Influence of Nonionic Surfactants on the Potentiometric Response of

Mar 6, 1998 - Development of in situ ion selective sensors for dissolution. Hugo Bohets , Koen Vanhoutte , Roy De Maesschalck , Paul Cockaerts , Bert ...
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Anal. Chem. 1998, 70, 1477-1488

Influence of Nonionic Surfactants on the Potentiometric Response of Ion-Selective Polymeric Membrane Electrodes Designed for Blood Electrolyte Measurements Elz3 bieta Malinowska* and Mark E. Meyerhoff†

Department of Analytical Chemistry, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, Poland

The effect of the nonionic surfactants Brij 35 and Triton X-100 on the selectivity of neutral carrier-based ionselective electrodes (ISEs) commonly used for measurements of electrolytes in whole blood is investigated. Studies are conducted with plasticized PVC membranes doped with several neutral ionophores commonly employed to prepare clinically useful potassium, calcium, and sodium ISEs. An observed increase in the electrodes’ EMF values upon the addition of surfactant to the test solution suggests a change in the ion selectivity of the polymeric membranes in the presence of Brij 35 or Triton X-100. For membranes doped with K+-selective valinomycin, the effect of nonionic surfactants is relatively small. However, in the case of calcium-selective membranes prepared with ETH 1001 and ETH 129, nonionic surfactants, especially Triton X-100, decrease the selectivity for calcium over potassium cations by nearly 1 order of magnitude. Such behavior is even more dramatic for sodium-selective membranes, with the degree of surfactant-induced loss of ion selectivity dependent on the specific sodium ionophore employed, the lipophilic tetraphenylborate derivative content of the membrane, and the surfactant type. A detailed theoretical model is presented to explain the effect of nonionic surfactants on the EMF response function of cation-selective polymeric membrane electrodes. Experimental results are in good agreement with theoretical predictions based on known binding constants for ionophores and surfactants with given cations. It is well known that nonionic surfactants containing poly(ethylene oxide) or poly(propylene oxide) subunits complex cations via ion-dipole interactions. The resulting positively charged complexes, in combination with lipophilic counterions (e.g., tetraphenylborates), have been used as electroactive components for the design of polymer membrane electrodes that respond potentiometrically toward barium, lead, strontium, calcium, magnesium, lithium, and sodium ions (see ref 1 and references therein). Such electrodes are also sensitive to the * Author for correspondence. Fax: (4822) 6607408. E-mail: [email protected]. † Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109. (1) Markuzina, N. N.; Mokrov, S. B.; Stefanova, O. K.; Sementsov, S. N.; Volkov, Yu. M.; Ranieva, E. A. Russ. J. Appl. Chem. 1993, 66, 1765-69. S0003-2700(97)00761-0 CCC: $15.00 Published on Web 03/06/1998

© 1998 American Chemical Society

concentration of corresponding free surfactant in aqueous test samples and can be used for potentiometric determination of such nonionic species. Since in these systems the surfactants are soluble within the organic polymeric membranes, it is also anticipated that, if such surfactant compounds were present in samples, they may induce interferences during measurements with more conventional neutral carrier-based polymer membrane cation-selective electrodes. Electrodes of this type are now used widely within many commercial blood gas/electrolyte analyzers. Moreover, such instruments operate with calibration and washing solutions containing certain nonionic surfactants.2 Considering the very narrow concentration ranges of physiologically important electrolytes (e.g., Ca2+, K+, Na+) and, as a consequence, the very small expected EMF responses, any instabilities of measured potentials or changes in an electrode’s selectivity induced by the presence of surfactant can result in significant errors. To date, only a few reports have mentioned the effect of surfactants on measurements using cation-selective electrodes.3-7 Potassium- and calcium-selective electrodes have been the primary targets of these investigations. It was found that cationic surfactants interfere significantly4,5 due to strong competition with primary cations for cation exchange sites within the membranes of these sensors. In contrast, it has generally been concluded that nonionic surfactants should have little influence on calcium and potassium sensors prepared with ionophore-doped PVC membranes.5 Recently, however, it was reported that poly(ethylene oxide)-based nonionic surfactants can interfere with the EMF response of pH-type polymer membrane electrodes prepared with lipophilic amines as neutral carrier proton ionophores.7 Enhanced surfactant-mediated extraction of interfering metal cations into the membrane from the sample solution results in a decrease in potentiometric selectivity for protons over background cations and, as a consequence, leads to a shortening of the pH measurement range (i.e., poorer detection limits). (2) Barton, E. C., et al., Eds. Advances in Automated Analysis, Technicon International Congress, 1976; Mediad: Tarrytown, NY, 1977; Vol. 2, pp 39, 43. (3) Hamonds, M.; Lambert, A. J. Electroanal. Chem. 1975, 53, 155-58. (4) Llenado, R. A. Anal. Chem. 1975, 47, 2243-49. (5) Hulanicki, A.; Trojanowicz, M.; Pobozny, E. Analyst 1982, 107, 1356-62. (6) Craggs, A.; Moody, G. J.; Thomas, J. D. R.; Birch, B. J. Analyst 1980, 105, 426-31. (7) Espadas-Torre, C.; Bakker, E.; Barker, S.; Meyerhoff, M. Anal. Chem. 1996, 68, 1623-31.

