Analytica Chimica Acta 548 (2005) 192–198

A novel potentiometric sensor for selective determination oftheophylline: Theoretical and practical investigations

Siavash Riahia, Mir Fazllolah Mousavia,∗, S. Zahra Bathaieb, Mojtaba Shamsipurc

a Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-111, Tehran, Islamic Republic of Iranb Department of Clinical Biochemistry, Tarbiat Modarres University, Tehran, Islamic Republic of Iran

c Department of Chemistry, Razi University, Kermanshah, Islamic Republic of Iran

Received 6 May 2004; received in revised form 23 May 2005; accepted 25 May 2005Available online 11 July 2005

Abstract

A novel theophylline potentiometric sensor is prepared, characterized and used in pharmaceutical analysis. The sensor is based on a PVCmembrane containing dibutyl phthalate as plasticizer, 2,6-bis(phenyl)-4(phenyl)3H-thiopyran (PPT) as ionophore and oleic acid (HOA) asadditive. A linear response in the range of 1.0× 10−6 to 1.0× 10−2 M of theophylline with a slope 54.5± 0.4 mV per decade was established.T ivityf membranes nd distanceb , to estimatet©

K sis

1

tcptmVtie[ap

ave-trys

s sol-

llarof ation

on

sence

ed inctive

0d

he optimum pH range was 5.3–7.3 and the lower detection limit was 5.5× 10−7 M of theophylline. The electrode displays a good selector theophylline with respect to a large number of common foreign inorganic and organic species, amino acids and drugs. Theensor was successfully applied to the determination of theophylline in its tablets. A theoretical study based on the optimum angle aetween theophylline and PPT molecules was conducted. These investigations were carried out based on ab initio calculations

he pair wise interaction energy between the two molecules.2005 Elsevier B.V. All rights reserved.

eywords: Theophylline selective electrode; PVC membrane; 2,6-Bis(phenyl)-4(phenyl)3H-thiopyran; ab initio calculations; Pharmaceutical analy

. Introduction

Theophylline (1,3-dimethyl xanthine) is a bronchodilatorhat is widely used in the treatment of asthma and bron-hospasm in adults. According to a 1992–1994 surveyublished in theAmerican Journal of Hospital Pharmacy,

heophylline was one of the three drugs most frequentlyonitored by pharmacokinetics services in the 160 U.S.eterans Affairs medical centers[1]. Theophylline has been

he cornerstone of asthma management for 70 years. Its still an important drug in the treatment of this disease,specially for patients with moderate-to-severe symptoms

2]. It is commonly prescribed for pediatric patients withsthma, other forms of reactive airway disease, and apnea ofrematurely[3].

∗ Corresponding author. Fax: +98 21 8006544.E-mail address:mousavim@modares.ac.ir (M.F. Mousavi).

Theophylline have been determined by square-wvoltammetry [4], spectrophotometry[5], thin layer chromatography (TLC)[6], GC coupled to mass spectrome(GC/MS) [7], capillary GC [8], electron capture gachromatography[9], capillary electrophoresis[10], high-performance liquid chromatography[11] and liquidchromatography–mass spectrometry (LC–MS)[12]. Someof these latter techniques include pre-treatments, such avent extraction[13], solid-phase extraction[14] and proteinprecipitation[15]. On the other hand, there is a direct miceliquid chromatographic method, which uses a solutionzwitterionic surfactant as mobile phase for the determinaof theophylline[16]. Other methods include isotope dilutiMS [17], amperometry[18], some immunoassays[19], latexnephelometry[20], chemiluminescence[21], homogeneouenzyme[22], homogeneous substrate labeled fluoresc[23] and fluorescence polarization[24].

In recent years, our research group has been involvthe design and preparation of chemical sensors for sele

003-2670/$ – see front matter © 2005 Elsevier B.V. All rights reserved.oi:10.1016/j.aca.2005.05.074

S. Riahi et al. / Analytica Chimica Acta 548 (2005) 192–198 193

Scheme 1.

determination of different anions and cations[25–28]. A veryinteresting development of potentiometric sensors is in theconstruction of electrodes that respond selectively to biolog-ical compounds. To the best of our knowledge, there is noprevious report on the potentiometric methods for the deter-mination of theophylline.

