World Journal of Chemistry 6 (2): 59-74, 2011ISSN 1817-3128© IDOSI Publications, 2011

Corresponding Author: Barkha Singhal, School of Biotechnology, Gautam Buddha University, Greater Noida, (U.P.) 201310 India.Tel: +0120-2344290.

59

Drug Analysis: A Perspective of Potentiometric Sensors

Barkha Singhal

School of Biotechnology, Gautam Buddha University, Greater Noida, (U.P.) 201310-India

Abstract: The remarkable specificity of biological recognition processes has led to the development of highlyselective bio-sensing devices. Electrochemical biosensors hold a leading position among the bio-probescurrently available and hold great promise for the task of pharmaceutical analysis. They are inherently sensitiveand selective towards electro-active species, fast and accurate, compact, portable and inexpensive. Among thempotentiometric sensors are very attractive strategy that can be used for the direct measurement of ions, gasesand bio-molecules in complex samples. In this report, an attempt has been made to provide a brief insight to theapplicability and advantages of potentiometric sensors in analysis of pharmaceutically active compounds.

Key words: Membrane sensors % Potentiometry % Biosensors % Ionophore % Drugs analysis

INTRODUCTION particular ion to be determined and poor affinity for

The largest group among potentiometric sensors is rapid exchange kinetics and adequate complex formationrepresented by ion-selective electrodes (ISEs), the oldest constants in the membrane. Also, they should be welland most widely used among them being a pH-sensitive soluble in the membrane matrix and have a sufficientglass electrode. Now-a-days there exists a large variety of lipophilicity to prevent leaching from the membrane intocommercially available ISEs that may be helpful in direct the sample solution. In addition, the selectivity of thedetermination of ion concentration in liquid samples of neutral carrier-based ISEs is known to be governingdifferent nature. Measurements with ISEs are performed by stability constant of the neutral carrier-ion complexwith reference to some stable and well defined reference and its partition constant between the membrane andelectrode contacting the sample solution through a liquid sample solution. A significant number of ionophoresjunction. In ISEs the signal is generated by charge including crown ethers, cryptands, aza-crowns,separation at the interface between ion-selective thiocrowns and thia compounds have already beenmembrane and the solution due to selective partitioning exploited for fabrication of poly(vinyl chloride) (PVC)of ionic species between these two phases. In classical membrane electrodes for series of alkali, alkalineISEs the arrangement is symmetrical which means earth, transition and heavy metal ions. Now-a-daysthat the membrane separates two solutions, the test developments in pharmaceutical analysis withsolution and the inner solution with constant ion-selective electrodes have enabled the direct andconcentration of ionic species. The electrical contact selective measurement of the activity of variousto an ISE is provided by a reference electrode organic cations or anions of pharmaceutical interest, in(usually Ag/AgCl) in contact with the internal solution most instances without prior separation of the activethat contains chloride ions at constant concentration. substance from the formulation matrix. SignificantPotentiometric sensors operate at thermodynamic technological advances have been envisaged duringequilibrium conditions. Thus, in practical potentiometric last decade to facilitate the pharmaceuticalsensing, the potential measurement needs to be made applications of these devices. Various reports haveunder zero-current conditions. been published which highlights the important

An important requirement for the preparation of contribution of ion-selective sensors for quantificationan ion selective sensor is that the electro active material of drugs [1-4]. This report highlights some of the(ionophore), which is used in the membranes, should important potentiometric sensors which have been usedexhibit high lipophilicity and strong affinity for a in pharmaceutical analysis.

others. Ionophores for use in sensors should have

µ

( )( ) ( ) ( )2.303 logA aqA aq A aq A aqRT a Z Fοµ µ φ= + +

( ) ( ) ( )A aq A aq A aqZ Fµ µ φ= +

( ) ( ) ( )A org A org A orgZ Fµ µ φ= +

( ) ( )A aq A orgµ µ=

World J. Chem., 6 (2): 59-74, 2011

60

Principle of Ion-selective Membrane: Ion-selective electrodes are typically investigated under zero current conditionby following cell set up.

