American JournDOI: 10.5923/j

nal of Chemistry

SpTartr

Department o

Abstract Ametoprolol taton-Robinson law within thcoefficient (r =determinationcomplex of M

Keywords

1. IntroduMetoprolol

antagonist whdisorders sucarrhythmias asensitive, and blockade. Thein sports and list of forbiddmittee (IOC)[method for thgreat significain USP 23 NFmetric and spseveral methoMPT in plasmgraphy (HPLCColorimetric dcarbon disulpChloroform wplex. Many ofdeterminationmany years, thical technique

* Corresponding aag518@ksu.edu.tr Published online aCopyright © 2011

.chemistry.2011y: 2011; 1(1): 9--15 0101.02 

pectroprate in

of Chemistry, Fa

A new, simplrtrate (MPT), buffer solutioe concentratio= 0.998) with

n of this drug iMPT (Cu2MPT2

β-blockers, M

uction tartrate (schem

hich is used inch as hypertenand myocardia

even a small e β-blockers artherefore thes

den drugs by t1]. Therefore the determinatiance. The assaF18 (1995)[2] pectrophotomeods have beenma using highC) with UV odetermination

phide and Cu(was used as anf these method

n of MPT by the use of compe was used in

author: (A. Golcu)

at http://journal.sapuScientific & Acade

photomPharm

Fo

aculty of Science

le, sensitive awhich is bas

on, to produce on range 8.5-7a limit of detein its tablets. 2Cl2) have been

Metoprolol, Co

me 1) is a selen the treatmentnsion, angina al infarction. dose of the drure also misusedse drugs have the Internationthe developmeion of metopray procedures and BP (1998

etric methods[n reported forh-performanceor fluorescencof some β-blo

(II) ions has bn extractant fords involve a cthis way has b

mplexation reaclot of areas su

ub.org/chemistry emic Publishing. A

metric Dmaceutiormatio

M. Cesme,

e and Arts, Univma

and accurate sed on the coma blue adduct.

70μg/mL. Regrection of 5.56μIn addition, thn reported.

omplexation, S

ective β-adrenet of cardiovasc

pectoris, carThe drug is qug gives sufficd as doping agbeen added to

nal Olympic Cent of an analyrolol tartrate iof this drug li

8)[3] describe [4,5]. In addir quantificatioe liquid chromce detection[6-ocking drugs ubeen reportedr the formed complex separabeen reported.ctions as an anuch as, paints

All Rights Reserved

Determical Doson with

D. Tarinc, A

versity of Kahramanmaras, Turkey

spectrophotommplexation of . The latter haression analysμg/mL. The prohe spectral dat

Spectrophotom

ergic cular rdiac quite cient gents o the Com-ytical is of isted titri-tion, n of

mato--15].

using [16]. com-ation For alyt- and

d

pigmendeterm(pharmalloys spectrobased then be

2. Ex2.1. Re

MPTprovidper(II)obtainused in

2.2. Ph

Thetained

inationsage Foh Cu(II

A. Golcu*

manmaras Sutcuy

metric method f drug with coas a maximum sis of the caliboposed procedta and stability

metry

nts, textile (mmination of mmaceuticals, bi

and natural teophotometric on its compleeen applied to

Schem

xperimenteagents

T and its dosaded by AstraZ) chloride dihyed from E. Men order to ensu

hysical Measu

e carbon, hydrusing a Leco

n of Metorms onI)

u Imam, Campu

has been devopper(II)[Cu(II

absorbance atbration data shdure has been sy constant for

mordantion remetals and dru

ological sampea)[17-21]. Inmethod for th

exation reactiothe analysis o

me 1. The struct

tal Section

age forms (BeZenaca Comp. ydrate and cheerck or Carlo Eure the absence

urements

rogen and nito 932 CHNS

toprolon Comp

use of Avsar, 461

veloped for thI)] at pH 6.0, t 675nm and ohowed a goodsuccessfully apr the binuclear

eactions), dyeugs in a lot oles, natural wa

n this paper, whe determination with Cu(II)of MPT in table

ture of MPT.

n

eloc Durules) w(Istanbul, Tu

emicals and soErba. Deionizee of any undes

trogen analyseelemental an

ol plex

100, Kahra-

he assay of using Brit-

obeys Beer’s d correlation pplied to the r copper (II)

e-stuffs and of materials ater samples,

we present a ion of MPT ), which has ets.

