrum were taken for them. The Stoichiometric of the formed complex were investigated by continuous variation (jobs- method) method. Jobs method was applied by placing (1 to 9) ml of (10^-4M) drug solution in to a series of (10ml) volumetric flasks, this was followed by adding (9 to 1) ml of (10^-4M) Ni (II) ion solution. These solutions were allowed to stand for the equilibrium time and then we measured the absorbance with against reagent blank. The results obtained were plotted against (X) mole fraction. Estimation of molar absorptive of the complex by prepared a series of solution of (1:1) (Ni-drug) complex in the range of (1×10⁻⁵to5×10⁻⁵) M concentration, then recording the absorbance spectrum of them. Then, we determine the rate constant and the order of interaction of Ni and drug, at different temperatures (298, 303, 308, 313 and 318°K) in (0–110) min. the absorbance was recorded. We determined the equilibrium constant by recording the absorption spectrum of them at different temperatures (298, 303, 308, 313 and 318°K).

 

RESULTS AND DISCUSSION:

Absorption spectroscopy:

Absorption spectra were measured with the UV-Vis spectrophotometer using a quartz cell of 1cm path length. The absorbance of Ni ion and the drug solutions were measured in a wave length of (282–310) nm; by the use the same solvent as a references. The electronic spectra of the mixture (drug- Ni (Π)) complex show a bath chromic shift (red shift) to the longer wavelength, which attributed to (n → π*) transition to the extent (Δλ=28 nm), and the change in the absorbance due to complex formation between metal and drug^18,19.

 

Applicability of Beer’s Law (Calibration Curve):

After fixing the optimum conditions, calibration graphs of the complexing agents (drug) were constructed. Into a series of solutions differ in concentration ranging from (1x10^-5 to 8x10^-5 M) were prepared by dilution from their stock solutions for drug. The absorption spectrum were measured at their λ_max.

Determination of the Stoichiometric Ratio (Job Method) of (drug- Ni(Π) complex:

A series of solutions have a mole fraction between (0.1 to 0.9), were prepared by mixing different volumes of equi molar of Ni(II), and drug stock solutions of a concentration (1x10^-4M) of each of them. The principle of this method involves the preparation of a series of equimolar solutions with the summation of total volume of Ni and drug. By use the continuous variation methods to estimate Stoichiometry of (drug- Ni [Π]) complex ²⁰. Plot of absorbance of (drug- Ni [Π]) complex at ʎ _max (310 nm) against mole fraction, so it clear from Figure. 3 illustrate the jobs method plot, prove that Stoichiometric ratio of (drug- Ni [Π]) complex at 298 °K is (1:1)as in (Figure2).

 

Figure 2: The jobs method plot for the formation of (drug -Ni) complex ʎ_max (310nm).

 

Determination of the equilibrium constant Keq: can be calculated by continuous variation method^18.

Ni + Drug [Ni - Drug] complex

The reaction amplify characterized using equilibrium: (1) where Keq to describe the stoichiometric stability constant, to describe (Ni) metal ion, and to present the (drug) ¹⁹. (Drug - Ni) complex eq: The Concentration of the (Ni-drug) complex at the equilibrium

[Ni]eq: The Concentration of (Ni) ion at the equilibrium.

[drug]eq: The Concentration of drug at the equilibrium.

 

[drug -Ni]eq = absorbance(max) / e l ………… (1)

 

e : The molar absorptive of (drug- Ni) complex (cm^-1. mol^-1. L).

l:    The path length in (cm).

 

Absorbance (max) = The maximum absorbance to (drug- Ni) complex²⁰.

 

The molar absorptive e of (drug- Ni) complex was calculated with registry the absorbance of concentration of (1:1) complex and plotting absorbance versus concentration at temperature (298, 303, 308, 313 and 318) °K, as to illustrate in (Figure.3) show the calculated absorbance for Concentration (0.5×10^-5 - 4×10^-5) M of the (1:1) (drug- Ni) complex at temperature (289, 303, 308, 313 and 318) °K, which given a straight line with a slope equals to e is molar absorptivity of the complex (L. mol^-1cm^-1) was illustrated in table (4) ²¹.

 

Stability constant (keq): using continuous variation method The equilibrium constant be able to computed as demonstrate in equation (2) ²²:

e complex = 27700 L. mol^-1cm^-1

k eq = [Ni-druge complex]_eq / [Ni] _eq [drug] _eq--------- (2)

Keq which is depends on the temperature but independent on the concentration²³.

 

Figure 3: The absorbance against concentration (0.5×10⁻⁵–4×10⁻⁵) M of the 1:1 (drug-Ni) complex at temperature 298, 303, 308, 313 and 318°K

The results illustrated that stability constant keq changes with temperature accepted in this research (298, 303, 308, 313 and 318°K)²⁴, it increases with increase of temperature for (drug - Ni) complex, which denote the bond becomes stronger between them²⁵.