The electromotive force (emf) across this cell is the is often the case for membranes that showsum of all individual potential contributions. Many of theoretical Nernstian response. Phase boundarythese are sample-independent and the measured emf can potential E arises from a charge separation caused byusually be described as the non-uniform distribution of ionic species between the

emf = E + E + E (1) boundary potential can be derived from basicconst J M

Liquid junction potential originates E from the potential contributions. The electrochemical potential, J

different mobility of ionic species in the sample solution for species A in aqueous phase could be written asand in the bridge electrolyte of the reference electrode if follows.ion-selective electrodes can be kept constant byemploying concentrated bridge electrolytes with similarmobilities of cations and anions (e.g. 1M KCl, NH NO , or (3)4 3

LiOAc).The utility of membrane electrodes depends upon the Similarly, the electrochemical potential for the analyte ion

determination of membrane potentials E , which is ideally (A) in contacting organic phase isM

a function of the sample ion activity [5]. So we will onlyfocus on the membrane potential E of electrode.M

Since the membrane is usually interposed betweenthe sample and an inner reference electrolyte, it is (4)commonly divided into three separate potentialcontributions, namely the phase boundary potentials at Where µ is the chemical potential and µ° is chemicalboth interfaces and the diffusion potential within the ion- potential under standard conditions, z is valency ofselective membrane. analyte ion A and a is the activity of the uncomplexed

E = E + E (2) universal gas constant, absolute temperature and FaradayM PB Diff

The potential at the membrane/inner filling solution complexation processes are relatively fast and therefore,interface can be assumed to be independent of the equilibrium holds at the interface so that thesample, whereas the diffusion potential within the electrochemical potential for both phases are equal. Thismembrane may become significant if considerable leads to a simple expression for the phase boundaryconcentration gradients of ions with different mobilities potential, i.e.arise in the membrane. If no concentration gradients occurwithin the membrane, diffusion potential E is zero. This (5)Diff

PB

organic membrane and the aqueous phase. The phase

thermodynamic considerations of chemical and electrical

A

A

ion A, N is the electric potential and R, T and F are the

constant. It is assumed that the interfacial ion transfer and

( )2.303

logM A aqA

RTE E a

Z Fο= +

World J. Chem., 6 (2): 59-74, 2011

61

Thus, equation (5) indicates that the phase boundary (TEHPY) as a solvent mediator. The use of TEHPYpotential is a simple function of sample ion activity (a ) suppressed the responses to lipophilic quaternaryA(aq)

particularly if a is not significantly altered by the ammonium ions and strengthened the response toA(org)

sample. The complexation of analyte ion A with the cocaine. The electrode exhibited a near-Nernstianionophore inside the organic membrane phase influences response over a concentration range of 10G to 10G Mfree analyte activity a and therefore, also the phase cocaine with a slope of 56 mV per decade.A(org)

boundary potential [6]. However, due to the strong Recently Abbas and coworkers reported novelcomplexation with the ionophore, concentration of the potentiometric membrane ion-selective electrodes forfree ion in the organic membrane is small relative to that of determination of papaverine hydrochloride [8]. They arethe complexed ions. Consequently, the concentration of based on the formation of the ion-association complexesthe complex is approximately equal to that of the anionic of papaverine (PA) with tetraphenylborate (TPB)(I) orsites provided by the anion discriminator and remains tetrathiocyanate (TTC)(II) counter anions as electro-unaltered if an excess of ionophore is added. This is so active material dispersed in a PVC matrix. The sensorsbecause, in order to maintain electroneutrality of the exhibited fast, stable, near Nernstian response for 1×10Gmembrane, only as many cations could enter the -6×10G M and 1×10G -1×10G M for PA-TPB and PA-membrane phase as are the anionic sites provided by the TTC, respectively with a cationic slope of 56.5±0.5anion excluder. By combining equations (2) and (5). mV/decade for both sensors, respectively. The direct

E = E + E (6) injection) gave results that compare favorably with thoseM constt PB

Since a remains constant under the and coworkers [9] reinvestigated the responseA(org)

experimental conditions, it can be put together with characteristics of a caffeine electrode, taking into all other sample-independent potential contributions, i.e. consideration the pKa value and constructed a newit could be included in a single term (E°). Thus, equation electrode with a combination of the lipophilic cation-(6) is reduced to a well-known Nernst equation. exchanger, tetrakis [3,5-bis(2-methoxyhexafluoro-2-

with high degree of dielectric constant, 2-fluoro-2’-(7) nitrodiphenylether (FNDPE). This electrode showed a pH-

Thus, it is clear from equation (7) that the cell detection limit of 50 µM with a slope of 55 mV perpotential is directly proportional to the concentration or concentration decade at pH 2. The electrode was appliedactivity of the sample ions in aqueous solution under for the determination of caffeine in some centralinvestigation. At 25°C, the value of 2.303 RT/ z F is stimulants.A

0.059/z volts. The membrane is said to exhibit Nernstian There have been reports for the selectiveA

response if the slope of a plot between cell potential and determination of different amino acids like alanine, leucine,log activity comes out to be 0.059/z volts. These plots are aspartic acid, L-tyrosine and L-phenylalanine. In all cases,A

then called Nernst plot and slope as Nernstian slope. short linear ranges and poor selectivities were observed.

