Synthesis and characterization of  Co(II) Cu(II) Zn(III) and La(II) complexes of standard antidiabetic drugs

Mohammad Tawkir

¹Department of ChemistryArts,Commerce and Science CollegeTukum Chandrapur,-442401(India)

DOI : http://dx.doi.org/10.13005/msri/110107

ABSTRACT:

Metal complxes of Glimeperide drugs were prepared and characterized based on elemental analysis, FT-IR, Molar conductance and thermal analysis (TGA and DTG) technique. From elemental analysis data, the complexes were proposed to have general formulae (GLM)₂Co2H₂O, (GLM)₂Cu, (GLM)₂Zn,and (GLM)₂La2H₂O. The molar conductance data reveal that all the metal complexes are non-electrolytic, IR spectra shows that GLM are coordinated to metal ions in a neutral bidentate manner from the ESR spectra and XRD-spectra. It is found that the geometrical structures of these complexes are tetrahedral Cu(II) ,Zn(II) and octrahedral Co(II), La(II). The thermal behavior of these complexesstudied using thermogravimetric analysis (TGA and DTG) techniques. The results obtained shows that the hydrated complexes lose water molecules of hydration followed immediately by decomposition of the anions and ligand molecules in the successive unseparate steps.

Thermogravimetric analysis was carried out to study the decomposition and various kinetic parameters. Freeman Carroll and Sharp Wentworth method have been applied for calculation of kinetic parameters. While data from freeman Carroll method have been used to determine various thermodynamic parameters such as order of reactions, energy of activation, frequency factor, entropy change, free energy change and apparent entropy change and order of reaction..

KEYWORDS: FTIR Spectra; TGA; DTG; Glimeperide

Copy the following to cite this article: Tawkir M. Synthesis and characterization of Co(II) Cu(II) Zn(III) and La(II) complexes of standard antidiabetic drugs. Mat.Sci.Res.India;11(1)

Copy the following to cite this URL: Tawkir M. Synthesis and characterization of Co(II) Cu(II) Zn(III) and La(II) complexes of standard antidiabetic drugs. Mat.Sci.Res.India;11(1). Available from: http://www.materialsciencejournal.org/?p=388

INTRODUCTION

Glimeperide, is abi-substituted urea derivatives can exist in keto andenolic form when dissolved in an organic solvent and react with various metal ions to form intensely coloured metal complexes that provide the basis for their use as a sensitive reagent.

The thermal degradation study of complexes has become a subject of recent interest. It is important property of complexes, which decides the thermal stability and processability of the complexes. The study of thermal behaviour of complexes in air at different temperature provides important information about its practical applicability.

Iqbal S.A.et.a1^l.,

(2005) synthesized the metal complexes of glimeperide characterized by FTIR, elemental analysis and TGA-DTG parameters. The thermal analysis (TGA) was performed at the heating rate of 10°C/min. in nitrogen atmosphere.

Wilma Cyrilet.al².,

(2011)studied kinetics and Thermal decomposition of Cu(II) complex of of hydroxyl quinoline-5-sulphonic acid

Thermal data have been analyzed by Freeman Carroll and Sharp-Wentworth method.

Thermal analysis (TGA and DTG) is a typical analytical technique to describe the relationship between physico-chemical changes and temperature.^1-2 In order to synthesize complexes having practical applications. There is a need to investigate the effect of heat on complexes in order to establish thermal stability.

Iqbal and co-workers^3-4

havesynthesized and characterized complexes of tolbutamide and glimeperide by FTIR, elemental analysis and TGA-DTA technique.

Thermal studies of complexes were carried out to determine their mode of decomposition, the activation energy (Ea), order of reaction (n), frequency factor(Z), entropy change (S), Free energy (ΔF) and apparent entropy change (*S). Thermal decomposition curves were discussed with careful attention of minute details. The freeman Carroll and Sharp-Wentworth methods have been used to calculate thermal activation energy and thermal stability.

However, very little work has been carried out on the synthesis and characterization and thermal degradation studies of the metal complexes of glimeperide.

