the construction and characteristics of drug-selective electrodes. applications for the...

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J. Chern. SOC., Furuduy Trans. I, 1988, 84(9), 3059-3070 The Construction and Characteristics of Drug-selective Electrodes Applications for the determination of Complexation Constants of Inclusion Complexes with a- and fi-Cyclodextrins including a Kinetic Study Norboru Takisawa,? Denver G. Hall, Evan Wyn-Jones* and (in part) Philip Brown Department of Chemistry and Applied Chemistry, University of Salford, Salford M.5 4WT Ion-selective membrane electrodes selective to the drugs chlorpromazine, dicyclomine, imipramine, desipramine and propranolol hydrochlorides have been constructed using a modified poly(viny1 chloride) membrane which has ionic end-groups as ion-exchange sites and which was cast using a solid polymeric plasticiser. These drug electrodes show excellent Nernstian responses in the concentration range 10-2-10-7 mol dmP3 and their selectivity coefficients with respect to each other, as well as their workable pH range have been investigated. The electrodes have also been used to determine the complexation constants of chlorpromazine and dicyclomine hydrochlorides with both a- and B-cyclodextrins. In all cases a 1 : 1 complex was observed. The kinetics associated with the formation of the complex involving a-cyclodextrin and dicyclomine hydrochloride have also been investigated using the ultrasonic technique. Ion-selective membrane electrodes which are selective to a variety of ionic drugs have attracted much interest because of their potential use in pharmaceutical analysis. Recently, two types of drug-selective membrane electrodes have been reported. The membranes used in these electrodes were made from liquid4” and liquid-plasticized poly(viny1 chloride) (PVC)5 and are based on a water-insoluble ion-pair complex acting as an ion-exchanger. Although these electrodes showed acceptable characteristics in pharmaceutical analysis, especially in the simple way they can be constructed and in which they show a fairly rapid response, some problems have been encountered with the membranes, e.g. the requirement of extensive pre-conditioning treatment, care in storage, sensitivity to some hydrophobic counter-ions and a relative short lifetime. In connection with a study of surfactant-selective electrodes some of the above disadvantages encountered with the above PVC membrane have been overcome by the use of a modified PVC which has ionic end-groups as ion-exchange sites6-* and a solid polymeric plasticiser to cast the membrane.8 The former inhibits the dissolution of the ion-exchanger and the latter method yields membranes which have longer lifetimes. Following these works the electrode design was modified and significantly i m p r ~ v e d , ~ resulting in a more robust device. In the present work, several drug-selective electrodes were constructed by the improved polymeric plasticized PVC method described above and have been characterised in the sense that e.m.f. values have been measured over a range of drug concentrations in the region 10-2-10-7 mol dmP3 and the resulting data analysed using the Nernst equation. In addition to these experiments the selectivity coefficients of these 7 Permanent address : Department of Chemistry, Faculty of Science and Engineering, Saga University, Saga 840, Japan. 3059 Published on 01 January 1988. Downloaded by Gebze Institute of Technology on 02/05/2014 08:30:06. View Article Online / Journal Homepage / Table of Contents for this issue

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J . Chern. SOC., Furuduy Trans. I, 1988, 84(9), 3059-3070

The Construction and Characteristics of Drug-selective Electrodes

Applications for the determination of Complexation Constants of Inclusion Complexes with a- and fi-Cyclodextrins including a Kinetic Study

Norboru Takisawa,? Denver G. Hall, Evan Wyn- Jones* and (in part) Philip Brown

Department of Chemistry and Applied Chemistry, University of Salford, Salford M.5 4WT

Ion-selective membrane electrodes selective to the drugs chlorpromazine, dicyclomine, imipramine, desipramine and propranolol hydrochlorides have been constructed using a modified poly(viny1 chloride) membrane which has ionic end-groups as ion-exchange sites and which was cast using a solid polymeric plasticiser. These drug electrodes show excellent Nernstian responses in the concentration range 10-2-10-7 mol dmP3 and their selectivity coefficients with respect to each other, as well as their workable pH range have been investigated. The electrodes have also been used to determine the complexation constants of chlorpromazine and dicyclomine hydrochlorides with both a- and B-cyclodextrins. In all cases a 1 : 1 complex was observed. The kinetics associated with the formation of the complex involving a-cyclodextrin and dicyclomine hydrochloride have also been investigated using the ultrasonic technique.