Construction and Performance of Various Ion-Selective electrodes based on p-1-adamantylcalix [8] areneSensors for Drugs: From the past two decades various ionophores for the determination of amino compounds aspotentiometric sensors for drugs have been reported. The well as amino acids [10]. The electrodes were based onpotentiometric characteristics of the various ion-selective lipophilic ion-associate tetraphenylborate. All membraneselectrodes for drugs are discussed below. exhibited extremely short response time (5-10 s) in wide

There have been reports on polymeric sensors for pH and analyte concentration ranges. Volf et al. reporteddetermination of various alkaloids like berberine, cocaine, novel potentiometric sensor for determination of cysteineheroin, codeine, ethaverine, nicotine. Watanabe and based on substituted poly(diphenylporphyrins andcoworkers reported a improved cocaine membrane metalloporphyrins) [11]. A remarkable selectivity forselective electrode [7] with the use of sodium tetrakis cysteine 1 × 10G M has been found. The comparison of [3,5-bis(trifluoromethyl)phenyl] borate as an ion- polymeric films with monomeric porphyrin units showedexchanger and tetrakis (2-ethylhexyl)pyromellitate the higher binding efficiency of the polymeric films.

2 6

2

5 2 5

determination of PA in some formulations (Vasorin

obtained using the British Pharmacopoeia method. Katsu

propyl)phenyl] borate (HFPB) and the solvent mediator

dependent response to caffeinium ion and gave a

Shvedene and coworkers reported ion-selective

2

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62

CH3O

CH3O

N

OO

+

N

CH2

CH2

CH

CH

CH

CH2

CHOCOC6H5CH3

OCOCH3

CH3COO

CH3COO

CH3

ON

Berberine Cocaine Heroin

OCH3

OCH3CH3O

CH3O

NC2H5O

OC2H5

OC2H5

C2H5O

N

OCH3

OH

NCH3

(CH2)2

O

Papaverine Ethaverine Codeine

CH3N

N

N

NN

O

O

N

CH3

CH3

CH3

Nicotine Caffeine Fig. 1: Structures of various alkaloids

O

NH2

CH3

O

NH2

CH3

CH3

O

ONH2

OH

Alanine Leucine Aspartic acid

O

NH2OH

O

NH2

NH2

OH

O

SH H

Tyrosine Phenylalanine Cysteine Fig. 2: Structures of various amino acids

World J. Chem., 6 (2): 59-74, 2011

63

The variety of antidepressants drugs were determined in both positively charged and uncharged forms underby potentiometric membrane electrodes like amitryptyline, normal in vivo condition. Most of them displayed linearimipramine, chlorpromazine and propranolol. Erdem and responses with near-Nernstian slopes in workingco-workers reported ion-selective membrane electrodes concentration ranges up to 1.0 × 10 - 1.0 × 10G M.for phenylpiperazine antidepressant, nefazodone (NFN), Alizadeh et al. reported ion-selective membranebased on its ion-pair complexes with phosphotungstate electrode to the drug ketamine hydrochloride [16] using(PT), tetraphenylborate (TPB), tungstosilicate (TS) and a modified PVC membrane which has ionic end-groups asreineckate (RN) in a poly(vinylchloride) (PVC) matrix [12]. ion-exchanger sites and which was cast using plasticizedThe best ion-selective electrode for determination of NFN with o-nitrophenyloctyl ether (o-NPOE) as plasticizer.contains NFN-PT as the active material. This electrode This electrode show excellent Nernstian responses (59exhibited a Nernstian response (62.6±0.4 mV per decade) mV/decade) in the concentration range 1 × 10G -1 × 10Gin the range 1.5×10G -1.0×10G M. M with a detection limit of 5 × 10G M. The electrode was5 2

El-Ragehy and coworkers described potentiometric applied for determination of ketamine hydrochloride inmembrane sensors for determination of fluphenazine pharmaceutical preparations using direct potentiometry.hydrochloride and nortriptyline hydrochloride [13]. The The sensor has also been used to study the interaction ofmethod is based on the formation of the ion-pair bovine serum albumin (BSA) with ketamine in buffercomplexes between the two drugs cations and sodium solution.tetraphenylborate (NaTPB) or tetrakis (4-chlorophenyl) There have been reports for the determination ofborate (KtpClPB). They showed linear responses for both vitamins such as ascorbic acid (vitamin C) biotin (vitamindrugs over the concentration ranges of 10G -10G , 10G - H), pyridoxine hydrochloride (vitamin B ) and thiamine3 5 2

10G , 10G -10G and 10G -10G M with cationic slopes of hydrochloride (vitamin B ) by potentiometric techniques5 3 5 2 5