Analytical Chemistry, Vol. 70, No. 8, April 15, 1998 1477

sensors, while the primary ionophore also does not exhibit appreciable complexation with interfering ions.

Figure 1. Structures of ionophores and surfactants used in this work.

Herein, we extend the study regarding the effect of nonionic surfactants with poly(ethylene oxide) units (Brij 35 and Triton X-100; see Figure 1) on the potentiometic response of cationselective polymeric membrane electrodes, other than pH sensors, prepared with a variety of neutral carriers (see Figure 1). It will be shown that the ion selectivities of cation-selective membrane electrodes (sodium, calcium, and potassium) can be greatly affected by the presence of Brij 35 or Triton X-100 in the sample. This phenomenon can be explained by the partitioning of nonionic surfactants into the membrane phase and the concomitant enhanced extraction of potassium and sodium ions present in the sample phase. The most pronounced effects are observed for membranes doped with ionophores that bind target cations weakly (e.g., methyl monensin). A model is developed that fully explains the loss in ion selectivity as a function of the relative binding constants of the surfactant and ionophore with metal ions, as well as the concentration and membrane partition coefficient of the given surfactant present in the sample. In contrast, the theoretical model presented in the previous work7 considered that only protons could complex with the neutral amine ionophores in pH 1478 Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

EXPERIMENTAL SECTION Materials and Reagents. The sodium ionophores 4-tertbutylcalix[4]arene-O,O′,O′′,O′′′-tetraacetic acid tetraethyl ester (I) (Aldrich Chemical Co., Milwaukee, WI) and monensin methyl ester (II) (Calbiochem-Novabiochem Co., San Diego, CA), were obtained from the indicated sources. Bis[(12-crown-4)methyl] dodecylmethylmalonate (Na+ ionophore) (III), 2-dodecyl-2-methyl1,3-propanediylbis[N-5′-nitro(benzo-15-crown-5)-4′-yl)carbamatel (BME-44) (K+ ionophore) (IV), valinomycin (K+ ionophore) (V), ETH 1001 (Ca2+ ionophore) (VI), ETH 129 (Ca2+ ionophore) (VII), potassium tetrakis(4-chlorophenyl)borate (KTpClPB), 2-nitrophenyl octyl ether (NPOE), bis(2-ethylhexyl) sebacate (DOS), highmolecular-weight poly(vinyl chloride) (PVC), and tetrahydrofuran (THF, distilled prior to use) were purchased from Fluka (Ronkonkoma, NY). Brij 35 (polyethylene glycol monolauryl ether, n ) 23) was obtained from Sigma (St. Louis, MO), and Triton X-100 (polyethylene glycol p-isooctylphenyl ether, x ) 9-10) was a product of Aldrich. All aqueous solutions were prepared with salts of the highest purity available using distilled, deionized water. Membrane Preparation. In general, the polymeric membranes evaluated for ion response contained 2 wt % ionophore, 30 wt % PVC, 67-68 wt % plasticizer, and varying amounts of KTpClPB (for details, see Tables 3-5). The membrane components, total 200 mg, were dissolved in 2 mL of freshly distilled THF. This solution was placed in a glass ring (24-mm i.d.) over a glass plate. After solvent evaporation overnight, the resulting membrane was peeled from the glass mold, and disks of 7-mm i.d. were cut out. Membrane disks were mounted in conventional ISE electrode bodies (type IS 561; Philips, Eindhoven, The Netherlands) for electromotive force (EMF) measurements. For each membrane composition, two electrodes were prepared. Potentiometric Measurements. All measurements were performed at ambient temperature (22 ( 1 °C) using a galvanic cell of the following type: Ag/AgCl/bridge electrolyte/sample/ ion-selective membrane/inner filling solution/AgCl/Ag. The