Ion-selective membrane electrodes which are selective to a variety of ionic drugs have attracted much interest because of their potential use in pharmaceutical analysis. Recently, two types of drug-selective membrane electrodes have been reported. The membranes used in these electrodes were made from liquid4” and liquid-plasticized poly(viny1 chloride) (PVC)5 and are based on a water-insoluble ion-pair complex acting as an ion-exchanger. Although these electrodes showed acceptable characteristics in pharmaceutical analysis, especially in the simple way they can be constructed and in which they show a fairly rapid response, some problems have been encountered with the membranes, e.g. the requirement of extensive pre-conditioning treatment, care in storage, sensitivity to some hydrophobic counter-ions and a relative short lifetime.

In connection with a study of surfactant-selective electrodes some of the above disadvantages encountered with the above PVC membrane have been overcome by the use of a modified PVC which has ionic end-groups as ion-exchange sites6-* and a solid polymeric plasticiser to cast the membrane.8 The former inhibits the dissolution of the ion-exchanger and the latter method yields membranes which have longer lifetimes. Following these works the electrode design was modified and significantly impr~ved ,~ resulting in a more robust device.

In the present work, several drug-selective electrodes were constructed by the improved polymeric plasticized PVC method described above and have been characterised in the sense that e.m.f. values have been measured over a range of drug concentrations in the region 10-2-10-7 mol dmP3 and the resulting data analysed using the Nernst equation. In addition to these experiments the selectivity coefficients of these

7 Permanent address : Department of Chemistry, Faculty of Science and Engineering, Saga University, Saga 840, Japan.

3059

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3060 Drug-selective Electrodes

Table 1. Drugs investigated

drug structure therapeutic

supplier m.wt category

chlorpropmazine hydrochloride

dicyclomine hydrochloride

imipramine hydrochloride

desipramine hydrochloride

propranolol hydrochloride

CH,CH2CH,N(CH3)2 I

n COOCH2CH2 N(C2 H5)2 3 HCI

CH2CH2CH2N(CH,)z a HCI

@ OH HCI

Sigma

Vick International R and D Labs

Geigy Pharmaceuticals

Geigy Pharmaceuticals

Sigma

355.3

346.0

316.9

302.9

295.8

antiemetic antipsychotic

anticholinergic

antidepressant

antidepressant

cardiac depressant adrenergic blocker

drug electrodes relative to the other drugs and the workable pH range of the electrodes were also determined.

Apart from their potential application in pharmaceutical analysis these electrodes could also be used to investigate the interaction of drugs with other solute species such as biopolymers and receptors." To demonstrate this we describe binding studies (to a- and j3-cyclodextrins) of two of the drugs used. The reasons for the use of cyclodextrin in these experiments were two-fold. First, these compounds are known to inhibit the side-effect of the drug'' and secondly, as cyclodextrins have been used as neutral carriers12 in membrane electrodes, data on complexation coefficients may give clues on how to improve the selectivity of these devices. Finally, the kinetics associated with the formation of the inclusion compound involving a-cyclodextrin and dicyclomine hydrochloride were also investigated using the ultrasonic technique.