58.9, 52.5, 59.3 and 54.3 mV/decade, respectively. The with various membrane electrodes. In 1999, Ahmed et al.direct potentiometric determination of fluphenazine and reported ion selective electrode for determination of anortriptyline hydrochloride in their pure forms using the thiamine derivative sulbutiamine [17]. The membraneproposed sensors gave recoveries of 98.8±0.9, 99.0±0.9, electrodes were based on molybdate, tetraphenylborate,98.7±0.8 and 99.4±0.8%, respectively. reineckate, phosphotungstate, phosphomolybdate as ion-

Khalil et al. reported potentiometric membrane pairing agents.sensors for determination of triiodide [14] consisting Mostafa et al. described two novel potentiometricof triiodide-fluphenazine (FP) and triiodide-trifluoperazine membrane electrodes responsive to the pyridoxine(TFP) ion pair complexes dispersed in PVC matrix hydrochloride vitamin B [18]. These sensors were basedplasticized with o-nitrophenyl octyl ether with unique on the use of the ion-association complexes of theselectivity toward I ions. The optimized membranes pyridoxine cation with molybdophosphate and3

-

demonstrate Nernstian response for triiodide ions over a tungstophosphate counter anions as ion pairs in awide linear range from 1.0 × 10G to 5.0 × 10G M at 25°C. plasticized PVC matrix. The electrodes showed a stable,2 6

The sensors were successfully used as indicator electrode near-Nernstian response for 6.0 × 10G –1 × 10G M with ain the potentiometric titration of triiodide ions and cationic slope of 54.0±0.5 and 54.5±0.4 mV/decade forascorbic acid. pyridoxine-molybdophosphate and pyridoxine-

Rizk et al. reported two novel polymeric membrane tungstophosphate, respectively.sensors for the analysis of Pb(II) based on two Polymeric membranes sensors have been developed fortherapeutic drugs, thiopental (TP) and phenytoin (PT) as determination of different classes of antibiotics.two ionophores and potassium tetrakis(p- There has been report of ion-selective electrodeschlorophenyl)borate (KTpClPB) as a lipophilic additive, in sensitive to penicillins (ampicillin, benzyl penicillin,plasticized PVC membranes [15]. The sensors showed a oxacillin, penicilin V) which were based on the use ofNernstian response for Pb(II) ions over the wide quaternary ammonium, phosphonium, or arsonium ions asconcentration ranges of 1×10G - 7×10G M and 1×10G - the exchange sites. In the subsequent years Kulapina et2 6 2

8×10G M for the sensors based on thiopental and al. [19] reported improved ion-selective electrodes with6

phenytoin, respectively. plasticized membranes based on ion pairs formed byThere are various anesthetics (procaine, tetradecylammonium and benzylpenicillin, ampicillin, or

tetracaine, benzocaine, oxybuprocaine etc.) or amide oxacillin were proposed. The procedures were alsotype (lidocaine, dibucaine, mepivacaine, bupivacaine etc.) developed for determining various penicillins indetermined by potentiometric sensors. These drugs exist pharmaceutical forms and biological fluids.

-4 2

5 2

6

6

1

6

5 2

World J. Chem., 6 (2): 59-74, 2011

64

CHCH2CH2N(CH3)2

CH2CH2CH2N(CH3)2

N

Amitriptyline Propranol

OH

OCH2CHCH2NHCH(CH3)2

FF

F

CH3

N

S

N

N

Imipramine Trifluoperazine hydrochloride

NHNH

OO

S

CH3CH3

CH3

Cl

N

N

N N

N

O

O

Thiopental Nefazodone

N

S

CF3

N

N

N

HMe

Fluphenazine hydrochloride Nortriptyline hydrochloride Fig. 3: Structures of various antidepressants

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65

COOC2H5H2N

NHCO

CH3

CH3

C4H9

N

Benzocaine Bupivacaine

CONHCH2CH2N(C2H5)2

OC4H9

N

CH3

CH3

NHCOCH2N(C2H5)2

Dibucaine Lidocaine

CH3

CH3

NHCO

CH3

N

COOCH2CH2N(C2H5)2

OC4H9

H2N

Mepivacaine Oxybuprocaine

C4H9HN COOCH2CH2N(CH3)2 H2N COOCH2CH2N(C2H5)2

Tetracaine Procaine

NMe H

Cl

O

Ketamine hydrochloride

Fig. 4: Structures of various anesthetics

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66

HClCH2OH

CH2OH

HO

H3C N CH2CH2OH

H3C

NH2H3C

CH2

HClN

SN

N

Cl

+

Pyridoxine hydrochloride Thiamine hydrochloride

S S

N

N N

O

N

NN

O

O

O

O

O

H3C

H2N

CH3

CH3

CH3

CH3H2N

H3C

CH3

Sulbutiamine

Fig. 5: Structures of various vitamins

CH3NH

CH3

CH3

O H

HO

O H

H2N H2NH2N

NH

CH3

O

O

O

O

N(CH3)2

CONH2

OH

CH3 OH

OHOH

O

HH

O

Gentamycin Doxyciline

Fig. 7 Structures of Gentamycins and related antibiotics

N

S

N

SCH3

CH2CH2CH3

N

N

N

N

O

O

Chlorpromazine Thioridazine Piribedil Fig. 9: Structures of various phenothiazine derivatives