In this paper we introduce a highly selective and sensi-tive PVC membrane electrode for potentiometric monitor-ing of trace amounts of theophylline using 2,6-bis(phenyl)-4(phenyl)3H-thiopyran (PPT) as a suitable ionophore(Scheme 1).

Initially, the ab initio quantum-mechanical (QM) calcula-tions at HF level were used for the calculation of interactionbetween theophylline and PPT molecules, and the optimumdistance and angle were obtained.

The proposed ion-selective membrane electrode (ISME)is very simple, durable, inexpensive, capable of reliableresponse in a wide concentration range and very useful inpharmaceutical analysis.

2. Experimental

2.1. Reagents

rom

),E)

andicaP),)edred

sedled

nstortric

2.2. Preparation of electrodes

The membrane composition was prepared by dissolving5.0 mg of PPT, 30 mg of PVC, 10 mg oleic acid and 55 mgof DBP in 5 mL of THF. The resulting mixture was trans-ferred into a glass dish of 2 cm diameter and the solventwas evaporated slowly until an oily concentrated mixture wasobtained. A Pyrex tube of 3–5 mm internal diameter in topwas dipped into the mixture for about 10 s, so that a mem-brane of about 0.3 mm thickness was formed. The tube waspulled out from the mixture and kept at room temperaturefor about 1 h. The tube was then filled with the internal fill-ing solution (1.0× 10−3 M theophylline). The electrode wasfinally conditioned for 12 h by soaking in a 1.0× 10−3 Mtheophylline. A silver/silver chloride electrode was used as areference electrode.

2.3. Tablets

A homogenized powder was prepared from 10 accuratelyweighed theophylline tablets. An appropriate amount of thispowder (0.200 g) was transferred into a 100-mL Erlenmeyerflask. Dissolution of the drug was assisted by means of a mag-netic stirrer. The solution was then diluted to the mark withwater in a 500-mL volumetric flask and the proposed elec-

lline

ng

M

as

deere

antere

eo-itiopair

PPT was synthesized and used after recrystalization fpure benzene and vacuum drying[29]. The plastisizerso-nitrophenyloctyl ether (NPOE), dibutyl phthalate (DBPdioctylphetalate (DOP) and nitrophenylpentyl ether (NPPwere obtained from Fluka. Reagent grade theophyllineits tablets were obtained from PharmaShimi pharmaceutcompany (Tehran, Iran). Sodium tetraphenyl borate (TBoleic acid (HOA), high molecular weight poly(vinyl chloride(PVC) powder and tetrahydrofurane (THF) were obtainfrom Fluka. The amino acids and drugs used were prepafrom Merck. Reagent grade nitrate salts of the cations u(from Merck or Aldrich) were of the highest purity availaband used without any further purification. Doubly distillatewater was used throughout.

Working solutions were prepared by successive dilutiowith water. All of the working solutions were buffered apH 6.0± 0.1 using a 0.05 M phosphate buffer solution. Fmeasuring the effect of pH, adjustments were made with niacid and potassium hydroxide solutions.

l

trode, using the calibration method, determined theophycontent.

2.4. Emf measurements

All emf measurements were carried out with the followiassembly:

Ag–AgCl, KCl (satd.)/internal solution (1.0× 10−3 M theo-phylline)/PVC membrane/sample solution/Ag–AgCl, 3KCl.

A model 692 Metrohm ion analyzer pH/mV meter wused for the potential measurements at 25.0± 1◦C. Singlejunction Ag–AgCl reference electrodes from Azar ElectroCompany (Orumieh, Iran) were used. All measurements wcarried out in a 50-mL double-walled glass cell, with constmagnetic stirring of the test solution. All pH adjustments wmade with diluted solutions of HNO3 or KOH. Activitieswere calculated according to the Debye–Huckel procedure[30].