Experimental Materials

All the drugs used in this work were of the highest purity available. Table 1 lists the drugs used, their structure and their suppliers. The PVC was made by Montefibre and kindly donated by Professor P. Meares. It contains 24.3 pequiv. per gram of SO,H+ end- groups. The plasticiser Elvaloy 742 was a Dupont product. Tetrahydrofuran (THF), BDH, was fractionally distilled each time before use. The a- and j3-cyclodextrins were carefully recrystallised commercial products (Aldrich). All the solutions were prepared in doubly distilled deionised water and stored in the dark to prevent photochemical oxidation of the drug.13

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N . Takisawa et al. 306 1

drug electrode test solution containing

lop2 mol dm-3 sodium chloride

electrode reversible to

sodium ion.

Preparation of the PVC Membrane

The polymeric plasticised PVC membranes used in this work were prepared in a similar way to the recipe described by Davidson.8 Initially the commercial PVC product is conditioned for use with the respective drug. Basically this procedure involves exchanging the hydrogen ion of the SO;H+ end charge groups with the drug cation. The method used to carry out this ion-exchange step was to dissolve 0.5 g of the powdered PVC in 30cm3THF and add the respective drug to this solution. Any insoluble gel components of the PVC and undissolved drug were removed from the solution by filtering through a 10 pm millipore filter, the filtrate being poured into 200 cm3 of water and stirred continually. This results in the precipitation of the conditioned PVC in a fibre form which was then filtered and washed thoroughly with water and dried in a vacuum desiccator for 48 h.

0.12 g of this PVCdrug complex and the polymeric plasticiser (0.18 g) were then dissolved in 30 cm3 THF and filtered through a 10 pm millipore filter into a flat-bottomed beaker (diameter 55 mm). This solution was left for 3 days for the THF to evaporate. The resulting PVC membrane was dried in a vacuum desiccator, peeled off, and punched out so that it could be attached to the electrode tip with a small amount of THF.

E.M.F . Measurements

The potentiometric measurements were made using a digital pH/millivolt meter (Corning ion analyser 150). In all the experiments the temperature was controlled to within f 0.1 "C by circulating thermostatted water through the double glass cell and the sample solution was continuously stirred using a magnetic air stirrer.

During the e.m.f. measurements the concentration of the test sample solutions was changed successively by adding a known amount of solution to the initial sample (30 cm3) using an Aglar microcylinder system. The response of the drug electrodes was tested in the concentration range 10-7-10-2 mol dm-3 at 25 "C. The binding of chlorpromazine and dicyclomine hydrochlorides to both a- and 8-cyclodextrins was measured in the

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3062 Drug-selective Electrodes

Table 2. Response characteristics of the drug membrane electrodes

slope/mV linear response drug electrode per decade intercept/mVa range/mol dmP3

chlorpromazine 57.7k0.2 -28.7f0.7 1 x 10-5-1 x dicyclomine 56.1 k0.5 -28.9+ 1.2 2 x 10-5-2 x imipramine 59.0k0.5 -28.2k0.5 1 x 10-6-2 x

propranolol 58.8k 1.0 -27.2k 1.5 1 x lO+-l x desipramine 58.8k0.3 -29.4k0.5 1 x 10-6-1 x

a Intercept is the e.m.f. measured when the inner and the outer solution have the same drug concentration.

drug concentration range 10-6-10-3 mol dm-3 and 10 mmol dmP3 a-cyclodextrin and 2.0 mmol dm-3 P-cyclodextrin at 25 "C. All the test solutions contained a constant amount (0.01 mol dmP3) of NaCl in order to ensure that the Na+ concentration was constant during the experiments.

Kinetic Measurements The kinetic measurements were carried out using the ultrasonic-relaxation technique in which measurements of ultrasonic absorption and velocity were made in solutions thermostatted at 25 "C. The Eggers resonance technique,14a for which the frequency range has recently been extended'** from 2 to 0.2 MHz, was used in the range 0.2-20 MHz, and a standard pulse technique was used for frequencies up to 95 MHz.

