Determination of the Stability Constants Comlexes of Metformin Hydrochloride With Cu(II), Cd(II) and Zn(II)

 

Serap Karaderi*, Caner Mazi, Saadet Yilmazbilek

Depertmant of Analytical Chemistry, Faculty of Pharmacy, Marmara University-34668, Haydarpaşa, Istanbul, Turkey.

 

*Email: skaraderi @ marmara.edu.tr

 

ABSTRACT

 

In the present work, binary complexes of Copper(II), Cadmium(II) and Zinc(II) with metformin hydrochloride have been studied potentiometrically. Stability constants of binary complex systems have been estimated by the method proposed by Irving-Rossotti at 25ºC and 0.11M ionic strength (NaClO4) in aqueous solution. The conditional formation constants of the complexes formed between ligand and metal were calculated according to pH function. The maximum values of the conditional formation constants were found to be in accordance with the mixed metal-ligand complex formation constants in a given pH region. In addition to these, the molar fractions were calculated using the formation constants of the mixed metal-ligand complexes. As a result of the experimental study, the values of stability constants of metal-ligand complexes at 25ºCare as noted below: logK1=8.45; logK2=8.30 for Zn(II)-Metformin hydrochloride; logK1=8.78 ; logK2=8.00  for Cu(II)-Metformin hydrochloride: logK1=8.18; logK2=7.36  for Cd(II) – Metformin hydrochloride.

 

Key words: Metformin hydrochloride, Zinc(II), Copper(II), Cadmium(II) and metal-ligand complex, stability constants.

INTRODUCTION

Potentiometric titration method is one of the techniques used to determine stability constants because this method is based on a powerful and simple electroanalytical method. In addition, potentiometric operation provides advantages for instance low cost, fast response, simple instrumentation, low detection limit and dynamic ranges. At the same time, the potentiometry method requires compensation with constant ionic power to ensure that the activity coefficients remain constant for all species in the experimental working environment [1, 2]. Metal ions usually bind to ligands through selective and strong interactions. The strength and selectivity of metal ligand bonds depend on stability constants. The complex properties of an aqueous sample against metal ions are very important because they determine the distribution of metal ions between different species and hence their solubility, mobility and toxicity. The stability constants of the metal-ligand complexes obtained as a result of the interactive relation between drugs with metals are very useful in determining the mechanism of drugs. However, the interaction of metals and ligands in complex media controls the stability of metal complexes [3, 4].

Metformin is a drug synthesized to reduce blood sugar [5]. Metformin hydrochloride is chemically designated as 2-(N,N-dimethylcarbamimidoyl) guanidine which  has the molecular formula as shown in  Figure 1. Given the chemical structure of Metformin hydrochloride, there are primary, secondary and tertiary amino groups as donor centers. In addition to these, Metformin hydrochloride is highly soluble in water but has poor solubility in lipids. Hence, it is difficult to extract it from the aqueous plasma matrix [6-8].

Currently, metformin hydrochloride has been used as a hypoglycemic agent in people with type-2 diabetes [9, 10]. It has further potential advantages in patients with the metabolic syndrome where hyperinsulinaemia is present [11]. One of the known clinical advantage of metformin hydrochloride over sulfonylureas is that doses of metformin hydrochloride do not cause hypoglycemia. Metformin hydrochloride does not reduce blood glucose in non-diabetic people because it has direct helpful impact on serum lipoproteins and lipids [12].

Figure 1. The chemical structure of Metformin HCI

EXPERIMENTAL

Reagents and chemicals

All other reagent used were analytical grade. Pure standard of metformin hydrochloride was purchased from Merck. Copper(II)nitrate trihydrate, cadmium(II)nitrate tetrahydrate and zinc(II)nitrate hexahydrate, perchloric acid (HCIO4), 0.1 N sodium perchlorate (0.1 N NaCIO4) and 0.1 N sodium hydroxide solution (0.1 N NaOH)  reagent were obtained from Merck Chemical (Germany).

Preparation of standard stock and titration solutions

0.01 M Metformin hydrochloride (dissolved in water), 0.1000 N NaOH, 0.100 M HClO4, 1.0 M NaClO4, 0.01 M Cu(NO3)2, 0.01 M Cd(NO3)2and 0.01 M Zn(NO3)2solutions were prepared. The solutions for determination of protonation constants of metformin hydrochloride and metal ligand complexes were prepared as follows.