3. Results and discussion

3.1. Preliminary theoretical calculations

In order to obtain a clue about the tendency of thphylline for PPT as a potential ionophore, some ab inquantum-mechanical calculations were carried out. Thewise interaction energy�EA–B between two molecules A

194 S. Riahi et al. / Analytica Chimica Acta 548 (2005) 192–198

and B is estimated as the difference between the energy ofthe complexEA–B and the energies of isolated partners:

�EA−B = EA−B − EA − EB (1)

The calculations were performed with the second-orderMøller–Plesset (MP2) perturbation theory[31,32], whichincludes the electron correlation energy in addition to theHartree–Fock (HF) energy. The use of such level of calcula-tion is fully justified by the fact that the description of basestacking requires calculations with explicit inclusion of theelectron correlation[33]. The interaction energy at a givenorder of the Møller–Plesset (MP) perturbation expansion iscalculated as:

�EMPn = �EHF +n∑

i=2

�ECorr(MPi) (2)

where �EHF is the HF energy and�ECorr(MPi) is theith order perturbative correction to the correlation energy.Only the valence electrons were explicitly correlated in ourcomputations, which correspond to the usual frozen coreapproximation. We have also limited the perturbation expan-sion (2) to the second order, which is expected to take intoaccount the major contributions to the van der Waals energies(electrostatic, polarization, dispersion, electron transfer andexchange contributions)[34].

(i.e.,C pidlyi , them stf erep

ten-t Eq.( inT al-ci do pos-s newt

thet twom e,t lts ares is-

TI

C

TCIHHA

Fig. 1. Change of total energy against distance between theophylline andPPT.

tance is 5.1A. Fig. 2illustrates the lowest energy structure ofthe complex and is based on the lowest energy conformationsof the theophylline and PPT. The ab initio calculations alsowere done on angle between theophylline and PPT at opti-mized distance, by varying between 0◦ and 180◦ in 10 steps.For each angle, the corresponding energy was calculated andthe optimized angle was obtained as 61◦.

Given the size of our systems, the computer needsPU, memory and disk space) for such calculations ra

ncrease with the size of the basis set. For this reasonedium size 6-31G* or 6-31G**[35] basis sets are mo

requently used with biomolecules. All the calculations werformed using the Gaussian 03 package[36].

Interaction energies for theophylline and some poial interference with PPT were calculated from1) and are listed inTable 1. From the data givenable 1 it is obvious that the interaction energy culated decreases in the order: theophylline� caffeine >midazole > histidine > histamine >l-arginine. Thus, basen the above ab initio calculation results, PPT couldibly be used as a suitable ionophore in preparation of aheophylline-selective membrane electrode.

A grid of ab initio data points was also computed forheophylline–PPT system by varying the distance of theolecules from 2.5 to 7.0A in 0.2A steps. For each distanc

he corresponding energy was calculated and the resuhown inFig. 1. Fig. 1clearly revealed that the optimum d

able 1nteraction energy between interference and PPT

ompounds Interaction energy (Kcal/mol)

heophylline–PPT −19.8affeine–PPT −17.6

midazole–PPT −14.2istidine–PPT −13.7istamine–PPT −13.1rgenine–PPT −11.4

Fig. 2. Optimum conformation of the theophylline–PPT system.

S. Riahi et al. / Analytica Chimica Acta 548 (2005) 192–198 195

Table 2Optimization of membrane ingredients

No. PVC (%) Plasticizer (%) PPT (%) Additive Slope Linear range (M) r

1 30 67, DBP 3 - 12.9± 0.7 1.0× 10−4 to 5.0× 10−3 0.9852 30 65, DBP 5 - 33.7± 0.5 1.0× 10−4 to 5.0× 10−3 0.9773 30 63, DBP 7 - 25.6± 0.6 7.0× 10−4 to 1.0× 10−3 0.9864 30 61, DBP 9 - 18.1± 0.6 7.0× 10−4 to 1.0× 10−3 0.9855 30 55, DBP 5 10, HOA 54.5± 0.4 1.0× 10−6 to 1.0× 10−2 0.9956 30 52, DBP 5 13, HOA 48.7± 0.4 7.0× 10−6 to 1.0× 10−2 0.9917 30 55, BA 5 10, HOA 8.3± 0.2 1.0× 10−5 to 1.0× 10−2 0.9908 30 55, AP 5 10, HOA 14.0± 0.3 7.0× 10−6 to 1.0× 10−2 0.9919 30 55, DOP 5 10, HOA 16.9± 0.2 1.0× 10−5 to 1.0× 10−2 0.989

