Electrochemical transport of organic ions through Polyvinylchloride

141

J. Elecrroanal. Chem., 296 (1990) 141-158 Elsevier Sequoia

!&A., Lausanne

Electrochemical transport of organic ions through polyvinylchloride L.L. Miller * and L.E. Lynch Department of Chemistry, University of Minnesota, Minneapolis, MN $5455 (U.S.A.) (Received

2 February

1990; in revised form 13 June 1990)

Abstract Thin (5-15 pm) polyvinylchloride membranes were cast from THF or cyclohexanone and characterized by infrared spectroscopy, micrometry and differential scanning calorimetry. The membranes were used in a diffusion cell whose donor compartment contained an organic salt and an electrode. The receptor compartment was a specially adapted UV cuvette used to measure, in situ, the amount of the organic ion that was transported electrochemically. This cuvette usually held aqueous 0.1 M sodium chloride and a second electrode. Using 4.0 M Nasal, the cathode in the donor compartment, and constant current pulses, which were typically 50 seconds in duration, the ionic flux was directly proportional to the current (0.1-0.5 mA). The efficiency (molecules Sal-/electron) was 22%. There was no Sal- fhtx when no current was passed or when the direction of current flow was reversed. The cations dimethyldopaminium and methyl viologen were similarly transported when the anode was in the donor compartment. Current/voltage curves were recorded. When voltages of the magnitude used for the transport experiment (30 V) were applied, the membrane resistance was substantially lower than at low applied voltages. Measurement of efficiency and membrane resistance were made when plasticizers and salts (Me4NSal, LiClO,) were added to the films, when the thickness and area of the film were changed and when solution compositions and concentrations were changed. It was determined that the membranes were weakly selective, and that the selectivity and resistance were not dependent, or very weakly dependent, on additives to the membrane. Sal- salts added to the membrane were not iontophoresed out. Comparison to a transport model from the literature is made.

INTRODUCTION

In this paper we report on the possibility of driving organic ions electrochemically through a polyvinylchloride (PVC) membrane. We are unaware of a study quite like this one, but experiments directed toward understanding PVC-based ion-selective-electrodes [l] have great pertinence. Most of these studies have focused on plasticized PVC containing neutral ionophores that act as cation carriers. At low

Manuscript prepared at IBM Almaden San Jose, CA 95120-6099, U.S.A. l

0022-0728/90/$03.50

Research

Division,

0 1990 - Elsevier Sequoia

S.A.

Almaden

Research

Center,

650 Harry

Road,

142

current (and voltage) these membranes are very selective for K+ transport. Our interest is in organic ions (drug ion models). Therefore, we have studied PVC without added ionophores. In the high current, high voltage region of interest only limited data are available from the literature, but these will provide important reference points for interpretation. A key conclusion from the previous work is that plasticized PVC is intrinsically cation selective even at high voltage and in the absence of ionophores [2]. Our interest in this subject arose from a project on the controlled release of drug ions. We have shown that a thin film of polymer on an electrode can be used to hold the drug until a pulse of electrical current releases it [3]. In one of several examples, cationic, conducting polypyrrole films were loaded with organic counter-anions. A cathodic pulse reduced (neutralized> the polymer so that the anions were forced out into the solution. A practical method using similar principles is tr~sderm~ iontophoretic drug delivery [4]. In this method ions are driven electrochemically from a reservoir through the skin. It is of practical interest because ions do not otherwise effectively penetrate the skin and because the method allows control over the delivery rate. Higher electrochemical current gives higher flux. Our practical interest in PVC is as a barrier or reservoir and as a model for the stratum comeum, the hydrophobic barrier of the skin. In application PVC is attractive because it is biocompatible and can easily be cast into films or membranes. Furthermore, the transport of inorganic cations through plasticized PVC films made it plausible that organic ions could also be transported.

Instruments A Princeton Applied Research (PAR) potentiostat/galvanostat, Model 173, was used as a current source. The spectrophotometer used for the spectroelectrochemical studies was a Shimadzu UV-160. In order to allow stirring in the receptor solution, a Tek Stir, catalog #58301, was adapted to fit into the spectrophotometer. A Perkin Elmer FT-IR, model 1710, a Model TA300 Mettler Differential Scanning Calorimeter, a Hamilton bench micrometer with 5 X 10e5 inch (1 inch = 254 cm) divisions and a JEOL Scanning Electron Microscope, Model 840 were used.