 

  1. HCIO4: 5 mL 0.100 M HClO4 + 5.0 mL 1.0 M NaClO4 were added and diluted to 50.0 mL by water.
  2. Metformin hydrochloride: 5.0 mL 0.100 M HClO4 + 10.0 mL 0.0100 M Metformin hydrochloride + 5.0 mL 1.0 M NaClO4 were added and diluted to 50.0 mL by water.
  3. HCIO4 + Metformin hydrochloride + Cu(II): 5.0 mL 0.100 M HClO4 + 10.0 mL 0.0100 M Metformin hydrochloride + 5.0 mL 1.0 M NaClO4 + 5.0 mL 0.0100 M Cu(II) were added and diluted to 50.0 mL by water.
  4. HCIO4 + Metformin hydrochloride + Cd (II): 5.0 mL 0.100M HClO4 + 10.0 mL 0.0100M Metformin hydrochloride + 5.0 mL 1.0 M NaClO4 + 5.0 mL 0.0100 M Cd(II) were added and diluted to 50.0 mL by water .
  5. HCIO4 + Metformin hydrochloride + Zn(II): 10.0 mL 0.100M HClO4 + 5.0 mL 0.0100M metformin hydrochloride + 5.0 mL 1.0 M NaClO4 + 5.0 mL 0.0100 M Zn(II) were added and diluted to 50.0 mL by water.

The Determination of Protonation Constants

To determine the protonation constants, the mixture containing HClO4 and ligand + HClO4 solutions were titrated on the potentiometer device using NaOH (0.1N) (Figures. 2-4). Average ¯nA values were calculated from the titration curves and for the calculation, the following equation was used. 

NA = y + ( v1 – v2 ) ( N + E0 )/( V0 + v1 ) TL0

        Where:

            Vº    = volume at the beginning                                                                      : 50.0 mL

             N     = normality of the base                                                                            : 0.100 N

            TLº  = total molar ligand concentration metformin hydrochloride               : 2.00.10-3 M

             E°   = concentration of acid                                                                            : 0.0102 M

             Y    = the number of protons given for metformin hydrochloride               : 0

The volumes of v1 and v2 were read from the titration chart which contain HClO4 and ligand + HClO4.  ¯nA values at different pH values were determined using v1 and v2 volumes. Then, using these values, ¯nA = f (pH) was plotted. The protonation constants and the acidity constants of Metformin hydrochloride are outlined in Table 1.

The Determination of Stability Constants

The stability constants of the binary complexes were determined potentiometrically using Irving-Rossotti method. Therefore, the mixtures which contain some metal ions were titrated with standard 0.1 N sodium hydroxide solution in potentiometer device and the titration chart were plotted (Figures. 2-4). ¯nL values were calculated using the equation given below. pL values were calculated using ¯nL values to calculate the stability constants. The following equation was used to calculate ¯nL values:

         nL =( v3 – v2 ) [ N + E0 + TL0 (y – nA) ]/ ( V0+v2). nA .TM0

       Where:

                V°= volume at the beginning                                                                : 50.0 mL

                N= normality of the base                                                                    : 0.100 N

               TL°= total molar ligand concentration                                                : 2.00.10-3 M

                  E°= concentration of acid                                                       : 1.02.10-2 M

                y= the number of protons given for Metformin hydrochloride           : 0

               TM°= total molar metal concentration                                                   : 1.00.10-3 M

 

      The following equation was used to calculate pL values.

 

             pL = log  ( 1+b1[ H+] + b2[ H+]2 )  / TL0 – nL .TM0

 

In order to establish stability constants of the mixed metal ligand complexes, Irving-Rossotti method was also used. The mixture of metals was consisted and ligand was titrated potentiometrically. The ¯nL=f(pL) graphs (Figures. 5-7) were plotted using ¯nL and pL values which were calculated from titration curves. The separation among (HClO4), (HClO4) and (HClO4 + L + M) plots in all potentiometric titration curves showed the formation of a mixed metal ligand complex (Figures 5-7). The approach of Irving-Rossotti to binary systems was applied for the mixed system. The results are summarized in Table 1.

                                                    M + L                                           ML

                                                    ML + L                                        ML2                                                

RESULTS AND DISCUSSION

 

 In this experimental study, the conditional formation constants were calculated and these constants were found to be in agreement with the formation constants of mixed systems. However, this study describes the complexation formation between metformin hydrochloride with Cu(II), Cd(II) and Zn(II). This result affords us to find the stability constants of mixed metal-ligand complexes. The stability constants of Metformin hydrochloride-Cu(II), Metformin hydrochloride-Cd(II) and Metformin hydrochloride-Zn(II) complexes were determined in aquous solution by pH-metric titration.  The conditional formation constants, namely the stability constants of metal-ligand complexes can also be calculated. The difference between the formation constants of mixed and binary complex systems is a parameter which characterizes the formation behaviour of mixed metal-ligand complexes. These results would be helpful for studies related to understanding pharmaceutical action of guanidines. Cu(II) – Metformin hydrochloride, Zn(II) –Metformin hydrochloride, Cd(II) –Metformin hydrochloride systems are also in agreement with our observations systems.