 

keq = 810.78 × 10⁴ L.mol^-1

 

Thermodynamic parameters:

Thermodynamic parameters; the standard enthalpy change ΔH^o, standard entropy change ΔS^o, and standard free energy change ΔG^o, and their relation to equilibrium of studied systems were calculated as follows: Keq were calculated from the concentration of all component at the equilibrium, which allows us to calculate ΔG^o at different temperatures (298, 303, 308, 313 and 318) ⁰K for complex [22].

 

ΔGo = - RT ln Keq ………………………..………….(1)

 

ln Keq = -ΔG^o / RT …………………………………..(2)

 

Both Keq and ΔG^o are temperature dependent amounts Differentiating equation (2) versus (1/T) gives

 

ln Keq = -ΔH°/RT + ΔS°/R…………………………...(3)

 

The enthalpy of communication can be determined by measuring the equilibrium constant for a system at different temperature. The enthalpy of the system can then be calculated from the slope (-ΔH^o/R) of the resulting linear vanʼt Hoff plot of (ln Keq) versus (1/T), the result as shown in Figure (4)and table (1)^22-24.

Entropy change for the system can then be calculated from the intercept by equation (4):

 

Intercept =ΔS°/R ……………………………………. (4)

 

The evaluation of changes in entropy (∆S^o) is done by the following equation (4).

 

………………………….…… (5)

 

Table1: The experimental thermodynamic parameters for (drug- Ni) complex at temperature (298, 303, 308, 313, 318) °K.

 

Figure 4: Vant Hoff plot for the interaction of (drug –Nickel) complex at temperature(298, 303, 308, 313 and 318°K).

 

The values of their equilibrium constant (Keq) increase with increases temperature that means the complex be more stable at higher temperature²⁶.

 

Negative values of Gibbs free energy (∆G°) mean that the reaction would be favored and would release energy (spontaneous interaction) between drug and Ni ion, and it increases with the increase in temperature depending on the ligand type and the change in the enthalpy and entropy. Enthalpy change and entropy change were the binding energy components during the complex formation. The positive values of entropy(∆S°) occur because water molecules that arranged around the drug and (Ni) ion became more random. The positive enthalpy ΔH° refers to the process is endothermic ²⁷.

 

Table2: The calculated thermodynamic parameters for (Ni(Π)-drug) complex at temperature (298, 303, 308, 313 and 318) °K.

 

Interaction kinetics:

To investigate the interaction kinetic of Ni(Π) ion with drug the absorbance of complex calculated with time at (310 nm) wave length, 298K and its (1:1) stoichiometric ratio.

The first order rate equation (7) and the second order rate equation (8) were applied.

 

ln A = - k t + ln A_o……….……. (7) First order equation

 

(1/A) -(1/A_o) = k T…….…… (8) Second order equation

 

A = absorbance at time t.

A_o= absorbance at time zero.

k = rate constant.

 

 

 

 

 

 

 

 

The complex will be stable in about (80-90 minute) which demonstrated from the constant absorbance. The application of the second order of the reaction was shown in Figure 5. Table (3) illustrate second order rat constant for the (drug –Ni) complex. The interaction between (drug –Nickel) complex is a second order with a rate constant.

 

k =2.4 x10^-2M^-1.min^-1

 

Reaction order and rate constant of (Ni (Π)-drug) complex:

Determination of the order of the interaction of Ni ion with drug and through a plot of (1/A) a ginst time (t) were presented in (figure-5) by the application of equation (8). The first order equation was applied in addition to the graph did not show us a straight line so it was considered the second order is the order of impact. A straight line were obtained which indicates the second order interaction between Ni ion and drug with a rate constant illustrated in (table 3).Which were calculated from the slope of the straight line.

 

Table 3: Data for application the second‑order equation for (1:1) (drug‑Ni) complex at temperature298, 303, 308, 313 ) °K.

 

Figure 5: The application of the second-order reaction for the (drug-Ni) complex at temperature 298, 303, 308, 313) °K.

 

Table 4: The calculated First order Rat constant and second order rate constant for (1:1) (drug-Ni) complex at temperature (298, 303, 308, 313) °K.

 

The interaction was in (table 4), which illustrated follows the second order rat constant for (drug- Ni) complex.

 

CONCLUSIONS:

This research was conducted to evaluate the efficiency of Theoplyline 1, 3-dimethyl- Xanthine (Therapy drug) as chelating agent with a hazard heavy metal Ni (Π)ion, using spectrophotometric techniques. The chelator was able to interact with Ni (II). The stoichiometric ratio between drug and Ni (II) in the complex was (1:1) depends to the kind of metal and ligand. The Thermodynamic Parameters shows that the formed complex is spontaneous with an electrostatic interaction and an increase in the order of orientation rate of Complexation. The kinetic show the complex formed was second order depending on a linearity of the straight line.

 

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Accepted on 19.04.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(3):1693-1698.