were kindly urkey). Cop-olvents were ed water was irable ions.

es were ob-nalyser. The

10   A. Golcu et al.: Spectrophotometric Determination of Metoprolol Tartrate in Pharmaceutical Dosage Forms on Complex Formation with Cu(II)

infrared spectra (4,000-400cm−1) were obtained on a Perkin Elmer Spectrum 400 FTIR spectrophotometer using KBr discs. The electronic spectra were recorded in DMSO on a Perkin Elmer Lambda 45 spectrophotometer. Magnetic susceptibilities were measured by the Gouy method at room temperature using Hg[Co(SCN)4] as calibrant. Molar con-ductance of the complex was determined in water (∼10−3M) at room temperature using a Jenway Model 4070 conduc-tivity meter. The metal content of the complex was deter-mined by an ATI Unicam 929 Model AA spectrometer in solutions prepared by decomposing the compounds in aqua regia and then subsequently digesting in concentrated HNO3/H2O2 (1/1).

2.3. Standard Solutions for Spectrophotometric Deter-mination

A stock solution in water containing 0.2mg/mL of MPT was prepared and was diluted as appropriate. This solution was stable for 1 week if kept in the refrigerator. CuCl2·2H2O solution 0.5% (w/v) was prepared in water.

2.4. Calibration Curve

Aliquot volumes of the stock solution containing 8.5-70 μg of MPT were transferred into a series of 10mL volumetric flasks. Britton-Robinson buffer (1mL) and CuCl2·2H2O solutions (1mL) were added, mixed well for 20 min while heating using a thermostatically controlled water bath at 35°C, and then cooled rapidly. The solutions were next completed to the mark with distilled water and the absorb-ance at 675nm was measured against a reagent blank. A calibration curve was plotted and the corresponding regres-sion equation then derived.

2.5. Procedure for Tablets

Ten tablets were weighed and pulverized, then a quantity of the powder equivalent to 40mg MPT was transferred into a small conical flask and extracted with 4 × 20mL of water, filtered into a 100mL volumetric flask and completed to the mark with water. Aliquots were transferred into a 10mL volumetric flask, than the procedure as described in Section 2.4 was applied. The nominal content of the tablet was determined either from the regression equation or using the calibration graph.

2.6. Preparation of the Binuclear Cu(II) Complex of MPT

Methanolic CuCl2·H2O solution (20mL, 0.171g, 1.0mmol) was added dropwise to a methanolic solution of MPT (20mL, 0.267g, 1.0mmol) according to the literature[22]. The reac-tion mixture was heated using a thermostatically controlled water bath at 35°C for 4 hours. The resulting blue precipitate was filtered, washed with methanol/water (1:1 v/v) and dried under vacuum over P2O5 for several days. Chloride ions in the resulting MPT2Cu2Cl2complex (Scheme 2) were deter-mined by titration with AgNO3. Molecular weight: 730.71 gr/mol, Elemental analysis: (Found/Calculated): C%:

49.26/49.31, H%: 6.50/6.62, N%: 3.40/3.83, Cu%: 17.01/17.39, M.P. > 200°C. Solubility: water, DMSO and acetonitrile/water (v/v, 1/1).

Scheme 2. The structure of MPT2Cu2Cl2.

3. Results and Discussion 3.1. Characterization of the Binuclear Cu(II) Complex of MPT

The goal of this study was to synthesize a Cu(II) complex of the anthypertensive drug MPT, which is as a loop an-thypertensive that blocks active sodium chloride transport in the thick ascending limb of Henle’s loop. The[M]:[L] ratios were varied from 1:10 to 10:1 to find out the optimal ratio for complex formation. The effect of heat on the complex for-mation was investigated by changing the reaction tempera-ture from +0°C to the boiling point of the solvent used. The effect of pH on the complex formation was investigated; pH 6.0 was found to be the optimal value. The complex forma-tion reactions were carried out with acetate and chloride salts of Cu(II). The highest yield for the MPT-metal complex was obtained with the chloride salt of Cu(II). This situation may be due to the role of the substituent groups attached to the benzene ring. Yield of the complex was investigated in different solvents such as water, methanol and acetonitrile. The best yield for the Cu(II) complex was obtained from water. The effect of the reaction time was also investigated. Reaction mixture was stirred in time intervals from 10 min to 48 hours. The molar conductance (LM) value (given in parentheses) in DMSO for MPT2Cu2Cl2 (21.42) suggests a 1:2 electrolytic complex[22].