bridge electrolyte consisted of 1 M lithium acetate. The inner filling solutions of the ISEs were 0.01 M solutions of the appropriate primary cation chloride salt (NaCl for Na+ electrodes, KCl for K+ electrodes, etc.). The EMF values were measured using a custom-made 16-channel electrode monitor. Details of this equipment were described previously.8 Potentiometric selectivity coefficients were determined according to the fixed interference method (FIM) using 0.1 M solutions of the interfering ion.9 Activity coefficients were calculated according to the Debye-Hu¨ckel approximation.10 The performance of the electrodes was examined by measuring the EMF of the primary ion solutions over the concentration range of 10-7-10-1 M. Measurements were made in 0.05 M tris(hydroxymethyl)aminomethane (TRIS) buffer, pH 7.4, containing a background of interfering cations of appropriate concentration. (8) Brzozka, Z. Pomiary, Automatyka, Kontrola 1988, 9, 197-98. (9) Guilbault, G. G.; Durst, R. A.; Frant, M. S.; Freiser, H.; Hansen, H. E.; Light, T. S.; Pungor, E.; Rechnitz, G.; Rice, N. M.; Rohm, T. J.; Simon, W.; Thomas, J. D. R. Pure Appl. Chem. 1976, 48, 127-32. (10) Meier, P. C. Anal. Chim. Acta 1982, 136, 363-69.

When surfactants were used, they were added as aliquots from a 0.05 M stock solutions to achieve the desired concentration. Calibration curves in the presence of surfactants were obtained once the potential had reached an approximately steady-state value after the initial addition of the surfactant to the test solution. THEORETICAL MODEL The following theoretical expressions are based on the model for cation-selective membranes11 containing an electrically neutral ionophore (L) and an anionic additive (R-). Although our work is similar in some respects to the theory put forth previously by Espadas-Torre et al. to explain the effects of nonionic surfactants on the selectivity of polymeric pH electrodes,7 this previous work did not consider the situation when the primary ionophore also exhibits appreciable complexation with interfering ions (i.e., it was assumed that only protons could complex with the neutral amine ionophores in such pH sensors). The assumptions made in the present work are as follows: 1. Any diffusion potential within the membrane and the internal solution/membrane phase boundary potential are constant and included in the cell E° value. 2. The concentration of anionic site additives, [RT-], is constant throughout the membrane. Any possible ion pair formation with such sites within the membrane phase is also neglected. 3. In the membrane phase, the activity coefficients of all ions and ion-ligand complexes are the same. The activity of any neutral species is equal to its respective concentration. 4. The total concentration [LT] of carrier (L) is treated to be constant in the membranes according to the following equation: +

+

[LT] ) [L] + ni[LniIzi ] + nj[LnjJzj ]

(1)

where [L] is the concentration of free ionophore, [LniIzi+] and [LnjJzj+] are the concentrations of complexes in the phase boundary layer, and ni and nj are the stoichiometric factors of the complex formed with primary and interfering cations (I and J, respectively). 5. The concentration of free ionophore [L] is assumed to be constant. 6. The concentration of uncomplexed ions, I and J ([Izi+] and + [Jzj ], respectively), in the organic membrane phase depends on membrane composition. The ionophore forms charged complexes, [LniIzi+] and [LnjJzj+], with primary ion I and interference ion J in polymeric films with the corresponding stability constants: +

βLI )

[LniIzi ] ni

zi+

(2)

Izi+org + Sorg T SIzi+org

(4)