World J. Chem., 6 (2): 59-74, 2011

67

Shvedene and co-workers also reported ion-selective The electrodes exhibited a Nernstian response in theelectrodes for antibiotics from the penicillin series [20], concentration range 5 × 10G -1 × 10G M with a slopewith membranes based on three different classes of between 55 and 57 mV/ decade.ionophores (anion exchangers, aza compounds and metal Khormosh and coworkers reported rapid and low-phthalocyanines). The proposed ISEs were suitable for cost potentiometric method for diclofenac determinationthe quantitative determination of benzylpenicillin, oxacillin in urine samples and pharmaceuticals [26]. The electrodeand ampicillin in pharmaceutical preparations. was constructed by incorporating the diclofenac ion pair

A variety of gentamycins were quantified by complex with rhodamine 6G. The electrode exhibited apotentiometric membrane sensors. Kulapina and co- Nernstian slope of 59±2 mV/decade. In recent years,workers reported ion-selective electrodes with polymeric membrane electrodes have been reported forplasticized membranes based on ion pairs of gentamycin the determination of antihistamines like hydroxyzine andand kanamycin [21] with tetraphenylborate and acid cetrizine dihydrochloride, triprolidine hydrochloride.chrome black. The electrodes exhibited excellent Nernstain Shamsipur et al. described potentiometric membraneresponse. The electrodes were successfully used for sensor for quantification of anti-histamine cimetidine [27].determination of aminoglycoside antibiotics in The electrode incorporates PVC-membrane withpharmaceutical dosage forms, serum and saliva from cimetidine–phospohotungstate ion pair complex andpatients with infectious pathologies. exhibited a Nernstian response for cimetidine in the

Recently, ion-selective electrode for the determination concentration range of 1.0×10G –1.0×10G M with a slopeof macrolide antibiotic azithromycin [22] has also been of 58±1 mV per decade. The limit of detection is 5.0×10Greported. The electrode was constructed by incorporating M. The electrode displays a good selectivity forthe azithromycin-tetraiodomercurate ion pair complex into cimetidine with respect to a number of common inorganicPVC matrix. The sensor exhibited good linear response and organic species and can be used to determineover the concentration range 1.0 × 10G -7.0 × 10G M with cimetidine in its tablets as well as its recovery from a urine2 6

Nernstian slope. sample. Ghoreishi et al. reported ketotifenPhenothiazine derivatives are compounds with well (KET)–selective electrode of both conventional polymer

known neuroleptic activity. Some of the most widely used membrane and coated graphite types, based onantipsychotic drug thioridazine was determined by incorporation of ketotifen-tetraphenyl borate (KETTPB)potentiometric electrodes. Issa and coworkers reported ion-pair [28]. The electrode showed a Nernstian responsePVC based membrane sensor for antipsychotic drug in the concentration range of 1.0×10G to 1.0×10G M andpiribedil [23] doped with piribedil-tetraphenylborate (PD- 5.0×10G to1.0×10G M with a slope of 57.5±1.07 andTPB) as electroactive component. The sensor displayed 59.0±0.9 mV/decade and lower limit of detection 1.0×10Ga linear response over the concentration range 2.0 × 10 M and 5.0×10G M for conventional and coated graphite–5

M with Nernstain slope 30mV/decade. Piribedil was types, respectively. The electrode was successfully useddetermined in tablets as well as in biological fluids with for determination of ketotifen both in pure solution and inthis sensor. pharmaceutical preparation.

Aubeck et al. reported ion-selective membrane New ion-selective electrodes have been developedelectrodes for the peripheral muscle relaxants. Ibrahim and for determination of some antiepileptic drugs such ascoworkers reported four PVC membrane electrodes for the lamotrigine, felbamate and primidone in theirdetermination of mebeverine hydrochloride (MvCl) [24]. pharmaceutical preparations as well as in biological fluidsThe membranes of these electrodes consist of [29]. The electrodes were based on poly (vinyl chloride)mebeverinium-silicotungstate (Mv-ST), silicomolybdate membranes doped with drug–tetraphenyl borate (TPB) or(Mv-SM), phosphotungstate (Mv-PT), or drug–phosphotungstic acid (PT) ion-pair complexes asphosphomolybdate (Mv-PM) ion-associations dispersed molecular recognition materials. The novel electrodesin PVC matrix with dibutyl phthalate plasticizer. The displayed rapid Nernstian responses with detection limitselectrodes showed near-Nernstian response over the of approximately 10G M. Calibration graphs were linearconcentration range of 4.0 × 10G -1.0 × 10G M MvCl and over the ranges 5.2 × 10G –1.0 × 10G , 1.5 × 10G 1.0 ×6 2