3.2. Infrared Spectra

In determining the mode of binding of the ligand to the metal ion in the complex. The following three regions of the infrared spectrum have been studied:

1) The 3459cm−1 associated with the ν(OH) vibrational mode.

2) The 2980 and 2872cm−1 region associated with the ν(NH2) and ν(NH) modes.

3) The region 487-318cm−1 due to ν(M-N), ν(M-O) and ν(M-Cl) vibrations.

  American Journal of Chemistry: 2011; 1(1): 9-15  11  

(a)

(b)

(c)

Figure 1. The infrared spectra of: (a) metoprolol tartrate; (b) binuclear MPT-Cu(II) complex; (c) far infrared of binuclear MPT-Cu(II) complex.

  A. Golcu et al. in Pharmac

12

The spectrabands at 345ν(OH), ν(NHtively, participmolecular H-bMPT shows bspectively, foobserved hereoxygen. Sharpdescribed as suggesting co(Figure 1)[23]vibrations wertively, in acco

3.3. Electroni

The electroin order to obvcomplex contrange (relativassigned to thtion. Thesse dthe formation tronic spectra molar absorptmarily ligand-is associated order to studymolar ratio busing Job’s ccated a molar respect to the

Figure 2. The reaction of MPT a

3.4. Atomic A

The ratios termined by awas decompo1.5 N HNO3. ports the struc

3.5. Magnetic

The magnecomplex, (Cutemperature fo

a of the free li59 and 2980-2H2) and ν(NH)

pating in the fbonds. The bbands at 2977r ν(NH2) and

e because of tp bands attributhe asymmet

oordination wit]. In the far-IRre observed at

ordance with li

ic Absorption

nic spectra of viate the effect ain some abso

vely weak, lowhe d-d transitiodata are in acco

of M-N, M-Oof the comple

tivity in the 6-centered transwith benzene

y the stoichiometween metal

continuous varratio of donor drug salt (Figu

continuous variaand copper(II).

Absorption Sp

of the metal patomic absorptsed in HNO3/HThe amount o

cture given in S

c Measuremen

etic moment (u(MPT)2(MeOound to be 1.25

e: Spectrophoto

igand (MPT) s2872cm−1 corr) stretching frformation of iinuclear Cu(II

7, 2892-3170 aδ(NH). No ν

the deprotonatutable to ν(NHtric (1606cm−

th the NH groR region, M-Nt 487, 430 andterature data[2

n Spectra

f the complex wof the solvent

orption bands w-energy bandons in a squareordance with t

O and M-CI boex contain a b75nm region, sition. The bane π-π * transimetry of the co

ions and druriation methodr to acceptor ofure 2).

ation plot for the

pectra

present in the tion spectroscoH2O2 (1/1) andof Cu was deteScheme 2[27-2

nt

(B.M.) of theOH)2), was m5; this also sup

eutical Dosage Fometric Determ

showed absorpresponding torequencies resintra- and/or inI) complex ofand 3213cm−1

ν(OH) bands wtion of the alcH2) motion ma−1) N-H stretcoup of the ligN, M-O and Md 318cm–1, res24,25]

was taken in w. The spectra oin the 811-27

ds) which maye planar configthe assumption

onds[26]. The eband with a hi

assigned to and at higher enitions (261nm)oloured producug was determd[22], which if 1:1 for MPT

e stoichiometry o

complex wasopy. The comd then dissolveermined. This 29].

e binuclear Cmeasured at rpports the prop

Forms on Compination of Metop

ption o the spec-nter-f the , re-were

cohol ay be ches, ands

M-Cl spec-

water of the 74nm y be gura-n for elec-igher a pri-nergy ). In

ct the mined

indi-with

 of the

s de-mplex ed in sup-

u(II) room osed

structuobeys larger has beCu(II) ture.