Jzj+org + Sorg T SJzj+org

(5)

and

with binding constants defined as +

[SIzi ]

βSI )

[S][Izi]

(6)

and +

βSJ )

[SJzj ] +

[S][Jzj ]

(7)

The formation of a surfactant-cation complex in the membrane phase is restricted by the ability of the ionophore to remain the primary cation-ionophore complex since electroneutrality conditions must be maintained within the bulk of the membrane phase. Thus, the changes in EMF due to the presence of surfactant will likely be observable only when the concentration of primary cation is low (i.e., where the interfering cation in the background electrolyte solution can effectively compete for cation exchange sites in the membranes via formation of an SJzj+ complex). Selectivity coefficients are assumed to be determined by the fixed interference method (FIM),9 where the potential of a cell is measured with solutions of a constant interferent ion activity, aJ, and varying activity of primary ion, aI. The potential values obtained are plotted vs the activity of the primary ion. Assuming that the composition of the inner filling solution of the electrode remains constant during the measurements, the EMF response of the neutral carrier membrane to the cation ion activity changes in the sample solution can be described by the expression for the phase boundary potential at the outer membrane/sample interface. Over the activity range where the electrode responds ideally to the primary cation, this potential is given by

EI ) E° +

kiaI RT ln ziF [Izi+]

(8)

[L] [I ]

and +

βLJ )

participate in binding metal ions (for simplicity, we assume 1:1 complexes) according to the following equilibrium:

[LnjJzj ] +

[L]nj[Jzj ]

(3)

7. When a nonionic surfactant, S, is added to the sample solution, it will partition into the organic phase, where it can (11) Morf, W. E. The Principles of Ion-Selective Electrodes and Membrane Transport; Akade`miai Kiaduˆ: Budapest, 1981.

where ki is a function of the relative free energies of solvation of the ion I in the sample and the membrane phase, aI is the activity of ion I in the sample, [Izi+] is the concentration of ion I in the membrane, and zi is the charge on primary ion I. However, at very low activities of the primary cation, the interfering metal cations can completely exchange with the primary cations, and the phase boundary potential is governed only by the activity of interfering cations, in accordance with the following expression:

EJ ) E° +

kjaJ RT ln zjF [Jzj+]

Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

(9) 1479

where kj is a function of the relative free energies of solvation of the ion J in the sample and the membrane phase, aJ is the activity of the ion J in the sample phase, [Jzj+] is the concentration of J ions in the membrane phase, and zj is the charge on interference ion J. For sample solutions with high primary cation activity, it can be assumed that molecules of nonionic surfactant are not able to compete with the carrier, which forms stable complexes with primary cation ([LniIzi+] . [Izi+] and [SIzi+]), and hence electroneutrality in the membrane phase is given by [RT-] ) zi[LniIzi+]. Therefore, the ideal electrode response toward primary ions, after inserting eq 2 into eq 8, is described by ni RT zikiβLI[L] aI EI ) E° + ln ziF [RT-]

(10)

used to calculate Kpot I,J in accordance with the following expresion:

Kpot I,J )

aI

(16)

aJzi/zj

For solutions containing the nonionic surfactant, the new selectivity coefficient (defined as Kpot I,J (S)) can be calculated from eqs 10 and 14 (when EI ) EJ,

zikiaIβLI[L]ni [RT-]

)

{zjkjaJ(βLJ[L]nj + βSJPcS)}zi/zj [RT-]zi/zj

(17)

and according to the definition: where [L] ) [LT] - ni/zi [RT-] for primary ion. In contrast, using the principle of electroneutrality when there are very low concentrations of primary cation in the sample, the charge balance for the total concentration of anionic sites, [RT-], can be expressed as

[RT-]

zj+

zj+

zj+

) zj[LnjJ ] + zj[SJ ] + zj[J ]

(11)

Kpot I,J (S)

)

aI aJzi/zj

)KJI

{zj(βLJ[L]nj + βSJPcS)}zi/zj ziβLI[L]nj[RT-]zi/zj-1

where the ion-exchange constant (KJI) for the interfering cation between the sample and the membrane phase (dependent on the relative lipophilicity of the cations) is given by +

KJI )