Materials Polyvinylchloride (70,000 MW) (PVC), sodium salicylate, gold label (NaSal), dioctylphthalate (DOP), dioctyladipate (DOA), lithium perchlorate, p-toluenesulfonate, sodium salt, cyclohexanone (gold label), and anhydrous sodium perchlorate were purchased from Aldrich Chemical Company and used without further purification. Poly(diallyldimethylammonium chloride) (PDDMACI), was purchased from Polysciences. Lithium salicylate (LiSal) and trioctylphosphate (TOP) were bought from Pfaltz and Bauer and used as received. The methylviologen dichloride hydrate was purchased from Aldrich and recrystallized from methanol/a~etone prior to use. The ~-(3,~d~ethox~henyl)ethyl~ne, was from Aldrich. Its hydro-

143

bromide salt was prepared by addition of it to a 1.2 fold molar excess of HBr (48%), cooled in an ice-salt bath. The mixture was stirred for 20 min. The raw product was recrystallized in water at 45 o C. Ether was added to precipitate the crystals. The crystals were rinsed with ether-saturated water until the pH of the eluate was neutral. The white product was dried under vacuum. The Et,NSal was prepared by stirring together a one to one mixture of Nasal and Et ,NBr in THF at room temperature for several hours, filtering off the solids (NaBr) and stripping off the solvent on the rovotap, to leave the final product. The Me,NSal was prepared in a similar fashion from Me,NCl and Nasal. Both structures were confirmed by IR spectroscopy.

CH,CH,NH:Br-

Sodium salicylate

Dimethyldopamine cl-

hydrobromide

cl-

CH,-Nm-CH,

Methylviologen dichloride Membrane preparation and experimental set-up The PVC membranes were prepared from a 1% PVC (wt) solution in THF or

cyclohexanone using the solvent casting technique. Specifically, 2-4 ml of solution was syringed into a glass petri dish and the solvent was evaporated at room temperature and ambient atmosphere [5]. When the membranes were dried, they were removed from the dishes with a metal spatula and their thicknesses were measured with a micrometer whose accuracy was f 1 pm. Only membranes whose thicknesses were the same (&10X) over the entire area were used in the experiments. An IR spectrum of each membrane was also run prior to its use in an experiment. From these spectra it was learned that there was a large concentration of casting solvent present in the membranes. The concentration of THF varied somewh?> with drying time, but the usual membrane had a 1: 1 mole ratio of THF to PVC monomer. THF was found even after several days at room temperature. Only at elevated temperature could the membrane be dried completely. The amount of-eyclohexanone (3 cyclohexanone : 1 PVC) was invariant at room temperature. Prior to the start of the experiment the membrane was clamped between the donor and receptor sections of a specially adapted cell. An area of 0.28 cm’

144

contacted the solutions. The receptor was filled with an aqueous 0.1 M NaCl solution and equipped with a magnetic stir bar and a Ag/AgCl wire electrode, unless otherwise specified. The donor cuvette had an aqueous solution of the organic salt and a Ag/AgCl wire electrode, unless noted otherwise. The cell was then placed in the spectrometer along with a reference cuvette containing the same solution as the receptor. Absorption spectra were run periodically for an hour prior to the application of current to check for membrane leakage. If there was none, currents of 0.5 mA, unless stated otherwise, were applied for 50 s every 300 s and transport of the donor ion of interest was monitored by its UV absorption at its x max.The experiments were broken up into 1200 s intervals and data was collected continuously in an absorption versus time fashion. The receptor solution was stirred throughout the experiment. Upon completion of each experiment a spectrum was run from 400-200 nm to make sure that the ions had been iontophoresed across the membranes unaltered. If the stirrer stopped during the experiment it caused the absorption to increase more slowly and non-linearly (i.e. peaks and valleys). Thus, stirring the receptor solution was found to be necessary for effective detection of transported donor ions. In all the experiments, the cell voltage was measured. To ascertain that this voltage was primarily due to the membrane potential (not the solution or electrodes), a four electrode system was also investigated. In this system, the additional electrodes were placed close to the membrane surface. The two original electrodes were situated further away from the membrane surface on either side. A constant current was passed as usual between the two outer electrodes, while the inner electrodes were used to measure the voltage drop across the membrane. Typically the inner electrode pair had a voltage drop which was less than 1 V smaller than that for the outer pair. Since the variability from run to run was greater than 448, this < 1 V difference was insignificant and the membrane potential was usually measured with the two electrode system. The small difference, < 1 V, was not surprising since both solutions were concentrated in salt, giving low solution resistance. Each experiment was repeated several times and the average values are reported, unless otherwise specified. Occasionally, the voltage drop across the membrane exceeded 100 V, the output capacity of the galvanostat. When this happened, the data were not used. On other occasions the membrane ruptured during the experiment. This was signified by increasing absorbance values even when the current was off. These experiments were discontinued. In general, membranes could not be re-used. Once they had dried, they wrinkled and on attempted reuse, leaked. Both platinum and Ag/AgCl electrodes were used. The measured efficiencies were not significantly different. Platinum electrodes gave slightly higher two-electrode voltages and caused the pH of the receptor solution to become more acidic. Using either Pt wires, coils or foils had no effect on the results. Because the receptor cuvette had a narrow side-arm open to the air it was possible to estimate the change in volume of this solution during iontophoresis. In the cases studied, a typical volume change was 15 ~1 when the total charge passed was 3 pm01 electrons.