3.6. An

Copdary aatenolothrougaliphatwith thadductblue amaxim

Theduced the optthe inmaximat appcarbonstudiedwas prance rCu(II) in agre

Figure μg/mL)

Figure MPT (20

The

plex Formation wprolol Tartrate with Cu(II)

ure[30,31]. Thethe Curie-Weisize of the lig

een assigned tocomplex may

nalytical Data

pper(II) is a laamines. Severol, acebutolol

gh this approactic amino derivhe formation ot. Under the ddduct has a ch

mum absorptione different exp

color were extimal conditionfluence of pH

mum absorptionproximately pHnate or phospd and compareroven to be sueadings were to Cu(OH)2 u

eement with th

3. Effect of pH with copper(II).

0

A

0 5.0 4.

0 6.

4. Effect of tem0 μg/mL) with co

e effect of tem

e magnetic susiss law. Due toand the lower

o these compley thus have th

a

abelling reagenal pharmaceutand proprano

ch[30]. Metopvative, that waf the binucleardescribed expharacteristic abn at 675nm. erimental para

xtensively studns for the deterH on the abson using BrittoH 6 (Figure 3hate having ted with Britto

uperior to the ohigher. This i

using the otherhose of Miyano

on the developm

25 30 35

. . .

mperature on the pper(II). 

mperature on t

sceptibility of to steric interaccoordination n

exes[31,32]. Thhe usual tetrah

nt for primarytical compoun

olol have been rolol tartrate is found to reacr complex resuperimental conbsorption spec

ameters affectidied in order trmination of thorption was s

on-Robinson bu3). Other buffthe same pH on-Robinson bothers becauses due to the h

r buffers. Theso et al[33].

ment of the comple

C5 40 45

. .

o

development of t

the produced

this complex ctions of the number four he binuclear hedral struc-

y and secon-nds such as

determined is secondary ct with Cu(II) ulting in blue nditions, the ctrum with a

ing the pro-to determine he drug. First, studied. The uffer occurs fers such as value were

buffer which the absorb-

hydrolysis of e results are

 ex of MPT (20

C the complex of

adduct was

Ammerican Journall of Chemistry: 22011; 1(1): 9-155  13 

studied, and itbetter than heperiod (Figure

The most imcolor of the adthat 1mL of 0tivity. Increasthe absorbancabsorbance ofproduct of Cu+

pH less than 4tion prior to background aadduct, hence

Figure 5. Effecof the complex of

Optimizatiotometric propdifferent expeand stability optimized. Fowas used. Theferent times (5until 50 min. T(SD ± 0.03).

The stabilitculated adopti

where A is correspondingin Figure 3, Cmum absorbaproduct. Using× 1010. Underelation betwetration of MPLinear regressconcentration-

Awhere C is

ance and ‘r’ is

t was found thaeating at a hie 4). mportant factodduct was the 0.5% w/v Cu+2

sing the volumce, which mayf the reagent. T+2, namely Cu(4. Therefore, a

the measuremabsorbancy wi, the sensitivity

ct of volume of copf MPT (20 μg/mL

on of the reactperties of the ferimental parof the compl

or stability stue absorbance v5-60 min). TheThe absorbanc

ty constant of ing the followi

( - /1f

A

AK =

maximum abg to intersectionC is the conceance, n is the g this equation

er the describeeen the absorbaPT was linear sion analysis o-absorption daA = 70,000C −

the concentras the correlatio

at heating at 35igher tempera

r affecting thevolume of Cu

2 solution gaveme of Cu+2 leady be due to theThe absorption(OH)2, compleacidification ofment remarkabithout affectiny of the proced

pper(II) (0.5%, w/) with copper(II).

tion conditionsformed compl

rameters affeclex were caredies, the UV values have be absorbance vce value is decr

the reaction ping formula[34/ Am

/ Am) C nn+1 nn

sorbance, Amn of the two ta

entration corresamount of the

n, Kf was founded experimentance at 675 nm

r over the 8.5of the ata gave the fol− 0.00271, r = 0ation in μg/mLon coefficient

5°C for 20 minature for a sho

the produced u+2. Figure 5 she maximum seds to a decrease high backgron of the hydrotely disappearef the reaction sbly decreasedng the drug-mdure increased

/v) on the develop

s. The spectroplex as well ascting developmefully studied spectrophotom

been measuredvalue is not chareased after 50

product Kf was4]:

n m is the absorbangests of the csponding to me drug in reacd to be equal total conditions,m with the con-70 μg/mL ra

llowing equati0.998

L, A is the absshowing exce

n was orter

blue hows ensi-se in ound lysis ed at solu-d the metal d.