Hence in this work we prepare complexes of Cu(II), Co(II), Zn(II) and La(II) transition and inner transition metals with glimeperide drug molecule. The solid complexes were characterized using different physico-chemical methods, like elemental analysis (C,H,N,S and metal content), IR and thermal analysis (TGA and DTG)

EXPERIMENTAL

2.1 MATERIALS AND REAGENTS

All chemicals used were of analytical reagent grade (A.R.) and of highest purity. They included glimeperide (Zim laboratories, Nagpur), Copper(II) Chloride ,Zinc(II) chloride,Cobalt(II) chloride andLanthanum(II) Chloride heptahydrate (Hi media Lab, Mumbai) organic solvents used absolute ethyl alcohol, DMF. These solvents were spectroscopic pure from BDH, hydrogen peroxide, hydrochloric and nitric acid (E.Merck) were used.De-ionized water was used in all preparations. 

2.2 INSTRUMENTS

Molar conductance of solid complexes in DMF was measured using Systronics conductivity meter, elemental microanalyses of the isolated solid complexes for C,H,N were performed at CDRI, Lucknow, using (HMS-932CLECO) Vario elemental analyzers. Infrared spectra were recorded on Perkin-Elmer, FTIR type 1650 spectrophotometer in wave number 400-4000 cm^-1. The spectra were recorded as KBr pellets.

The thermogravimetric (TG and DTG) analysis was carried out in dynamic nitrogen atmosphere (20 ml.min^-1) with a heating rate of 10°C/min. using shimatzu TGA-50H Thermal Analyzer at IIT Bombay (Mumbai) Electronic spectra recorded at Qualichem Laboratory, Nagpur.

2.3 SYNTHESIS OF METAL COMPLEXES

Metal complexes are synthesized by adding metal salt solution in appropriate solvent to the solution of the ligand. The mixture was refluxed for 3-4 hours. Then the precipitate of metal complexes was obtained. It was filtered, washed and dried in vacuum desiccators.

All selected metals forms 1:2 complexes with glimeperide, were confirmed by Jobs method of continuous variation⁵as modified by Turner and Anderson⁶.

2.4 ESTIMATION OF  METALSIN COMPLEXES

An accurately weighed portion of the different complexes ranged from 10 to 30 mg was placed in Kjeldhal flask. A measured volume of concentrated nitric acid ranged from 5 to 10 ml was added initially to the powdered complexes to start the fast wet oxidation digestion. This mixture had been digested with some drops of H₂O₂ solution using a gradual heating. This treatment was conducted until most of the powdered complexes were dissolved and the remaining solution had the colour of the corresponding metal salt. This solution was then diluted upto a 50 ml. with distilled water and the metal content was determined by titration against standard EDTA solution at a suitable pH value using the suitable indicator.

RESULTS AND DISCUSSION

3.1 COMPOSITION AND STRUCTURES OF METAL COMPLEXES.

The isolated solid complexes of Cu(II), Co(II), Zn(II) and La(II) with GLM ligands were subjected to elemental analysis (C, H, N, S. and metal content), I.R., Molar conductance, thermal analysis (TG and DTG) to support the tentative structure. The results of elemental analysis listed in table (1) suggest the formulae [Co(GLM)₂]2H₂O, [Cu(GLM)₂],[Zn(GLM)₂], and [La(GLM)₂]2H₂O for respective complexes. 

3.2 MOLAR CONDUCTANCE

The complexes were dissolved in DMF and the molar conductivities of 10^-3M of their solutions at 298 K are measured. It is concluded from results listed in table (1) that the complexes are found to have molar conductance values of 13.18 to 30.15Ω^-1 mole^-1 am^-2 indicating that all the metal complexes are non-electrolytes.

3.4 ELECTRONIC SPECTRAL STUDIES

Electronic spectra of the ligand shows two high intensity bands at 47431 and 32233 cm^-1,indicating n  n*and  transitions respectively of the ligand moity.The electronic spectra of La(II) complex displays band at 32130 and 27393cm^-1 The two bands corresponds to ⁴T_1g ⁴A_2g(F), ⁴T_1g ⁴A_1g(P) suggesting octahedral geometry of these complexes. The Cu(II) complex displays a band at 26130cm^-14E_1g ⁴T_2g(F),Zn(II) complex displays single absorption band at 31225cm^-1.This is due to Ligand Metal charge transfer spectra..