145

Scanning electron microscopy (SEM) The samples were prepared by taking unplasticized

PVC membranes, whose thicknesses were measured and IR spectra were run, and cutting them in half. One half was used in an experiment, the other half was not, and both were submitted for SEM. The membranes were secured to the sample holders with a special double-stick adhesive. They were then coated with a thin layer of Au-C to enhance their conductivities. An uncoated membrane was prepared, but beam damage was too great to see any surface morphology. An accelerating voltage of 10 or 20 keV was used. Differential scanning calorimetry (DSC)

In these experiments the membranes were solvent cast from THF, weighed, and placed in DSC aluminum sample tins and scaled. The reference was an empty, sealed aluminum tin. A hole in each tin allowed air flow. The experiments were done under a steady stream of nitrogen. The samples were heated at 10 o C min from - 40 o C to 100 o C unless otherwise noted, and data were collected only on heating. The glass transition temperature (T,) of each sample was taken from the average of three determinations and the samples were run at least in duplicate. The first value obtained for each sample was discarded since it was several degrees lower than that of all subsequent measurements. The Ta’s were estimated as the midpoints of the DSC curves as measured from the extension of the pre-transitional and post-transitional baselines. Infrared (IR) spectroscopy

An IR absorption spectrum of each membrane was run prior to its use in an experiment. Some were also run after the experiment. There were no changes in the spectra. The principal peaks of the unplasticized PVC membranes were at: 2972, 2911,2867,1426,1332,1254,1065 (THF), 965,695,637 and 616 cm-‘. We attribute the peak at 1065 cm-’ to THF because the spectrum of a KBr pellet of PVC contained no such peak and THF showed a broad absorption at 1065 cm-‘. The principal peaks of the PVC/DOP membranes were at: 2960,2929, 2872,2860,1723, 1580, 1462, 1426, 1380, 1254, 1125, 1974, 1040, 959, 747, 694, 637 and 615 cm-‘, and there was none at 1065 cm-‘. The principal peaks of the PVC/DOA membranes were: 2960, 292, 2859, 1729, 1462, 1334, 1254, 1194, 963, 695, 637 and 615 cm -l. A good correlation was found between membrane thickness, measured with a micrometer, and the absorption at 1254 cm-’ (PVC). From the calibration curve generated, it was found that there was 0.045 absorption units/pm. Some of the unplasticized PVC membranes were also annealed for one hour at either 58” C, 100 o C or 158 o C in an oven. The membranes had “bubbles” on them after annealing. Then a typical experiment was done using the annealed membranes. Analysis of the IR spectra showed that the THF was completely driven out at 100 o C and 158OC and partially driven out at 58 o C.

146 RESULTS

Films were freshly cast in petri dishes, dried, and removed. The thickness of the membrane was measured with a micrometer and the IR spectrum was taken. IR spectroscopy established the purity, and by calibration of the intensity at 1254 cm-‘, it confirmed the thickness. The measured thickness of identically prepared membranes was reproducible to 510%. The IR spectra of unplasticized PVC membranes showed the presence of casting solvent (THF or cyclohexanone). The usual membrane contained l/l THF to PVC and even prolonged standing at room temperature did not remove all the THF. Using the less volatile cyclohexanone, a constant composition was reached which gave a ratio of cyclohexanone to PVC monomer of 3/l. With plasticized PVC membranes, IR spectroscopy gave no evidence for THF, although it could have been present in small amounts. The membrane was clamped between the donor and receptor compartments of a specially designed diffusion cell (Fig. 1). Several other experimental set-ups were used. A conventional side-by-side diffusion cell leaked with these thin films. Another set-up used a glass tube, which was secured in the specially adapted sample compartment of our spectrophotometer. At the bottom of the glass tube a membrane was attached and secured with parafilm. This worked satisfactorily, but the membrane area varied from one experiment to the next. The top compartment (donor) of the cell used for all experiments reported here held one ml of an aqueous solution of the organic salt and a Pt or Ag/AgCl electrode. The bottom receptor compartment was completely filled with 3 ml of aqueous 0.1 M NaCl solution, a

UV-VIS Detector

QUttt-tZ Cuvette Fig. 1. Spectroelectrochemical

O--t cell.