Figure 2. The potentiometric titration chart of metformin HCl - Copper (II) complex

Figure 3. The potentiometric titration chart of metformin HCl - Cadmium (II) complex

Figure 4. The potentiometric titration chart of metformin HCl - Zinc (II) complex

Table 1. The protonation constants of Metformin Hydrochloride

Metformin Hydrochloride

logK1=11,02

logK2=2,79

pL values were calculated using b values. The relation ¯nL = f (pL) was plotted using ¯nL and pL values which were calculated for each metal ion. The stability constants were determined from these graphs (Table 2).

Table 2. The stability constants of binary and ternary complexes

Ligand-Metal

logK1

logK2

Cu(II)-Metformin hydrochloride

8.78

8.00

Cd(II)-Metformin hydrochloride

8.18

7.36

Zn(II)-Metformin hydrochloride

8.45

8.30

Figure 5. nL=f(pL) curve for Cu(II)-Metformin Hydrochloride

Figure 6. nL=f(pL) curves for Cd(II)-Metformin Hydrochloride

Figure 7. nL=f(pL) curves for Zn(II)-Metformin Hydrochloride

 

In addition, the conditional formation constants were calculated and were plotted as a function of pH (Figures. 8-10).

Figure 8. Conditional formation curve of Cu (II)-Metformin hydrochloride

                                 Figure 9. Conditional formation curve of Cd (II)-Metformin hydrochloride

                                    Figure 10. Conditional formation curve of Zn (II)-Metformin hydrochloride

The mole fractions of different species of mixed complexes were found by means of the calculated formation constants and were plotted as a function of pH (Figures. 11-13).

Figure 11. Mole fraction diagram of the Cu(II)-Metformin hydrochloride complex as a function of pH

Figure 12. Mole fraction diagram of the Cd(II)-Metformin hydrochloride complex as a function of pH

Figure 13. Mole fraction diagram of the Zn(II)-Metformin hydrochloride complex as a function of pH

CONCLUSION

As a summary, in our study we have determined the stability constants of binary complexes of Metformin hydrochloride and three metals (Cu(II), Cd(II) and Zn (II)). The conditional formation constants were calculated and these constants were found to be in agreement with the formation constants of mixed systems. Also mole fraction diagrams showed the formation of binary complexes.

REFERENCES

  1. ANSARI¹ FB, Farooqui M, Quadri SH. Complexation of some metal ions with metformin hydrochloride in acidic aqueous solutions. Oriental Journal of Chemistry. 2010;26(2):667-70.
  2. Hussain S, Qasem A, Mohsin M. Study of Stability constant of binary & ternarycomplexes of Cefpodoxime and glycine with some metal ions by potentiometric titration method. JUC, 2016 ; 12(3) : 64-70.
  3. Karaderi S, Bilgiç Alkaya D, Kurt Cücü A. The Determination of The Stability Constants of Mixed Ligand Comlexes of Creatinine-L-Cysteine and Creatinine-L-Cysteine Hydrochloride With Co (Ii), Cd (Ii), Zn (Ii), Mn (Ii): Using Potentiometric Method. Turkish Journal of Pharmaceutical Sciences. 2014 Jan 1;11(1).
  4. Magare BK, Ubale MB. Stability Constants of Transition Metal Complexes with Piperacilin Drug and Alanine, Glycine Amino Acids. Asian J. of Biochem. and Pharma. Res. 2013;3(3):91-5.
  5. Shenfield G. Metformin: Myths, Misunderstandings, and Lessons from History. Editorial. Austr. Prescr. 2013; 36: 38–39.
  6. Annapurna MM., Nagoji KEV, Srinivasa Rao S, Patro SS. Spectrophotometric determination of metformin in formulations. Asian J. Chem. 2002; 14 : 1775-78.
  7. Georgiţă CR, Sora I, Albu F, Monciu CM. Comparison of a LC/MS method with a LC/UV method for the determination of metformin in plasma samples. Farmacia. 2010;58(2):158-69.
  8. Klepser TB, Kelly MW. Metformin hydrochloride: an antihyperglycemic agent. American journal of health-system pharmacy. 1997 Apr 15;54(8):893-903.
  9. Mansour O, Isbera M. Assessment of physicochemical properties of metformin hydrochloride (850mg) tablets marketed in Syria. J Chem Pharmaceut Sci. 2016;9:726-
  10. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care. 2009 Jan 1;32(1):193-203.
  11. Campbell IW, Howlett HC. Worldwide experience of metformin as an effective glucose‐lowering agent: a meta‐analysis. Diabetes/metabolism reviews. 1995 Sep;11(S1):S57-62.
  12. Klip A, Leiter LA. Cellular mechanism of action of metformin. Diabetes care. 1990 Jun 1;13(6):696-704.

 

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