Results and Discussion Electrode Responses The response characteristics of the drug-selective membrane electrodes constructed in this work are summarized in table 2. In all cases these membrane electrodes showed stable e.m.f. values over 30 min. and the response time was always < 3 min. With the exception of the chlorpromazine and dicyclomine electrodes, the present electrodes showed excellent Nernstian behaviour in the sense that a plot of e.m.f. against log concentration was reproducible and linear over a wide concentration range with a slope of 59 mV (very close to the theoretical value expected from the Nernst equation). In addition, the intercept of this plot was always constant within the range - 28.5 0.8 mV. Typical e.m.f. data are shown in fig. 1. The slopes of the e.m.f. plots for chlorpromazine and dicyclomine electrodes were 57.7 and 56.1 mV, respectively (values which are slightly smaller than those predicted from the Nernst equation), but in all cases the data were found to be reproducible. The cause of this slight deviation is not known but could be due to a small amount of self-aggregation of the drug molecule or an impurity in the sample.

Deviations from linear 'Nernstian' behaviour are found both at high and low drug concentrations (fig. 1). The former deviations are due to aggregation of the drug, the latter at concentrations of the order 10-6mol dm-3 or less, are presumably due to the transport number of the drug in the membrane falling below unity. In these respects the drug electrodes behave in much the same way as surfactant electrodes, but the concentration range over which linear ' Nernstian ' behaviour occurs is sometimes significantly greater for drugs than for surfactants.

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C

- 5c

> E 4 1

- 10(

-15(

N . Takisawa et al. 1 I I 1

/

0 /, I 1 I

-6 -5 -4 -3 log (C/mol dm-3)

3063

Fig. 1. E.m.f. response of chlorpromazine hydrochloride electrode.

Table 3. Selectivity coefficients for drug membrane electrodes

KDJ

interferent, J, drug chlorpromazine dicyclomine imipramine desipramine

chlorpromazine 1 .o 2.3 5.7 7.0

imipramine 0.17 0.41 1 .o 1.3

propranolol 0.05 0.08 0.25 0.27

dicylomine 0.52 1 .o 2.7 3.4

desipramine 0.16 0.36 0.99 1 .o

Selectivity Coefficient Relative to Interferent Drugs

The selectivity coefficient K,,, of a drug (D) membrane electrode towards another drug as an interferent ion (J) is defined by the equation:

(1) RT nF E = - In [CD + KDJ C,] + constant.

The selectivity coefficients of the drug electrode were measured relative to the other drug as follows : a solution was prepared containing a known amount of the interferent drug (J) and the e.m.f. of the solution was measured with the drug (D)-membrane electrode. To this solution was then added small amounts of drug (D) ion. From the resulting e.m.f. measurements the selectivity coefficient KDJ was evaluated for each drug concentration and the values averaged out. The KDj values are listed in table 3. The selectivity of the drug electrode increased in the order chlorpromazine > dicyclomine > imipramine > desipramine and propranolol, i.e. in the same trend as the molecular weights. We could not find any correlations between the selectivity and the lower limit of the linear response of the electrodes.

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3064 Drug-selective Electrodes

Fig. 2. Effect of pH on e.m.f. response of drug electrodes. 0, Chlorpromazine; 0, dicyclomine; A, desipramine ; A, imipramine ; 0, propranolol.

Table 4. Working pH ranges of drug-selective electrodes

drug pH range

chlorpromazine 2 4 . 5 dic yclomine 2-6.5

desipramine 2 6 . 5 imipramine 2.5-7.5

propranolol 2.5-8.5

The e.m.f. of the drug electrodes used in this work were measured relative to an electrode which was reversible to sodium ion used as a reference. It was found that the performance of the electrode was unaffected by altering the concentration of the reference electrolyte by a factor of 100. In addition to this, these electrodes did not respond significantly to hydrophobic counter-ions; the e.m.f. changed less than 10 mV by addition of dodecyl sulphate ions in the concentration range 1 x 10-6-5 x lo-* mol dm-3.