Magnetic Stir Bar

147

1.0 -

0.0 0

200

400

600

800

1000

1200

Time /s Fig. 2. Spectroelectrochemical

data.

stirring bar and another electrode. This compartment was built from a quartz cuvette and the entire cell fit into a UV spectrophotometer modified to allow leads to be attached to the electrodes. A galvanostat was used to apply constant current pulses. The fluxes of several UV absorbing ions were studied, but salicylate (Sal-) received the most intensive study. Sal- is an analgesic, a model for many carboxylates, and could be compared to other carboxylates which have been studied using skin as a membrane. In the following sections the “usual” conditions refer to 4.0 M aq Nasal in the donor section, 0.1 M aq NaCl in the receptor, Ag/AgCl electrodes and a membrane area of 0.28 cm*. Current pulses of 0.5 mA were applied for 50 s every 300 s.

Sodium salicylate In the “usual” experiment the constant current was applied and the UV absorbance due to the Sal- in the receptor promptly appeared and increased linearly with time (Fig. 2). When the current was turned off, the absorbance stopped increasing and was constant until another 50 s pulse was applied 150 s later. This behavior was found in all other Sal- experiments, i.e. there was no flux at zero current and a constant flux with the current on. Extrapolation of the absorbance time line gives an intercept near zero. This means that the lag time for appearance of Sal- is less than a few seconds and unmeasurably small with this apparatus. The slope of the line gives the flux (mol/s) which can be compared to the current expressed as mol electrons/s. Expressed in %;, this gives the efficiency of the process (%eff), a number comparable to the transference number that will be used to characterize the phenomenon as shown in Table 1. The average efficiency in the experiment described above was 22%, i.e. of all the ions that somehow traversed the membrane to carry the current, 22% of them were Sal-.

148 TABLE 1 Results for Sal- using different ions in the receptor solution Recevtor solution (0.1 M)

x/am

- E/V

ZEff

NaCl LiCl PDDMACl a NaPVS NaOTs Et ,NCl

10 9 10 11 9 10

33 43 105 42 25 31

22 19 0 23 32 29

a Cont. calculated as mol of monomer/l.

After the first 50 s pulse, which was sometimes anomalous, the same (&-3)s efficiency was obtained for ten repetitive pulses. Using identically prepared 10 pm membranes the reproducibility was somewhat less (* 10%) and it was occasionally true that a membrane would leak or would be so resistive (galvanostat limit 100 V) that Sal- was not passed. Reversing the current direction gave no Sal- transport as expected. When a constant current of 0.5 mA was applied, a constant flux of Salwith time was found for 2 h, after which the absorption went off scale. The experiment was continued for 5 more h, during which time it was found that the voltage drop did not fluctuate and thus, that the membrane had not ruptured. Using the usual experimental protocol the Sal- flux was measured over the current range 0.1-0.5 mA. A linear relationship (r = 0.99; intercept = 0.0) was determined indicating that the flux of organic ions can be controlled in a predictable manner by controlling the current. To investigate the effect of Sal- concentration, the aqueous donor solution was varied from 1.0 M to 4.0 M in one molar increments and the efficiencies were monitored. Figure 3 shows that increasing the concentration of Sal- caused an increase in the Seff. This is expected if there is competition between Sal- and Na+ transport, and changing [Sal-] in solution, changes [Sal-] at the interface or in the membrane. However, assuming an intercept of 0,O (no Sal-, no flux), the relationship was not linear. Non-linear solution concentration effects can come from the action of DOME equilibrium and exclusion (see below) or from ion pairing which should be prevalent in these concentrated donor solutions. Because of the mechanical difficulty of replacing the receptor solution, results using different concentrations of NaCl in the receptor were only reproducible if a fresh membrane was used in each experiment. Under these conditions the %eff was 30 + 6 for 0.01 M, 23 f 3 for 0.1 M and 19 + 5 for 1.0 M. It is concluded that the Sal- flux is slightly dependent on the NaCl concentration over this lOO-fold range. It was of interest to vary ions in the receptor solution, to see what effect this would have on the voltage and %eff. Data for several salts are shown in Table 1. Replacing Na+ with a larger (Et,N+) or smaller (Li+) cation made little difference on the experimental results. This suggests that all cations in the receptor solution are transported similarly. Replacing Cl- with a larger (OTs-) or polymeric (PVS-)

149

0

1

2 [Nasal]

3

4

/ mol

I-’

5

Fig. 3. The change in ‘R,efficiency as donor [Nasal] is varied using a 10 pm PVC (THF) membrane at 0.5 PA.