were applied to the potentiometric determination of 10G M and 2.6 × 10G –1.0 × 10G M for drug-TPB and 5.8mebeverinium ion in pharmaceutical preparations, serum × 10G –1.0 × 10G , 1.8 × 10G –1.0 × 10G and 6.6 × 10G –1.0and urine. Bouklouze et al. reported three types of × 10G M for drug-PT electrodes, with slopes ranging frompolymeric electrodes for determination of tizanidine [25]. 52.3 to 62.3 mV/decade, respectively.

6 2

5 2

6

5 2

6 2

5

6

7

7 3 6

3 7 3

7 3 7 3 7

3

2Br-

CH3COO

CH3

CH3CH3CH3

CH3COO

NN

H

H

H

H

+ +2 Cl

CH3 CH3

CH3OOH

CH2

OCH3OH

CH3

N

N

H

O

H

O

H

+

+

3

OCH2CH2N(C2H5)3

OCH2CH2N(C2H5)3

OCH2CH2N(C2H5)3I

+

+

+2Br-

CH2- COOCH2CH2N(CH3)3

CH2- COOCH2CH2N(CH3)3+

+

O

OO

N

O

N

N

O

O H

H O

O

NH2

NH2

O

O

Cl

Cl

H2N

NN

N NH2

O

ON

N

CH3

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68

Pancuronium bromide Tubocurarine chloride

Gallamine triethiodide Succinylcholine bromide

Mebeverine hydrochlorideFig. 10: Structures of various muscle relaxants

Recently El-Tohamy et al. described potentiometreic membrane electrode for determination of phenytoin sodium[30] based on two types of electrodes plastic membrane I and coated wire II. The electrodes were based on theincorporation of phenytoin sodium with tungstosiliic acid. The electrodes showed a Nernstian response with a meancalibration graph slope of 30.9±0.1 and 28.9±0.1 mV decade-1 at 25°C for electrode I and II respectively, over a phenytoinsodium concentration range of 510G -5×10G M and 1×10G - 1×10G M with a detection limit of 1.3×10G M and 2.5×10G3 6 3 6 6 7

M for electrode I and II, respectively. The results obtained by the proposed electrodes were also applied successfullyfor the determination of the drug in pharmaceutical preparations and biological fluids.

Phenytoin Felbamate

Primidone Lamotrigine

O

O

O

O

Cl

N

N

Cl

ClO

O

O

N

N

O

CH3

N

N

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69

Drotaverine hydrochloride incorporates PVC membrane with clotrimazole-

Fig. 15: Structures of Anti- spasmodics exhibited a Nernstian response for clotrimazole in the

Clotrimazole electrodes have been described for the quantification of

ketoconazole a fast, stable and linear response for alfuzosin over the

Fig. 16: Structures of Anti-fungals 10G to 1.0 × 10G M, 7.5 × 10G to 1.0 × 10G M AzCl with

El-Sharty et al. [31] described poly(vinyl chloride) respectively.membrane sensors for the determination of anti- Saber et al. [35] reported the potentiometricspasmodic drug drotaverine hydrochloride. The sensors determination of anti-atherosclerosis drug clopidogrel.were based on the use of the ion association complexes of The measurments are based on tetrakis (p-chlorophenyl)drotaverine cation with sodium phosphotungestate and borate-clopidogrel ion-pair as an electroactiveammonium reineckate counter anions as ion exchange material incorporated a plasticized PVC membrane withsites in the PVC matrix. The performance characteristics of o-nitrophenyl octyl ether. The sensor exhibited fast andthese sensors, revealed a fast, stable and linear response stable Nernstian response for clopidogrel over thefor drotaverine over the concentration range 10G to 10G concentration range of 1.0 × 10G -1.0 × 10G M. The5 2

M with cationic slopes of 49.5 and 51.3 mV/decade. The sensor displayed reasonable selectivity towardssensors were used for determination of drotaverine clopidogrel hydrogen sulphate in presence of manyhydrochloride in tablets, in its mixture with caffeine, cations, drug excipients and diluents.paracetamol and in plasma. Pandey and coworkers reported potentiometric

The fabrication and analytical applications of two sensing device for quantitative estimation of creatininetypes of potentiometric sensors for the determination of [36]. The polyaniline modified electrode is developedantifungal drug ketoconazole (KET) have been reported by electropolymerization of aniline based on sweeping[32]. The polymer membrane and carbon paste sensors the electrode potential with respect to Ag/AgCl in

were based on the use of KET-molybdophosphoric acid(MPA) ion pair as electro-active material. Both sensorsshowed a linear and near Nernstian slope of 57.8mV/decade and 55.2 mV/decade for PVC membrane andcarbon paste sensors, respectively over a relatively wideconcentration range. The proposed sensors weresuccessfully applied for the determination of KET inpharmaceutical formulations.