The Effect of pH on the Response of the Drug Electrodes The effect of pH on the e.m.f. response of the drug electrodes was studied by recording e.m.f. values at various pHs. The cell used was the type Ag I AgClI5 x mol dm-3 drug hydrochloride-10-2 mol dm-3 NaCl (inner solution) I membrane I test-drug solution in

In the acidic region the e.m.f. values of all five drug electrodes are unaffected by mol dm-3 NaCl (outer solution) 11 calomel electrode.

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I?. Takisawa et al. 3065 changes in pH even at pH = 2 as shown in fig. 2. On the other hand, the e.m.f. values decreased at the higher pH values because the concentration of unprotonated drugs is increased. In addition, all drugs except propranolol hydrochloride precipitate in the outer solutions at higher pH.

The working pH range of these drug electrodes is listed in table 4 and is essentially determined by the basicity and solubility product of the respective drugs. The propranolol hydrochloride electrode shows widest working pH range, pH 2-8.5, and that of chlorpromazine hydrochloride, pH 2-6.5, is almost the same as that of the liquid and liquid-plasticized membrane electrodes described in the l i terat~re .~.

In principle it is possible to estimate the pKa values of the drugs from the data presented in fig. 2 ; the pKa being equal to the pH where the initial concentration of protonated drug is halved. In the present case it was possible to use this method only for propranolol hydrochloride, which gave a value of 9.3. For the other drugs studied, precipitation of the unprotonated drug occurs which prevents an estimation of pKa being obtained. 46

Lifetime and Maintenance of Electrodes

The electrodes constructed in this work can be used continuously for at least 1 month before any damage to the membrane occurs. The membranes do not require any pre- conditioning before measurements or storage in the respective drug solutions before use. They were washed thoroughly with water after each run and kept in a desiccator under atmospheric conditions. Overall, these PVC membranes are easy to handle and use and appear to have a distinct advantage over the corresponding liquid-plasticised membranes.

Complexation Constant of Drug Binding to 01- and p-Cyclodextrins

Inclusion compounds in which the host can admit a guest compound into its cavity without any covalent compounds being formed have been used extensively in fundamental studies and have also found a wide variety of appl icat ion~.~~-~’ The cyclodextrins are known to form several inclusion compounds with substrates and, indeed, are also known to inhibit side-effects in drugs.ll In general, a drug which is in solution with cyclodextrin is expected to form an inclusion compound of the type:

drug + cyclodextrin inclusion compound. (2) The purpose of this exercise was to demonstrate how the complexation constant associated with the formation of the inclusion compound can be evaluated using the drug electrodes.

The measurements were carried out using the following procedure. First the e.m.f. of the drug electrode relative to the sodium reference electrode was measured as a function of monomer drug concentration up to the high-concentration limit of the electrode, when self-aggregation of the drug begins. The experiment was then repeated by measuring the relative e.m.f. of the drug electrode in the presence of a constant amount of cyclodextrin, again ensuring that measurements were taken in the concentration range where the drug exists as a monomer only. These measurements on the drug/cyclodextrin formulations were performed in such a way that the reversibility of the above equilibrium was confirmed. Once the e.m.f. measurements on the drug/cyclodextrin formulations were finished the e.m.f. of the drug electrode was rechecked against monomer drug to ensure consistency.

All the measurements were made in solutions containing 0.01 mol dm-3 NaCl, and typical data are shown in fig. 3. From these data it is possible to evaluate the drug monomer concentration, m,, at each total concentration of drug, C, for which the

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3066 Drug-selective Electrodes

Fig. 3. log (C/mol dm-3)

E.m.f. response of chlorpromazine hydrochloride electrode with and without dmP3 /?-cyclodextrin. 0, Calibration : a, with B-cyclodextrin.