anion also had little effect on the results. This was not surprising since the receptor solution anion should not be transported. A surprising result was obtained using a polymeric cation instead of Na+. Thus, when poly(diallyldimethylammonium chloride) (PDDMACl) was used in the receptor solution, no Sal- was transported, and the voltage drop was high (i.e. > 100 V). Further experiments using a 0.1 M PDDMACl receptor solution began with the galvanostat set to give -0.5 mA pulses. This gave no Sal- transport. Next the receptor solution was removed leaving a thin film of PDDMACl coated on the membrane, which could be seen and felt. After replacing the receptor solution with a 0.10 M NaCl solution, using precautions not to disturb the membrane, the experiment was repeated. Initially the voltage was high and the %eff was low for the NaCl receptor solution. However, after two or three current pulses were applied, the values returned to the level normally found for NaCl solutions. It is concluded that the large polymeric cations could not be transported across the membranes from the receptor to the donor causing the high voltage drop. The galvanostat was overloaded and could only provide small currents and little Sal- transport; however, the membranes were not damaged permanently or coated permanently by PDDMACl, so that when Na+ had an opportunity to be iontophoresed, it behaved normally. Organic cation transport

In addition to Sal-, the electrochemically driven transport of two other donor ions, methylviologen dichloride, MV’+, and dimethyldopamine hydrochloride, DMOP+, was investigated. These cations were chosen because they absorb UV light. DMOP+ is of interest because it represents a large class of drugs that are protonated amines. A 1.0 M aqueous solution of methylviologen was used in the donor cell and the experiments that were done with Sal- were repeated except that anodic 0.5 mA

Fig. 4. SEM. (A) PVC membrane during iontophoresis.

that has been used for iontophoresis.

(B) PVC membrane

tha

wptured

151

current pulses were used instead of cathodic ones. Spectroelectrochemistry gave a zero time intercept and a linear increase of receptor MV*+ with time. The Seff = 25. However, since a dication is being transported the maximum %eff is only 50. Linear I/t behavior was also found when an aqueous saturated solution (i.e. - 0.2 M) of dimethyldopamine hydrobromide (DMOP+) was used in the donor cell and for this cation %eff = 27. The voltages were somewhat smaller for cations than for Sal-. Because the efficiencies for Sal- and DMOP+ are less than 50%, it is suggested that small inorganic ions (Na+ and Cl-) are transported in preference to large organic ions. The data are not very definitive with regard to classification as cation selective, but they do not argue against such a conclusion. Scanning electron microscopy was employed to search for changes in morphology caused by the electrochemical treatment in the “usual” NaSal/PVC/NaCl experiment. In half of all the samples analyzed, evidence for such changes was obtained. These samples showed linear defects on the surface (Fig. 4a). The SEM’s of the halves of the membrane which had not been used in experiments showed no such defects. In one membrane, application of the potential led to rupture of the membrane, i.e. Sal- leaked through when the current was turned off. The SEM of this membrane showed a hole (Fig. 4b), which appeared on the linear defects. Thus, in this case electrical breakdown is confirmed, and may be correlated that at least in part with a thinning of the membrane in the manner identified by SEM. It is noted that although the applied voltage is high, 3 X lo4 V cm-‘, it is well below the breakdown voltage of PVC [6], which is about 5 X lo6 V cm-‘. Membrane resistance Two electrode voltage measurements were performed routinely as described in the Experimental section. It is believed that these measurements reflect the membrane resistance within the rather generous boundaries of reproducibility in these experiments. In an earlier study the I/Y behavior of plasticized PVC membranes was reported by Buck and co-workers [2]. We have made similar galvanostatic, steady state measurements on the “usual” Sal- delivery system using unplasticized PVC. It was found that the results depended substantially on the sequence and size of current steps employed. Figure 5 shows the non-linear 1/V behavior when points are taken starting at 0.1 mA and increasing to 0.5 mA, as well as the declining resistance as voltage increases. Clearly the membrane is responding to the high field to provide less resistive pathways. At 0.5 mA the resistivity of the membrane is 3 X lo7 G cm. In the next experiment a 5 pm PVC membrane and Pt wires were used. The current was started at 0.01 mA and increased in 0.01 mA increments up to 0.1 mA after which it was increased in 0.1 mA increments up to 0.9 mA. A linear relationship was found up to 0.1 mA, after which a change in slope occurred (Fig. 6). The current was then stepped down in the same increments. There was hysteresis in the curve with later data points showing lower voltages at the same current. These results correspond qualitatively to those previously reported for KC1 solutions with plasticized PVC.

152

0.0

., 0.1

.

I. 0.2

I',' 0.3 0.4

\

I ',5OoOo 0.5 0.6

I/d Fig. 5. Z/V and I/R for a 5 pm PVC (THF) membrane.