A novel clotrimazole ion selective membraneelectrode has been reported [33]. The electrode

phosphomolybdate ion pair complex. The electrode

concentration range 1.3×10G -1.0 × 10G M with a slope of5 3

59±2 mV decadeG . The limit of detection is 1.0×10G M.1 5

The membrane sensor was successfully applied to thedetermination of clotrimazole in its tablets and creams aswell as its recovery from a urine sample.

Miscellaneous Potentiometric Sensors: The constructionand characterization of potentiometric membrane

benign prostatic hyperplasia (BPH) drug alfuzosinhydrochloride [34]. The membranes of these electrodesconsist of alfuzosin hydrochloride-tetraphenyl borate,(Az-TPB), chlorophenyl borate (Az-ClPB) andphosphotungstate (Az -PT) ion associations as molecular3

recognition reagent dispersed in PVC matrix. Theperformance characteristics of these electrodes, revealed

concentration ranges of 8.3 × 10G to 1.0 × 10G M, 3.8 ×6 2

6 2 7 2

cationic slopes of 57.0, 56.0 and 58.5 mV/decades,

5 2

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non-aqueous medium. Five poly(vinyl chloride) matrix Ganjali and coworkers described potentiometricmembrane sensors responsive to some $-blockers(atenolol, bisoprolol, metoprolol, propranolol and timolol)have been reported by Arvand and coworkers [37]. Thesensors were based on the use of the ion-associationcomplexes of the $-blocker cations withtungstophosphate anion as electro-active materials. Thesensors were used for direct potentiometry of $-blockersin some pharmaceutical preparations.

Katsu and coworkers reported determination of anti-arrhythmic drug mexiletine. The electrode was based oncrownether 4’4’’(5’’)-ditert-butylcyclohexano-18-crown-6and ion exchanger sodiumtetrakis [3,5-bis(2-methoxy-hexafluoro-2-propyl)phenyl] borate [38]. The sensorshowed detection limit up to 30 µM and 3 µM,respectively. The sensor showed good selectivity againstinorganic cations and successfully applied fordetermination of the level of mexiletine in saliva.

Saad et al. reported paraquat selective sensors basedon sodiumtetrakis [3,5-bis(trifluoromethyl)phenyl] borate(NTB) and tetrakis (4-chlorophenylborate) (KtpClPB) asan ion-exchangers [39]. These sensors displayed distinctadvantages for depicting resistance to fouling bysurfactants as well as applied in various water samples.Othman and coworkers developed potentiometric sensorsbased on the formation of the complex ion-associates ofsildenafil citrate with tetraphenyl borate (sc-TPB) andphosphomolybidic acid (sc-PMA) as ionophores in PVCmatrix. Both sensors showed a linear and stable potentialresponse with a near Nernstian slope of 55.5 and 53.5mV/decade over a wide concentration range up to 10G -2

10G M with good reproducibility. The sensors were also5

applied for the analysis of this drug in pharmaceuticalpreparations and blood serum [40]. Peng et al. describedmembrane electrode based on fentanyl-phosphotungstateion-association complex in PVC matrix [41]. The sensorshowed linear response for 1.0 × 10G -1.0 × 10G M drug5 2

with a slope of 55.9 mV/decade. The electrode had beensuccessfully applied to determine fentanyl citrate ininjections.

Aubeck et al. reported the comparison of ion-selective poly(vinyl chloride) liquid membrane electrodesfor the determination of pyrantel (PY) based on fourdifferent ion-pairing agents, viz., tetraphenylborate (TPB),dipicrylaminate (DIPIC), reineckate (REINE) andtungstosilicate (SIWO) [42]. The four electrodes showedsimilar detection limits of 1-2 µg mlG and nearly the same1

linear ranges of 1×10G $10G mol lG for pyrantel in 1005 2 1

nM sodium phosphate-buffered solutions of pH 7.0.Significant differences between the electrodes wereobserved in protein-containing solutions.