10 30 55, DOP – 10, HOA 10.1± 0.3 1.0× 10−5 to 1.0× 10−2 0.98011 30 60, DBP 7 3, TBP 11.0± 0.3 8.0× 10−6 to 1.0× 10−2 0.98512 30 59, DBP 7 4, TBP 11.1± 0.3 8.0× 10−6 to 1.0× 10−2 0.985

3.2. Optimization of membrane composition

The response characteristics of the PVC membranesincluding the Nernstian behavior, the working concentrationsrange, the response time, the lifetime and the stability areknown to be depend on the ratio and nature of the membraneingredients. Thus, several membranes of different compo-sitions were prepared and, after conditioning for 12 h in a10−3 M theophylline solution, their potential responses werestudied.Table 2shows the effect of membrane compositionon the potential response of the sensors.

As it is seen fromTable 2, the membranes with DOP,BA, AP as plasticizer and TPB as ionic additive, and themembrane with DBP as plasticizer without any additive orwith TPB as ionic additive showed poor responses with low orvery low slopes. Only the PVC membranes plasticized withDBP in the presence of HOA as additive responded fairlywell, with optimum composition of 30% PVC, 55% DBP, 5%PPT and 10% oleic acid (No. 5) and response parameter ofnear Nernstian value of 54.5 mV/decade from 1.0× 10−6 to1.0× 10−2 M theophylline. Addition of oleic acid as suitableadditive has been shown to have a beneficial effect on theresponse characteristics of ion selective electrodes[37–39].

3.3. Effect of internal solution concentration

ont trodewr cen-t cantd xceptf lots.A itea em.

3

em-b no ts are

showed inFig. 3. As can be seen, the membrane electrodecan be suitably used in the pH range 5.3–7.3. However, theobserved changes below and above this pH range may bedue to the increased protonation of the theophylline at differ-ent nitrogen atoms of the drug molecule and the decreasedamount of TheophH+ species in solution, respectively.

3.5. Response characteristics of the electrode

The optimum equilibration time for the membrane sen-sor in the presence of 1.0× 10−3 M theophylline was 12 h,after which it was found to generate stable potentials incontact with theophylline solutions. The dynamic responsetime obtained was <15 s over the entire concentration range(Fig. 4) [40]. The sensing behavior of the membrane sen-sor remained unchanged when the potentials were recordedeither from low to high concentrations or vice versa. Themembrane electrodes prepared could be used for at least 4weeks without any measurable divergence.

The emf response of the proposed theophylline sensor(prepared under optimal membrane ingredients) indicates arectilinear range from 1.0× 10−2 to 1.0× 10−6 M. The slopeof the calibration curve was 54.5± 0.4 mV/decade of theo-phylline concentration. The limit of detection, as determinedfrom the intersection of the two extrapolated segments of thec −7

F f thes

The influence of the concentration of internal solutionhe potential response of the theophylline-selective elecas studied in a 1.0× l0−6 to 1.0× l0−3 M concentration

ange. The results showed that a variation of the conration of internal solution does not cause any signifiifference in the potential response of the electrodes, e

or an expected change in the intercept of the resulting p1.0× l0−3 M concentration of internal solution is qu

ppropriate for smooth functioning of the electrode syst

.4. Effect of pH

The influence of pH on the response of the proposed mrane electrode to 1.0× l0−3 M theophylline concentratiover the pH range 1.8–11.7 was studied and the resul

alibration graph was 5.5× 10 M.

ig. 3. Effect of pH of the test solution on the potential response oensor.

196 S. Riahi et al. / Analytica Chimica Acta 548 (2005) 192–198

Fig. 4. Dynamic response of theophylline membrane electrode for stepchanges in concentration.