The effect of membrane thickness on the voltage at 0.5 mA in the “usual” experiment is shown in Fig. 7. The change in voltage between a 5 pm and a 12 pm membrane was comparable to the experimental error, but the thinner membranes may be microscopically rough and because it is suspected that the applied voltage causes structural changes the nominal thickness may not be a useful measure. On the other hand interfacial processes may be important in determining the resistance at 0.5 mA and may lead to behavior of the type observed. To check the effect of membrane area, a new cell with a small diameter donor compartment and a smaller neck on the receptor was used. This cell exposed a membrane area of 0.07 cm*. In the usual experiment it gave data shown in Fig. 7

0.0

0.2

0.6

0.4

0.8

1.0

IlmA Fig. 6. I/V for a 5 pm PVC (THF) membrane. (0) Increasing current steps. (B) Decreasing

current steps.

153

0

2

4

6

8

10

12

14

x/pm

Fig. 7. Voltage as thickness is varied for PVC (TX-IF). (0) Area 0.28 cm2. (X) Area 0.07 cm’.

indicating no change in resistance or efficiency compared to a membrane area of 0.28 cd. This demonstrates that “edge-effects”, which wuld come from ciamping the membrane in place, are unimpartant.

TABLE 2 Ion

~embr~e

x&m

%Eff

-E/V

T/c

sal(4.0 M)

PVC(THF) PVC(THF)

10 5

22 18

33 28

49

PVC/TOP(4/1} PVC/TOP(4/1)

10 5

30 27

22 29

37

PVC/DOA(4/1) PV~/DOA(4/1)

IO 5

19 29

29 24

21

PVC,‘DOP(4/l) PV~/DOP(4/1)

10 5

23 27

32 22

24

PVC/DOP(2/1) PVC/DOP(2/1)

10 5

14 27

47 33

25

PVC(THF) PVC(THF)

10 5

32 22

27 23

69

PVC/TOP(4,‘1) PVC/TOP(4/1)

10 5

24 28

18 23

37

PVC(THF) PVC(THF)

10 5

54 46

13 13

69

PV~~OP~4/1) PVC/TOP(4/1)

10 5

40 54

25 12

37

DMUP + ( - 0.2 M)

MV2+ (I.0 M)

154

Membrane

composition

In one set of experiments the plasticizers dioctylphalate (DOP), dioctyladipate (DOA) and trioctylphosphate (TOP) were added. IR demonstrated that the plasticizers were present and that little or no THF was present. Differential scanning calorimetry (DSC) revealed that the plasticizers lowered the Tg of PVC to the expected values [7]. When these membranes were used in the usual transport experiment the data in Table 2 resulted. There was little effect on the voltage or the efficiency for the transport of Sal-, DMOP+ or MV2+. Indeed, if anything the materials with the lowest Tg had higher resistances. Considering that membranes with Tg above and below room temperature were used for Sal- (and neither contained THF) the values are surprisingly constant. Apparently under these conditions PVC chain mobility is not important. A more thorough test was provided by measuring the I/V curve for 10 pm 4 : 1 PVC/DOP membranes. The current was started at 0.01 mA, increased to 0.1 mA in 00.1 mA increments and then increased to 1.2 mA in 0.1 mA increments. The shape of the curve (Fig. 8) was similar to that for unplasticized PVC. However, at low currents the resistance of the PVC/DOP was smaller [2]. At 0.5 mA the voltage was about 30 V. Some effort was made to prepare PVC membranes free of THF by annealing. At 100” the THF was removed (IR spectroscopy) but gave somewhat more resistive membranes without improved reproducibility. It was also possible to cast good films from cyclohexanone. IR spectroscopy showed that the membrane had a molar ratio of three cyclohexanones to one monomer unit. Transport experiments using Nasal gave data identical within experimental error to those with PVC (THF) membranes. Examination of the IR spectra of membranes after use showed that the THF and cyclohexanone concentration was unchanged.

0.0

0.2

0.4

0.6

Fig. 8. Z/V for a 1 pm PVC/M)P

0.8

(l/4)

1.0

1.2

membrane.

1.4

155 TABLE 3 Sal- data for PVC membranes containing added electrolytes Electrolytes (wtW) =

- E/V

SEff

x/pm

Et,NSal(O.O5)

37 40 31 18 10 15 15

26 21 20 10 11 4 8

15 10 5 10 5 8 5

Me,NSal(O.O5) LiClO, (0.1) LiSaI (0.1)

a With 1% PVC in THF solution for fii

casting.