membrane electrode for determination of calcium channelblockers diltiazem [43]. The sensor comprised ofdiltiazem-tetraphenylborate (DTM-TPB) complexes aselectroactive material and displayed wide linear range 1.0× 10G -1.0 × 10 M and low detection limit (3.2 µg/ml). The5 –1

sensor was successfully applied for determination ofdiltiazem hydrochloride in pharmaceutical formulationsand urine. Recently Ganjali et al. described PVC membranesensor for the decongestant drug phenylpropanolamine(PPA) [44]. The sensor was fabricated usingphenylpropanolamine tetraphenylborate ion-pair as anelectro-active material in the plasticized PVC membrane.This electrode illustrated a fast, stable and Nernstianresponse (55.9±0.4 mV/decade across a relatively widephenylpropanolamine concentration range (1 × 10G to 15

× 10G M). The sensor has been successfully applied for2

the quality control analysis of phenylpropanolaminehydrochloride in pharmaceutical formulation and urine.

A new potentiometric sensor has been reported foranti-diuretic amiloride by Ensafi and coworkers [45].The sensor having amiloride-sodium tetraphenylphthalate (ion-pair) as an electroactive material andexhibits suitable response to amiloride in a concentrationrange of 1.0 × 10G - 1.0 × 10G mol LG with a limit of2 6 1

detection of 9.9 × 10G mol LG . The sensor was7 1

successfully applied to determination of amiloride inpharmaceutical samples with satisfactory results.Ganjali and coworkers reported potentiometric liquidmembrane sensor for simple and fast determination ofanti-parkinson’s drug memantine in pharmaceuticalformulation and urine [46]. Computational studies wereperformed electronically and geometrically on memantineand tetraphenylborate before and after complex formation.The sensor exhibited wide linear range (10G -10G mol5 2

LG ), low detection limit (9.0 × 10G mol LG ).1 6 1

Belal et al. reported three polyvinylchloride (PVC)membrane sensors for the determination of orallyactive non-sulfhydryl angiotensin-converting enzyme(ACE) inhibitor moexipril hydrochloride [47]. The sensorsare based on the use of the ion-association complexes ofmoexipril cation with either ammonium reineckate(sensor1) or tetraphenyl borate (sensor 2) orphosphotungistic acid (sensor 3) counter anions as ionexchange sites in the PVC matrix. The performancecharacteristics of these sensors reveal a fast, stable andlinear response for moexipril over the concentration rangeof 10-6 to 10-2 M for the three sensors with cationicslopes of 29.1, 30.1 and 30.2 mV per concentration decadefor the three sensors, respectively.

CH3O

OH

H

CH2=CH

H

NH

N

HCl

O

ONN

NCoEt

O

N

O

OO

HSH

H

H

HO

NH2

O

O N

O

N

O

O

OH3C

H3C

NH2

HN

H3C

O

O

N

N

N

S OO

O

O

O

O

S S

O

O

O

S OO

O

O

O

O

OH

OH

OHOH

OH

OH

H2N

NH2

NN

N

N

NH

O

ClNH2

CH3

CH3

O

O

OH

NH

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Adiphenine hydrochlorideFentanyl

Quinine

Glutathione Alfuzosin Propantheline bromide

Pentosan sulphate Neostigmine bromide Tripelenamine

Ketamine

Atenolol

Fig. 16: Structures of some miscellaneous drugs

CONCLUSION targeted at the general analytical chemist, in ion-selective

In recent years, the well-established field of reviews and specialized articles have already appeared inpotentiometric sensors has undergone a quiet recent years. This is compilation of the drug basedrevolution that did not go unnoticed in the general potentiometric sensors and their future directions will beanalytical chemistry community. This review is predicted.

electrode (ISE) development, for whom a variety of

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Future Directions: The last few years have witnessed 7. Watanabe, K.K. H. Okada, K. Oda, Furuno, Y. Gomitasignificant activity in understanding the principles ofpotentiometric sensors and in finding protocols andexamples of successful improvements. Because of this,perhaps, a novice in the field may seem somewhatoverwhelmed by the various choices. It will therefore becrucial to see a unified, simplified approach to producingpotentiometric sensors with lower limit of detection, rapidresponse time, sufficient chemical ruggedness and longlifetime, so that they become widely accepted in a rangeof applications. Recent developments towards thisgoal have been very promising. Improvements will bemade to enhance the sensitivity of such sensors. This willalleviate the need for robust, accurate referenceelectrodes, although the response will then be based onkinetic, rather than thermodynamic, principles. Advancesin this direction have recently been realized withinstrumentally controlled membranes in double- or triple-pulse experiments, where defined current and potentialpulses are imposed on the measuring cell for accuratecontrol.

ACKNOWLEDGEMENT

The author acknowledges Indian Institute ofTechnology Roorkee, Roorkee for supporting her researchon potentiometric sensors as well as Gautam BuddhaUniversity for updating literature work.

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