3.6. Response mechanism

In fact, the proposed sensor can detect theophylline onlywhen the molecule is charged. For theophylline, the pKa,pKb1 and pKb2 values are 8.77, 13.5 and 11.5, respectively[41]. At a working pH 6.0, theophylline exists as a protonotedcharged species, TheophH+. While examination of the elec-trode at pH 9.0 (Fig. 5), where theophylline exists as a neutralspecies, does not show a significant potentiometric response

s pH.

to theophylline. Thus, in the presence of theophylline, withhigh coordination ability towards PPT, the membrane reac-tion can proceed by association of theophylline and PPT ionand the release of a proton to the membrane electrode. Thepositive change in potential upon increasing concentration oftheophylline may be related to such proton dissociation in themembrane, as:

TheophH(aq)++PPT(m) � Theoph. PPT(m)OA(m)

− + H(aq)+

As it obvious from Section3.2andTable 2, HOA plays animportant role in the response of the proposed electrode, byimproving both the sensitivity and the linear range. This couldpossibly happen by its effective contribution (via HOA�H+ + OA− process) to the extraction of theophH+ speciesinto the membrane phase and consequent release of protonfrom membrane the aqueous phase[42,43].

3.7. Selectivity coefficients

The potentiometric selectivity coefficients, whichreflected the relative response of the membrane sensor forthe theophylline over other ions present in solution, havebeen usually investigated by either the separate solution orthe fixed interference methods[44]. Both of these methodsare based on the extended Nernst equation that is suitablew thes fort auset ousc eaua uali di iont iduali reg

thatt anyc elec-t inoa ect spa-r ctiv-i> r>C , ase nsor.I ores

witht able

Fig. 5. Potentiometric response of the proposed electrode at variou

hen the primary and the interfering anions possessame charge. However, this equation is not well suitedhe theophylline selective electrodes proposed, beche interfering effects of a number of anions with variharges were investigated[45,46]. Thus, in this work, thctivity ratio method proposed Glazier and Arnold[47] wassed to measure the selectivity coefficientKPot

i,j = ai

aj, where

j represents the activity (or concentration) of the individnterfering ion tested in the range of 0.01–0.001 M anai

s the activity (or concentration) of the theophyllinehat results in the same potential change as the indivnterfering ion[47]. The resulting selectivity coefficients aiven inTable 3.

The selectivity coefficient patterns clearly indicatehe sensor is very selective for theophylline over mommon anions, several amino acids and drugs. Therode respond in the following order of preference to amcids, drugs, imidazole and histamine: theophyllin�affeine > imidazole > histidine > histamine >l-arginine >riptophane > ephedrine hydrochloride > glutamine > aagine and the others. Meanwhile, the order of selety for the anions tested is as follows: theophylline� I−SCN− > N3

− > ClO4− > acetate > salycilate > oxalate > B−

SO42− > CO3H− > NO2

− > Cl− > NO3− > F− > PO4H2−.

affeine has a structure similar to theophylline andxpected, is the most interfering compound for this set is well known that the aromatic amines coordinate mtrongly than aliphatic amines[48].

The stronger interactions of imidazoles, as comparedhese of aliphatic amines, is related to the more favor

S. Riahi et al. / Analytica Chimica Acta 548 (2005) 192–198 197

Table 3Selectivity coefficients of the PPT-based membranes at pH 6

Interference KPoti,j

F− 1.22× 10−4

Cl− 1.45× 10−4

Br− 1.76× 10−4

I− 2.41× 10−2

NO2− 1.40× 10−4

NO3− 1.32× 10−4

CO3H− 1.54× 10−4

ClO4− 3.61× 10−4

PO4H2− 1.14× 10−4

SCN− 3.27× 10−3

Azide 5.22× 10−4

Acetate 3.01× 10−4

SO42− 1.41× 10−4

Oxalate 1.95× 10−4

Methionine <10−4

Phenylalanine <10−4

Proline 1.21× 10−3

Serine <10−4

Cysteine <10−4

Tyrosine 6.08× 10−4

Asparagine 1.01× 10−3

Glutamine 9.54× 10−4

Aspartic acid 2.29× 10−4

Glutamic acid 3.86× 10−4

Lysine 4.52× 10−4

Arginine 1.26× 10−2

Histidine 4.61× 10−2

Caffeine 7.92× 10−2

Histamine 4.04× 10−2

Imidazole 5.67× 10−2

Ephedrine 2.24× 10−3

Isoleucine <10−4

Alanine <10−4

Threonine 2.19× 10−4

Glycine <10−4

Tryptophan 3.21× 10−3

Leucine <10−4

Valine 1.01× 10−4

Salysilate 2.12× 10−4

bond angle of the five-membered imidazole ring, whichacts to remove much of the steric interaction with hydro-gen of the adjacent carbon[49]. The imidazole selectivitysequence of the present sensor at the working pH 6.0, his-tamine > histidine > imidazole (Table 3) may be the result ofseveral factors such as protonation of the imidazole ring,charge carried by the ligand, and steric effects of the imi-