3.3 IR SPECTRAL STUDIES

The IR data of the spectra of GLM ligand and there complexes are listed in table (4). The IR spectra of the complexes are compared with those of the freeGLM ligands in order to determine the coordination sites that may be involved in complexation^7-15 The tautomeric equilibrium depends on the extent of conjugation, nature and position of the substituent, polarity of the solvent etc

3.5 MAGNETIC SUSCEPTIBILITY STUDIES

The roomtemperature magnetic moment of the complexes was  found to be 4.66 B.M. which corresponds to the presence of Co(II), La(II) in octahedral geometry. Zayed et al¹⁶., (2000)Cotton et.a¹⁷., (1999)

In addition to that, the Cu(II), and Zn(II) complexesare found to have magnetic moment value of 4.62 B.M.and 4.72B.M.respectively which indicates the presence of Cu(II) and Zn(II) complexeshave tetrahedral structure.

3.6 THERMAL ANALYSIS (TGA AND DTG)

In the present investigation, the weight losses for each complex were calculated within corresponding temperature ranges. The obtained data are listed in table (4). All complexes are thermally decomposed in three decomposition steps within the temperature range of 50-600°C .The TGA/DTA data for the complexes are shown in Table-1,2 and 5

The thermoanalytical data are presented in table 1,2 and 5. In studying the decomposition kinetics^18-26, three methods mentioned in the literature were used in each case the least square plots were drawn. The first few points that did not fall on straight line were discarded. These types of deviations of points are reported in literature by several research workers. This is explained as due to the failure of obeying as first order kinetics always by the solids in their decomposition in the early stages fig-1 and 2..

Theoretical Consideration

To provide further evidence regarding the degradation system of analyzed compounds we derived the TG curves by applying an analyticalmethod proposed by Freeman-Carroll^27-28 and Sharp-Wentworth^29-30.

Freeman-Carroll Method^26-27

The straight line equation derived by Freeman and Carroll, which is in the form of 

Where rate of change of weight with time

 

Wr = Wc-W

W_c = Wt. loss at completion of reaction

W = Total wt. loss upto time ‘t’

E_a = Energy of activation

n = Order of reaction

The plot between the term 

gives a straight line from which slope can be calculated, also we obtained energy of activation (Ea) and intercept on Y-axis as order of reaction (n). The change in entropy (ΔS), frequency factor (Z), apparent entropy (S*) can also be calculated by further calculation.

Sharp-Wentworth Method^28-29

Using the equation derived by Sharp and Wentworth

Rate of change of fraction of weight with change in temperature. β = Linear heating rate

 

by plotting the graph between

We obtained the straight line which gives energy of activation (Ea) from its slope.

The thermodynamic activation parameters of decomposition process of dehydrate complexes namely activation energy (Ea), enthalpy (ΔH), Entropy (ΔS) and Gibb’s free energy change of decomposition (ΔG°) are evaluated graphically by employing Free man-Carroll and Sharp-Wentworth relation. The data are summarized in Table 1,2,5.The activation energies of decomposition are found to be in the range 29.70 to 204.7 KJ.Mole^-1. The high value of activation energies reflect the thermal stability of complexes. The entropy of activation is found to have negative values in all the complexes which indicate that decomposition reactions process with lower rate than the normal ones^31-

 

Fig9.8: X-ray difractogram of GLM-Cu Complex   Click here to View Figure

 