It was also determined that there were no infrared bands due to Sal-’ present in the membranes after the experiments. Similarly, visual inspection of membranes after (colored) MV2+ iontophoresis showed no color, demonstrating that only undet~tably small ~ncen~ations of MV2+ were present. From both a practical and mechanistic viewpoint it was of interest to study membranes that were loaded with electrolyte. It was anticipated that this might reduce the resistance and if the additive was a Sal- salt it might improve the efficiency of Sal- transport. Several salts were investigated and it was determined that translucent, visibly homogeneous films could be cast using the four salts listed in Table 3. Higher concentrations of these salts gave inhomogenous films. As shown in the Table, membranes cast using 0.05 solution wt% of Me,NSal or Et,NSal (and 1% PVC) gave results indistinguishable from those in the absence of the salts. Membranes cast from THF solutions containing 0.1% LiClO, or LiSal gave slightly lower voltages, and smaller efficiencies. In a practical sense these were negative results. Mechanistically, it is interesting, especially in terms of IR analyses conducted before and after the experiment. Using Lisa1 Me,NSal or Et,NSal, IR spectroscopy showed no change in the Sal- concentration in the membrane due to the el~~~he~c~ treatment. Using LiClO, gave a 23% decrease in the ClOi concentration. In these experiments, up to 3 pmol electrons were passed, which iontophoresed 0.6 prnol of Sal- into the receptor. We estimate that the 10 pm film contained 0.1 pmol of Et,NaSal. Therefore, about 6 times more Sal- was delivered than originally resided in the membrane. When a LiSal loaded membrane was used with LiCl in the donor (instead of Nasal), IR spectroscopy gave no evidence for Sal iontophoresis out of the membrane. Over a period of an hour, a tiny amount of exchange took place, but the applied current did not increase this. Clearly, the M+Sal- in the film was not dissociated and driven out by the field. Most probably the added M+Sal- are not involved in Sal- iontophoresis. To summarize, changing the com~sition of the membrane with plasticizers, a different solvent or with salts had virtually no effect on the results. The selectivity and membrane resistance are surprisingly insensitive to membrane composition.

156

Even more surprising is the observation that Sal- salts are not iontophoresed PVC.

out of

DISCUSSION

Perhaps the most important point here is that controlled iontophoretic transport of organic anions and cations is possible through PVC membranes. These membranes are thin and when unplasticized contain much solvent but they are sufficiently strong and they allow fairly reproducible control of the ionic flux. This flux can be precisely and predictably adjusted or stopped by changing the current. From a practical viewpoint currents of 0.1-l mA cme2 are desired for many drug delivery applications [4], and this can be accomplished. The negative result in terms of application is that the membrane resistance is very high and it was not improved significantly by any additive that we employed. It is of interest to compare PVC (THF) with a typical skin sample, excised hairless mouse skin. These skin samples are a few millimeters thick. Of this thickness the stratum corneum makes up about 10 pm. Comparable experiments M NaCl or 0.1 M Na utilized 0.5 mA cm-’ and either 1 M NaSal/PVC/O.l benzoate/skin/Sorensen buffer (0.19 M Na+) [9]. It is found that skin is less resistive, requiring about 2 V instead of the about 20 V required for PVC (THF). The lag time for skin is longer and there is a break-in period of minutes during which the voltage drops by as much as 50%. The very different time scale for PVC emphasizes the differences and the complexity of the skin’s response. The %eff found for PVC and skin shows great similarity. (I) Using symmetrical bathing solutions, others have found that there is a selectivity for Na+ or K” over Cl- [lO,ll]. In our PVC expe~ents Sal- efficiencies are small even from concentrated solutions and there is a net water flow from anolyte to catholyte. For skin, benzoate efficiencies are similarly small and there is also a net water flow toward the catholyte. Both PVC and skin show higher efficiencies for organic cations than organic anions, when they compete with NaCl [12]. Both PVC and skin show non-linear dependence of the efficiency on the organic anion solution concentration. Neither PVC nor skin showed much effect on the efficiency of organic anion transport from changes in the anolyte (NaCl, Sorensen buffer) inorganic salt concentration. Explanations of these observations have in both cases invoked cation selectivity due to fixed anionic sites [9b]. As discussed below these sites favor cation transport and, by Donnan exclusion, tend to abbe effects of the concentration of the anolyte. The remainder of this discussion will be devoted to organizing the facts and analyzing them in light of the transport model proposed by Buck [12] and by Simon [lo] and their respective co-workers. Although our data are usually insufficient in reproducibility or range of conditions to allow good quantitative tests, we have examined a wide range of variables that can be compared with expectations from the model. Of importance is an explanation of the non-effect of additives and the observation that Sal- salts are not iontophoresed out of PVC.