dazole side chains[48]. The charge of the ligand is a deter-mining factor in coordination-based potentiometric sensors.Therefore, such sensors can detect imidazole, histamine orhistidine only when molecules are charged, although imida-zole and histidine exist predominantly as neutral moleculesat pH 6.0. On the other hand, the protonated imidazolering cannot coordinate, because no lone pair of electrons isavailable for the coordination[50]. Since the pKa of imi-dazole is 7.0, about 90% of its molecules are protonatedat pH 6.0, and therefore, cannot coordinate to the S+ cen-ter. Histamine and histidine are better potential ligands thanimidazole in regard to the protonation, but higher selectiv-ity of the electrode toward histamine may be related to thesmaller steric effect of this compound with that of histidine[42].

As it is obvious fromTable 3, the iodide and thiocyanateions as soft anions show some response to the membranesensor. This is most probably due to the soft–soft electrostaticinteractions of the S+ group of the ionophore and these anions.Such a behavior was already observed[51]. However, otheranions do not show any significant interfering effect on theresponse of the proposed theophylline electrode.

3.8. Applications

In Table 4are compared some figures of merit of the pro-p hodsrT oft spect.I n oft ntra-t

ul fort para-t sedt ning2 sultso to be1 ac-t sultsoo ientst

Table 4Comparison of some figure of merit for various different methods for determi

Ref. Method it

[4] Square-wave voltammetry[14] Solid-phase extraction[49] Moleculary imprinted solid-phase extraction[50] Capillary chromatography[51] Amperometry[52] Fiber optic immunosensor[53] FluoroimmunosensorThis work Potentiometry

osed ion-selective electrode with those of different meteported for the determination of theophylline[4,14,52–56].he data given inTable 4clearly revealed the superiority

he proposed electrode over the other methods in this ren fact, there is no previous report on the determinatioheophylline at such a short response time, wide conceion range and low detection limit.

The proposed membrane sensor proved to be usefhe assay of theophylline content of pharmaceutical preions by using direct reading of the potential. It was uo analyze the theophylline content of a tablet contai00 mg of the drug, as declared by the company. The rebtained from three replicate measurements were found99.1± 0.3 mg theophylline per tablet, which is in satisf

ory agreement with the declared amount as well as the rebtained by a standard USP method[57]. This is indicativef non-interference of the other ingredients and the recip

hat are present in the formulations.

nation of theophylline

Linear range (M) Detection lim

1.0× 10−4 to 1.0× 10−1 1.0× 10−4

1.38× 10−6 to 5.5× 10−3 6.6× 10−7

1.1× 10−5 to 1.1× 10−4 1.1× 10−5

2.0× 10−6 to 5.0× 10−4 1.0× 10−6

2.0× 10−6 to 3.0× 10−4 2.0× 10−6

5.5× 10−6 to 1.1× 10−5 5.5× 10−6

2.3× 10−4 to 4.2× 10−4 1.6× 10−5

1.0× 10−6 to 1.0× 10−2 5.5× 10−7

198 S. Riahi et al. / Analytica Chimica Acta 548 (2005) 192–198

4. Conclusion

On the basis of the results discussed in this paper, PPT canbe considered as a natural carrier for construction of a PVC-based membrane theophylline selective electrode has beenshown to have good operating characteristics (sensitivity, sta-bility, response time, detection limit and a wide linear range).The electrode was successfully applied for a determination oftheophylline content some real samples. Calculation studiesclearly revealed that interaction of between PPT and theo-phylline molecules can help to understanding actual groupson the molecules that interact to gather.

Acknowledgements

We would like to thank Dr. Sabzyan for providing hard-ware/software facilates to carry out the computations viaInternet and also the authors gratefully acknowledge the sup-port of this work by the Tarbiat Modarres University.