2 x 10-3 mo1

measurements were taken. The data were analysed by first assuming that equilibrium (2) between the drug and cyclodextrin involves a 1 : 1 complex, in which case the equilibrium complexation constant, K, for each solution can be evaluated from the e.m.f. data as using the classical Scatchard equation in the form:

V -- - K-KV m1

(3)

where : v = concentration of drug complexed with cyclodextrin/

total concentration of cyclodextrin. (4)

The plots of v /m, us. v for the data involving the drugs chlorpromazine and dicyclomine hydrochlorides binding to P-cyclodextrin are shown in fig. 4. In the case of both drugs binding to a-cyclodextrin the binding constants are lower by a factor of CQ. 100 than that of /3-cyclodextrin, and in these circumstances the Benesi-Hildebrand plot in the form l/v plotted against l/ml [eqn (5)] were used. These are shown in fig. 5.

l/v = (l/Kml)+ 1. ( 5 ) The linearity and intercepts of these plots confirm the 1 : 1 stoichiometry of the complex and the equilibrium constants, listed in table 5, were obtained. The large difference in K between chlorpromazine and dicyclomine hydrochlorides suggests the possibility of constructing drug membranes which are more selective to dicyclomine hydrochloride than chlorpromazine hydrochloride by using modified /3-cyclodextrin as a neutral carrier in the membrane.12

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N. Takisawa et al. 3067

V

Fig. 4. Scatchard plot for the binding of drugs to /3-cyclodextrin in 0.01 mol dm-3 NaCl at 25 "C. 0, Chlorpromazine ; , dicyclomine.

mi'/& m m ~ r ' Fig. 5. Benesi-Hildebrand plot for the binding of drugs to a-cyclodextrin in 0.01 mol dm-3 NaCl

at 25 "C. 0, Chlorpromazine; 0, dicyclomine.

Kinetic Studies Recently there has been some attention directed towards investigating the kinetics associated with the inclusion compounds of dyes20 and related molecules2' with cyclodextrins. In the present work a 1 : 1 complex was observed for all the drugs studied and it was therefore decided to determine whether the ultrasonic relaxation method

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3068 Drug-selective Electrodes

Table 5. Binding constants (mole' dm3) of chlor- promazine and dicyclomine hydrochlorides to a- and P-cyclodextrins in 10 mmol dmP3 NaCl at

25 "C

drug a-cyclodextrin P-cyclodextrin

chlorpromazine (1.2k0.1) x lo2 (1.1 kO.1) x lo4 dicyclomine (2.8 0.3) x lo2 (9.5 +_ 0.9) x lo4

Table 6. Ultrasonic relaxation parameters for mixtures of dicylomine hydrochloride and a-cyclodextrin

single relaxation

[a-CD]/mol dm-3 [DCH]/mol dm-3 A / 10-15 s2 m-l f,/ 1 O6 Hz B/ s2 m-'

0.05 0.05

0.07 0.04

614 509

0.69 0.65

double relaxation

51 50

A,/10-15 s2 m-' jJ106 Hz A2/10-15 s2 m-I f,/lO-'j Hz B/10-15 s2 m-'

0.05 0.07 506 0.76 77 6.9 32 0.05 0.04 488 0.62 47 12.5 26

could be used to investigate the kinetics associated with the formation of these inclusion compounds. For the purpose of the present exercise the most suitable drug to use is dicyclomine hydrochloride (DCH) since it is known from previous studies22 in this laboratory that the relaxation of the monomer/aggregate equilibrium associated with the self-aggregztion of this drug at concentrations exceeding the c.m.c. (50 mmol dm-3) occurs in the ultrasonic frequency range. We have chosen a-cyclodextrin (a-CD) as the host molecule since the excess ultrasonic absorption associated with pure aqueous solution of this compound is only marginally in excess of that of 24 As a result, ultrasonic measurements have been carried out on two solutions containing a-CD and DCH. The initial concentrations of both a-CD and DCH used together with their equilibrium concentrations evaluated from the complexation constant derived using the e.m.f. data are listed in table 6. The relaxation data for these solutions are presented in fig. 6 in which the quantity a/ f 2, where a is the sound adsorption coefficient at frequency f, is plotted against frequency. Also included in this figure are the ultrasonic measurements calculated for a 50 mmol dm-3 solution of a-CD from the relaxation data reported by Kato et al.24 in a previous publication. Some selected measurements carried out in the present work were consistent with these calculated values. We did not observe any excess adsorption in solutions of DCH in water at concentrations below the c.m.c. (50 mmol dm-3).