pment

pho-s the ment

and meter d dif-ange min

cal-

ance curve maxi-ction o 1.5 , the

ncen-ange.

on:

sorb-ellent

lineariThe

trationthe limtrationμg/mL

Table 1nation M

MeasuLinearSlope Absorbε * InterceCorrelLOD (LOQ (RepeatRepeatReprodReprod

* Mola

Table

ProducLabeleAmouRSD%Bias%t-test (F-test AddedFoundRecovRSD%Bias%

a Each

Statand obetweeaccura

Thetion oftabletsof anaanalysand dinificanaccuraphotombeen gadvantterminmetal simpleuniform

ity. e limit of deten at a signal-tomit of quantificn at a sigL[31,32,35].

1. Regression daMPT by UV metho

ured wavelength (λrity range (μg/mL) bance range

ept lation coefficient ((μg/mL) (μg/mL) tability of absorbatability of wavelenducibility of absorducibility of wave

ar absorption coef

e 2. Assay result

ct ed claim (mg)

unt found (mg) a

% % (ttheoretical = 2.31)(Ftheoretical = 2.60)

d (mg) d (mg) a very% % of recovery %

value is the mean

tistical analysisofficial methoen the performacy and precisie proposed metf MPT in tables are: sodium chalysis of tablsis of the resultirect UV-specnt difference acy (t-test) anmetric method given in Table tageous over t

nation of Cu(II)are drawn). A

e, and accuratmity or routi

ction (LOD), o-noise ratio 3 cation (LOQ),gnal-to-noise

ta of the calibratiod.

λmax as nm) )

(r)

ance (RSD%) ngth (RSD%) rbance (RSD%) elength (RSD%)

fficients have been

s from MPT dosag

n of five experimen

s of the resultsds revealed n

mance of the twion as shown inthod was next ets. Inactive inhloride and titaets are shownts obtained by ctrophotometri

between the nd precision (F

was validated2. However, t

the reference ) can be done (

Also, the propte. It can be aine quality co

expressed as s/m, was 5.56 expressed as

ratio 10

on line for quanti

Complexa-tion method

675 8.5-70

0.7 × 105 0.254-0.921

91.900 -0.0271 0.998 5.56 7.11 1.54 0.04 0.45 0.12

n calculated for 30

ge forms and mea

MPTBeloc Duru

200199.500.004−0.340.700.2240

40.56100.61.30

−0.46

nts.

s obtained by thno significantwo methods ren Table 1. applied to the

ngredients contanium dioxiden in Table 2both the propo

ic method shotwo method

F-test). The Ud by us and the the proposed pmethods sinc

(if calibration cosed method applied for eitontrol and no

the concen-6 μg/mL and

the concen-s/m, 7.11

itative determi-

UV-spectrophotometric method

274 68.4-205.40.25 × 104 0.276-0.79

2565 0.0148 0.998 8.10 26.98 0.21 0.02 0.63 0.03

0 μg/mL.

an recoveries.

T ules

he proposed t difference egarding the

e determina-tained in the . The results

2. Statistical osed method ows no sig-s regarding

UV spectro-results have procedure is e direct de-curves of the is sensitive, ther content o expensive

14   A. Golcu et al.: Spectrophotometric Determination of Metoprolol Tartrate in Pharmaceutical Dosage Forms on Complex Formation with Cu(II)

laboratory techniques are needed.

4. Conclusions A simple, sensitive and accurate spectrophotometric

method has been developed for the assay of metoprolol tartrate (MPT), based on the complexation of drug with copper(II)[Cu(II)] at pH 6.0, using Britton-Robinson buffer solution, to produce a blue adduct. The developed method is more selective, sensitive, reproducible, rapid, cheap and simple than in most of the analogous methods cited in the literature[6-15]. For these reasons, it can be used in routine analysis and can be applied for the determination of MPT in pharmaceutical formulations and biological samples.

ACKNOWLEDGEMENTS The author gratefully acknowledge the funding of this

work by the Research Fund (Project No: 2009-4/12) of Kahramanmaraş Sutçu Imam University, Kahramanmaras, Turkey.

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