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The existing transport model follows from the following observations made on PVC with symmetric aq KC1 bathing solutions. The work of Simon and co-workers [lo] showed that in the potential range of interest here the transference number (Seff) for K+ through PVC, plasticizer, ionophore membranes was 0.77. That for chloride was less than 0.01 and the remainder was suggested to involve ions from water. 1/V curves for plasticized and unplasticized PVC, without ionophore have been reported by Buck and co-workers [2]. They resemble the curves and hysteresis found here. Based upon the observations that the film resistance decreased at high voltage, that there was hysteresis in the I/V curves, and that more hydrophobic anions gave more reduction in the resistance, they proposed that salt was incorporated into the membrane from concentrated KC1 solutions at high voltage. Based on impedance m~urements [13] they showed that there was an interfacial, as well as the bulk resistance. All authors agree that the cation selectivity of any PVC membrane depends on the presence of fixed (or poorly mobile) anionic sites: These provide a pathway for K+ or K+ (ionophore) transport and control I/V at low voltages through Donnan exclusion. A similar pathway is not available for anions and only at high voltage or high salt concentrations can anion transport be effective. Such conditions were employed here. Many of our results can be accommodated by this ion-exchange model in which cations are transported via fixed anionic sites, and both cation and anion transport are effected by salt incorporation under these high voltage conditions. Thus, the efficiencies are consistent with cation selectivity, while the solution Nasal concentration effect and lowered resistance at high voltage are consistent with salt incorporation. The insensitivity to changing [NaCl] or changing NaCl to LiCl to Et,NCl in the anolyte (Table 1) would seem to require that each of these salts is extracted into the PVC (THF) membrane to a similar extent. The high resistance which resulted from the polymeric cation, PDDMACI, in the anolyte could demonstrate the necessity of incorporating some cations from the anolyte, to neutralize the fixed anionic sites. To agree with this model it would have to be postulated that the non-effect which resulted from changing PVC (THF) to PVC (cyclohexanone) or plasticized PVC arose because these additives did not affect the amount of salt extracted or the relative mobility of the various ions. That is, there were no significant (therefore, variable) chemical interactions between the solvents or plasticizers and the ions being transported. Furthermore, the polymer chain motions evaluated by Tgwere not important in determining transport rate. In the same vein (but with more trepidation) it could be postulated that the added salts, like Et,NSal did not lower the resistance or get iontophoresed out because they were not dissociated under these conditions and were not useful in providing ionic pathways. That undetectable amounts of Sal- (IR) or MV2+ (color) were present at the end of the experiment could be accommodated if the salt incorporated due to the voltage diffused out rapidly once the voltage was turned off. All of these results do, however, strain the theory and we are unsatisfied that understanding has been achieved. A more satisfactory alternative is that under these conditions the membrane morphology is changing to provide a few, lower-resis-

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tance, polar pathways. The SEM data is suggestive of such changes and at 3 x lo4 V cm-’ it would not be surprising. These induced polar pathways or “channels” could have a structure which is relatively independent of plasticizer or salt added to the membrane and the salt in regions away from a channel would not participate. If the channel was mildly selective for small ions, and involved immobile anions, the small solution concentration and solution composition dependencies could be accommodated. If the number of channels was not large and the ion mobility was high only small amounts of Sal- and MV2’” would be incorporated at the end. ACKNOWLEDGEMENTS

This work was supported by the National Science Foundation. from R.P. Buck are ac~owledg~.

Helpful comments

REFERENCES 1 See references in E. Lindner, E. Graf, 2. Niegreisz, K. Toth, E. &mgor and R. Buck, Anal. C&em_,60 (1988) 295. 2 M.L. Iglehart, R.P. Buck and E. Pungor, Anal. Chem., 60 (1988) 290. 3 L.L. Miller, Q.X. Zhou and J.R. Valentine, J. Electroanal. Chem., 261 (1989) 147. 4 J. Hadgraft and R.H. Guy, Transdermal Drug Delivery, Marcel Dekker, New York, 1989. 5 J.K. Sears and J. Darby, The Technology of Plasticizers, Wiley, New York, 1982, p. 258. .6 Reference 5, Ch. 4; S. Is&&i, M. Yamamoto, S. Chabota, T. Mizoguchi and M. Ono, IEE Trans. PAS-93, (1974) 1419. 7 Reference 5, Ch. 3. 8 A.F. Kydonieus in A.F. Kydonieus and B. Bemer (Eds.), Transdermal Delivery of Drugs, Vol. 1, CRC Press, Boca Raton, Ch. ‘1. 9 (a) H.H. Bellatone, S. Rim, M.L. Francoeur and B. Rasadi, Int. J. Pharm., 30 (1986) 63; (b) L.L. Miller and G.A. Smith, ibid., 49 (1989) 15. 10 A.P. Thoma, A. Viva.&Nauer, S. Avanitis, W.E. Morf and W. Simon, Anal. Chem., 49 (1977) 1567. 11 R.R. Bumette and B. Ongpipattanakul J. Pharm. Sci., 76 (1987) 765. 12 G.A. Smith and V. Kwan, unpublished work. 13 K. Toth, E. Graf, G. Horvai, E. Pugnor and R. Buck, Anal. Chem., 58 (1986) 2741.