The substantial decrease in a / f with increasing frequency clearly demonstrates that a strong relaxation occurs in both solutions containing a-CD and DCH. This relaxation occurs only when these two components are mixed together and therefore must be associated with interaction between them which we attribute to the perturbation of equilibrium (2) involving the formation of the 1 : 1 inclusion complex. It is also clear from the data presented in fig. 6 that this new relaxation is orders of magnitude stronger than any excess absorption due to 50 mmol dmw3 a-CD. To a first approximation we have

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N . Takisawa et al. 3069

600

500

- 400 E

% v)

300 2

% 5 200

-.- N n

100

( 1

~

I 0.3 0.6 1.6 4.0 10.0 25.1 63.1 fIMHz

Fig. 6. Ultrasonic relaxation data for dicyclomine hydrochloride complexing with a-cyclodextrin. 0, 40 mmol dm-' DCH + 50 mmol dmP3 aCD; a, 70 mmol dm-' DCH + 50 mmol dm-3 aCD ;

(-) 50 mmol dmP3 a-CD.

neglected the weak contribution from a-CD and attempted to analyse the data using the relaxation equation :

= c(1 +$.,),)tB

where Ai are the relaxation amplitudes, f,$ are the relaxation frequencies and B is frequency-independent excess absorption term. The relaxation parameters for a single relaxation (i = 1) are given in table 6; the fits to the experimental data were excellent in the low-frequency range 0.2-5 MHz and deteriorated at higher frequency. It is therefore clear that the relaxation data at the higher frequencies cannot be described in terms of a single relaxation. As a result we reanalysed the data using eqn (6) with i = 2 and obtained excellent fits over the whole frequency range (table 6).

An examination of the relaxation data associated with the formation of the 1 : 1 complex shows that, as expected, the relaxation frequency increases as the drug concentration is increased. The following values were calculated :

forward rate constant k, = 1.5 x 10' dm3 mol-1 s-l

backward rate constant k-, = 5.2 x lo5 s-l.

For the purpose of the present exercise it is the order of magnitude of the rate constant that is of importance, especially when compared with those found in recent studies20, 21

involving the 1 : 1 complexation of a-CD with alcohol, and also for 2: 1 complexes with dyes. From the amplitude analysis the value of IAVJ the volume change associated with equilibrium (2) was estimated to be 6.3 f 5.0 x

The second relaxation of very weak amplitude observed at the higher frequencies certainly deserves further investigation and is more likely to be associated with the a-CD molecule itself. We are presently turning our attention to this problem.

m3 mol-'.

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3070 Drug-selec t ive Electrodes

We thank the S.E.R.C. for a research grant and a CASE award (P. B.) and the University of Salford for a CAMPUS Fellowship (N. T.). We also thank Dr Derek Bloor for several useful discussions.

References 1 V. V. Cosofret, Membrane Electrodes in Drug Substances Analysis (Pergamon Press, Oxford, 1982). 2 V. V. Cosofret and R. P. Buck, Ion-selective Electrode Rev., 1984, 6, 59. 3 R. P. Buck and V. V. Cosofret, ACS Symp. Ser., 1986, 309, 363. 4 (a) A. Mitsana-Papazoglou, T. K. Christopoulos, E. P. Diamandis and T. P. Hadjiioannou, Analyst

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references therein.

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Paper 711809; Received 9th October, 1987

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