a(Å) = 21.5867  Volume(abc)Å = 14060.360

b(Å) = 23.5386   Dcal.  =   5.38736 g/cm³

c(Å) = 27.6713 Dobs. =   5.38524 g/cm³

Standard deviation = 0.027% Crystal system =   Orthorhombic

α=90°, β=90°, λ=90°   Porosity(%)   =   0.03935

Density     = 0.074306g/cm³ Particle size   = 15.5602microns

Space group = Pm

2θ	I/I0	D(Obs)	D(Cal)	h	k	l
12.7240	21.84	6.95731	6.96397	25	3	0
16.4612	100.00	5.38524	5.38736	0	1	5
17.7016	16.05	5.01057	5.00820	0	2	5
19.8348	2.59	4.47624	4.48231	0	4	4
20.8349	5.00	4.26360	4.26359	2	5	1
22.5976	9.06	3.93484	3.93691	4	4	1
25.3489	5.04	3.51367	3.51709	3	4	5
32.5464	46.93	2.75121	2.74909	-3	2	9
39.8827	35.12	2.26043	2.26123	0	6	10
50.4146	7.61	1.81016	1.81016	6	2	13
53.8220	5.99	1.70192	1.70195	3	13	4

 

Table1: Thermogravimetric data of Glimeperide-Cu complex by Sharp-Wentworth28-29method Click here to View table

 

Table2: Thermogravimetric data of Glimeperide-Cucomplex by Freeman and Carroll26-27 method  Click here to View table

 

Fig1: FC,Kinetic plot of Glimeperide complexes using TGA data.(FC=Freeman and Carroll)  Click here to View Figure

 

Fig2: Determination of activation energy by SW method Click here to View Figure

 

TABLE-(3-ANALYTICAL DATA OF GLIMEPERIDE COMPLEXES

Sl. No.	Molecular formula of complexes	Molecular weight (gm/mol)	% Analysis found (calculated)
			C	H	N	O	S	Metal	H2O
1	(C24H34N4O5S)2Co·2H2O	1076.164	53.18 (53.52)	6.18 (6.13)	10.38 (10.40)	17.82 (17.84)	5.84 (5.94)	5.37 (5.47)	3.54 (3.34)
2	(C24H34N4O5S)2Cu	1044.774	55.14 (55.13)	6.18 (6.31)	10.78 (10.72)	18.30 (18.37)	6.52 (6.12)	6.00 (6.08)	–
3.	(C24H34N4O5S)2Zn	1044.604	55.10 (55.14)	6.18 (6.31)	10.82 (10.72)	18.48 (18.38)	6.28 (6.12)	6.82 (6.06)	–
4.	(C24H34N4O5S)2La·2H2O	1156.144	48.88 (49.82)	2.82 (5.70)	9.66 (9.68)	16.80 (16.60)	5.62 (5.53)	11.98 (12.01)	3.28 (3.11)

 

TABLE (4): I.R. SPECTRA (4000-400cm^-1) OF THE GLM AND THEIR METAL COMPLEXES

Compounds	γ (OH) Enolic	γ (NH)	γ (SO2) Asym	γ (SO2) Sym	γ (C=O) Amide	γ (m-O)
(C24H34N4O5S)2Co·2H2O	3100-3320 Br.	–	1375 sh.	1100 sh.	1460 sh.	530 m.
(C24H34N4O5S)2Cu	3220-3320 br.	3100 br.	1365 sh.	1120 sh.	1481 sh.
(C24H34N4O5S)2Zn	3220-3363 br.	3024 br.	1340.8 m.	1160.6 sh.	1481 sh.
(C24H34N4O5S)2La·2H2O	3280-3310	–	1305 sh.	1160 w.	1480 sh.	577  m.-

 

Table (5): Thermogravimetric data of Metal complexes of GLM drugs with corresponding to heating rate of 10°C/min.

Complexes	Decomposition Temp. (°C)	%Wt. loss	Ea(Kj/mole)		ΔS* (Kj/mole)	ΔF (Kj/mole)	Z	S*	n
			F.C.	W.W.
[CC (C15H20N3O3S)2Cu	30-150 150-350 350-510	9.926 58.408 65.68	32.87 51.21 110.30	31.37 51.01 109.23	-28.85 -64.65 -112.5	-8.708 -27.29569 -69.9772	281.2 269.8 252.7	-44.2681	0.9
(C15H20N3O3S)2Co.2H2O	30-150 150-350 350-510	5.815 51.027 69.718	33.67 55.14 109.37	32.66 54.38 108.38	-33.98 -82.07 -116.8	-10.26227 -34.66047 -72.65703	322.8 268.3 252.3	-48.5380	1.01
(C23H27O5ClN3S)2Zn	30-150 150-350 350-510	10.413 58.409 65.042	29.77 67.76 114.2	28.68 66.14 113.92	-24.59 -67.76 -116.50	-7.421 -29.94992 -72.4653	284.3 263.0 252.0	-43.2123	0.98
(C24H33N4O6S)2La	30-150 150-350 350-510	2.577 61.536 81.344	52.66 85.94 138.23	52.16 85.13 138.14	-43.48 -82.05 -102.2	-13.12178 -39.54421 -43.09237	269.2 269.2 257.6	-44.2381	0.99