References

[1] C.E. Howard, C.C. Capers, D.T. Bess, R.J. Anderson, Am. J. Hosp.Pharm. 51 (1994) 1672.

[2] A. Goodman-Hilman, T. Rall, A. Nier, P. Taylor, The Pharmacolog-

5.

arm.

, J.

eer,

ett,

976)

[ 995)

[ 999)

[ r. A

[ 976)

[[[ 993)

[ Anal.

[[ im.

[ lin.

[ , S.rug.

[22] J. Chang, S. Gotcher, J.B. Gushaw, Clin. Chem. 28 (1982) 361.[23] T.M. Li, J.L. Benovic, R.T. Buckler, J.F. Burd, Clin. Chem. 27 (1981)

22.[24] I.N. Papadoyannis, V.F. Samanidou, H. Tsoukali, F. Epivatianou,

Anal. Lett. 26 (1993) 2127.[25] M.F. Mousavi, M. Shamsipur, S. Riahi, M.S. Rahmanifar, Anal. Sci.

18 (2002) 137.[26] S. Riahi, M.F. Mousavi, M. Shamsipur, H. Sharghi, Electroanalysis

15 (2003) 1561.[27] H. Karami, M.F. Mousavi, M. Shamsipur, Talanta 63 (2004) 743.[28] H. Karami, M.F. Mousavi, M. Shamsipur, Anal. Chim. Acta 481

(2003) 213.[29] R. Wizinger, Helv. Chim. Acta 39 (1956) 207.[30] P.C. Meier, Anal. Chim. Acta 136 (1982) 363.[31] C. Møller, M.S. Plesset, Phys. Rev. 46 (1934) 618.[32] M. Head-Gordon, J.A. Pople, M.J. Frisch, Chem. Phys. Lett. 153

(1988) 503.[33] J. Siponer, I. Berger, N. Sipacikova, J. Leszczynski, P. Hobza, J.

Biomol. Struct. Dyn. 11 (2000) 383.[34] G. Chalasinski, M.M. Szczesniak, Chem. Rev. 94 (1994) 1723.[35] R. Ditchfield, W. Hehre, J.A. Pople, J. Chem. Phys. 54 (1971)

724.[36] M.J. Frisch, G.W. Trucks, M. Head-Gordon, P.M.W. Gill, M.W.

Wong, J.B. Foresman, B.G. Jonhson, H.B. Schlegel, M.A. Robb, E.S.Replogle, R. Gomprets, J.L. Andres, K. Raghavachari, J.S. Binkley,C. Gonzalez, R.L. Martin, D.J. Fox, D.J. Defrees, J. Baker, J.J.P.Stewart, J.A. Pople, GAUSSIAN 2003/DFT, Gaussian Inc., Pitts-burgh, PA, 1993.

[37] D. Ammann, E. Pretsch, W. Simon, E. Lindner, A. Bezegh, E. Pun-gor, Anal. Chim. Acta 171 (1985) 119.

[38] M. Akhond, M.B. Najafi, J. Tashkhourian, Sens. Actuators B 99

[ 163

[[ als,

usersion

[ . 71

[ 999)

[ . 48

[ 88)

[[[[[[ am-

[ 35.[ n. 7

[ 0)

[ 11

[ , C.

[ poeia,D,

ical Basis of Therapeutics, McGraw-Hill, New York, 1996.[3] R. Wyatt, M. Weinberger, L. Hendeles, J. Pediatr. 92 (1978) 12[4] J.M. Zen, T.Y. Yu, Y. Shih, Talanta 50 (1999) 635.[5] Z. Senturk, N. Erk, S.A. Ozkan, C. Akay, S. Cevheroglu, J. Ph

Biomed. Anal. 29 (2002) 291.[6] A. Mirfazelian, M. Goudarzi, M. Tabatabaiefar, M. Mahmoudian

Pharm. Pharm. Sci. 5 (2002) 131.[7] L.M. Thienpont, B. Van Nieuwenhove, D. Stoeckl, A.P. Leenh

Clin. Chem. 40 (1994) 1503.[8] O.H. Drummer, S. Horomidis, S. Kourtis, M. Syrjanen, P. Tipp