 

Discussion

The complexes of Cu,Zn,La and Co were synthesized with oral hypoglycemic agents i.e. glimeperide the formulae suggested for the complexes are well supported by the Jobs method of continuous variation as modified by Turner and Anderson,moreover,the formulae of the complexes further gets supports from the analytical data.

The structure of the complexes are supported from variety of spectroscopic techniquelike I.R,Electronic spectra,TGAmethod whose results are summarized in Tables-3,4,5. All the complexes prove to be formed in2:1 ligand metal ratio The complexes are formed after enolisation of the drugs which is indicative  by the presence of only metal oxygen bonds and not the metal nitrogen. The Cu and Zn complexes shows tetrahedral structures while La and Co complexes shows octahedral structures in which the six co-ordination is fulfilled by two water molecule in which the oxygen of the water is vertically joining to the metal atom, above and below the plane of the molecule.

Thus on the bases of analytical data and spectroscopic studies the following structure-1 and 2 may be assign for the Cu,Zn and La, Co complexes respectively.

 

Scheme 1   Click here to View Scheme

 

CONCLUSION

As the reported metal complexes of Glimeperide drugs are able to dissociate at stomach pH, therefore its dosages, to be given to subject animals should be such that it should not be dissociate in stomach i.e. at pH 1.2 for this complexes prepared enteric coated to make at the drug bioavailable as it is, i.e. at duodenum and small intestinal pH (5.5 to 6.8 pH)

Drug is coated with a polymer HPMC-5CPS (Hydroxy propylmethyl cellulose) which does not permit drug to dissolve in stomach (i.e. pH 1.2) and such polymer dissolves rapidly at deodenal pH (5 – 5.5) thus drug releases at 5.5 pH and is available for absorption. At this pH complex is stable, non-dissociatable and absorbable. Therefore dosage forms for animals study is prepared as enteric coated, polymerized in this dosage forms are not soluble at pH 12. This drug delivery system is adopted for further study³⁶

The hypoglycemic effects Glimeperide the well known sulphonyl ureas, were inverstigated on the blood sugar levels of male albino rats by using Folin Wu method.³⁷ . Analysis of data show that thisdrugs caused a marked decrease in blood sugar level to the extent while their complexes reduced the blood sugar level to than the parent drug.

This blood sugar lowering effect of sulphonyl ureas seems to be related to the stimulation of insulin secretion on the other hand, many studies have strongly indicated the presence of long term or extra pancreatic action of sulphonyl ureas³⁸. The hypoglycemic activity of sulphonyl ureas may also be attributed to the stimulation of glycolysis and to the inhibition of glycogenesis in the liver by itself or by enhancing insulin action³⁹.

On comparing the hypoglycemic effect of these complxes with their parent drugs, it was revealed that in the three groups Glimeperide-Zn(II) treated albino rat had lowest blood sugar level being 49.72 mg/100 ml. respectively on an average. These facts clearly indicate a better hypoglycemic activity of complexes as compared to their parent drugs which is in agreement with the earlier findings of Iqbal and co-workers⁴⁰. This improved hypoglycemic activity may be related to smaller particle size of metal complexes than drugs as on complexation particle size is reduced which may promote the ratio of absorption of complexes in gastro-intestinal tract. 

Results of the present work are also in conformity with the hypoglycemic effect of copper-phenformin complex over parent drug phenformin as mentioned by Piccini et al.,⁴¹

These interesting observations on metal-complexes of oral sulphonylureas used as anti-diabetic agents for lowering blood sugar concentration may likely substantiate the use of these complexes after extensive clinical studies.

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