J. Anal. Toxicol. 18 (1994) 134.[9] H.A. Schwertner, T.M. Ludden, J.E. Wallace, Anal. Chem. 48 (1

1875.10] Z.Y. Zhang, M.J. Fasco, L.S. Kaminsky, J. Chromatogr. B 665 (1

201.11] P.V. Devarajan, P.N. Sule, D.V. Parmar, J. Chromatogr. B 736 (1

289.12] H. Kanazawa, R. Atsumi, Y. Matsushima, J. Kizu, J. Chromatog

870 (2000) 87.13] R.F. Adams, F.L. Vandemark, G.J. Schmidt, Clin. Chem. 22 (1

1903.14] W.M. Mullett, E.P.C. Lai, Anal. Chem. 70 (1998) 3636.15] K.Z. Shihaby, J. Liquid Chromatogr. 11 (1988) 1579.16] D. Habel, S. Guermouche, M.H. Guermouche, Analyst 118 (1

1511.17] F. Susanto, S. Humfeld, M. Niederau, H. Reinauer, Fresenius J.

Chem. 344 (1992) 549.18] J. Wang, E. Dempsey, M. Ozsoz, Analyst 116 (1991) 997.19] K.S. Lee, T.H. Kim, M.C. Shin, W.Y. Lee, J.K. Park, Anal. Ch

Acta 380 (1999) 17.20] L. Borque, A. Rus, C. Maside, J. Del Cura, Eur. J. Chem. C

Biochem. 30 (1992) 307.21] D.P. Malliaros, S.S. Wong, A.H. Wu, J. Campbell, H. Leonard

Houser, M. Berg, T. Giornet, C. Brown, Y.J. Feng, Ther. DMonit. 19 (1997) 224.

(2004) 410.39] M. Szpakowska, J. Szwacki, A. Lisowska-Oleksiak, Desalination

(2004) 55.40] Carlo Macca, Anal. Chim. Acta 512 (2004) 183.41] Merk Index, in: S. Budavari (Ed.), An Encyclopedia of Chemic

Drugs and Biologicals, 12th edn., Merk & Co., Inc., WhitehoStation, NJ, 1996, p. 1584. (SAS/STAT, 1989. User’s Guide, Ve6. Vol. 2, 4th edn.).

42] M.K. Amini, S. Shahrokhian, S. Tangestaninejad, Anal. Chem(1999) 2502.

43] M.K. Amini, S. Shahrokhian, S. Tangestaninejad, Analyst 124 (11319.

44] G.G. Guilbault, W. Simon, J.D.R. Thomas, Pure Appl. Chem(1976) 127.

45] Y. Umezawa, M. Kataoka, H. Nada, Anal. Chem. 60 (192392.

46] R.W. Cattral, D. Drew, Anal. Chim. Acta 77 (1975) 9.47] S.A. Glazier, M.A. Arnold, Anal. Chem. 63 (1991) 754.48] T. Tatsuma, T. Watanabe, Anal. Chem. 64 (1992) 143.49] F.A. Walker, J. Am. Chem. Soc. 95 (1973) 1150.50] T. Tatsuma, D.A. Buttry, Anal. Chem. 69 (1997) 887.51] T. Poursaberi, M. Hoseini, M. Taghizadeh, H. Pirelahi, M. Sh

sipur, M.R. Ganjali, Microchem. J. 77 (2002) 72.52] W.M. Mullett, E.P.C. Lai, J. Pharm. Biomed. Anal. 21 (1999) 853] C.J. McNeil, J.M. Cooper, J.A. Spoors, Biosens. Bioelectro

(1992) 375.54] A. Wang, L. Li, F. Zang, Y. Fang, Anal. Chim. Acta 419 (200

235.55] C.M. Hanbury, W.G. Miller, R.B. Harris, Biosens. Bioelectron.

(1996) 1129.56] R.M. Garcinuno, P. Fernaqndez, C.P. Conde, A.M. Gutierrez

Camara, Talanta 52 (2000) 825.57] US Pharmacopoeial Convention Inc., United States Pharmaco

XXIII ed., US Pharmacopoeial Convention Inc., Rockville, M1993, p. 951.