By inserting eqs 3 and 7 into eq 11, +

[RT-] ) zj[Jzj ](1 + βLJ[L]nj + βSJ[S])

+

[RT-] zj(βLJ[L]nj + βSJ[S])

nj RT zjkjaJ(βLJ[L] + βSJPcS) ln zjF [R -]

(13)

(14)

T

(15)

[S] is the equilibrium concentration of surfactant in the organic phase, and cS is the equilibrium concentration of the surfactant in the aqueous sample phase. To assess changes in potentiometric selectivity due to the presence of surfactants, the potentiometric selectivity coefficient can be determined using the FIM method.9 In general, such data are obtained by determining the extrapolated intersection for the two linear segments of a given calibration curve (toward aI) in the presence of a fixed level of aJ, with the value of the x-coordinate for the intersection point indicating the aI value that should be 1480 Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

Kpot I,J ) KJI

kjzi/zj ki

(19)

(zjβLJ[L]nj)zi/zj

(20)

ziβLI[L]ni[RT-]zi/zj-1

In the simplest case, when the complexes of the ionophore with cations of the sample solution are of identical stoichiometry (i.e., ni ) nj ) 1), by inserting eq 20 into eq 18, an expression for selectivity coefficient in the presence of surfactant, Kpot I,J (S), can be found as

{

pot Kpot 1+ I,J (S) ) KI,J

where the partitioning of the surfactant between the organic and aqueous phases is defined by the constant

P ) [S]/cS

+

aJzi/zj[Izi ]

)

When there is no surfactant in the sample solution (cS ) 0 in eq 18), the selectivity coefficient is expressed as

Therefore, the electrode response toward interfering cations, in sufficiently low concentration of primary cation, is described by

EJ ) E° +

aI[Jzj ]zi/zj

(12)

and, for stable complexes (βLJ[L]nj + βSJ[S] . 1),

[Jzj ] )

(18)

βSJPcS

}

zjβLJ([LT] - (1/zj)[RT-])

zi/zj

(21)

where [LT] - (1/zj)[RT-] is the free ionophore concentration in sufficiently low concentration of primary cation and in the absence of surfactant in the sample solution. Equation 21 indicates that the greater the surfactant’s ability to partition into the membrane phase (P), the stronger its complexation of interferent ions (βSJ), and the higher its concentration in sample solution (cS), the greater the increase in the value of selectivity coefficient (and, correspondingly, the detection limit for primary cation induced by the presence of surfactant in the test solution). Moreover, the extent of the surfactant effect depends on the ratio of the stability constants of complexes formed with interfering cations by the surfactant and neutral carrier, respectively (βSJ/βLJ). The stronger the complexation of interfering cation with surfactant, and the weaker the interaction of the

using eqs 20 and 21, above). The plots shown in Figure 2a are for the case when the primary and interference ions are both monovalent, while Figure 2b shows the results when the primary ion is monovalent and the interference ion, J, is divalent. As expected, for the same ratio of βSJP/βLJ, greater increases in the selectivity coefficient occur for the case of monovalent vs divalent interfering cations.

Figure 2. Calculated increase of selectivity coefficients (log Kpot I,J (S) - log Kpct I,J ) as a function of the ratio of the stability constants for the interfering cation-ionophore/interfering cation nonionic surfactant complexes and the partitioning of the surfactant between the organic and aqueous phases (βSJP/βLJ) for three levels of surfactant concentration: (1) 5 × 10-3, (2) 5 × 10-4, and (3) 5 × 10-5 M. The primary ion is assumed as monovalent cation, and interfering cation is assumed as (a) monovalent and (b) divalent.

primary ion with the main carrier within the membrane, the greater the change in the potentiometric ion selectivity that can be expected. Furthermore, increasing the carrier concentration (L) leads to a decrease in the expected surfactant effect, while increasing the amount of lipophilic anionic additives (R- sites) increases this effect. Figure 2a illustrates the theoretical increase of selectivity pot coefficients (reported as [log Kpot I,J (S) - log KI,J ]) in the presence of nonionic surfactant in the sample solution as a function of the ratio of βSJP/βLJ (as log of this term) for three different concentrations of surfactant in the test solution (as determined

RESULTS AND DISCUSSION Previous experiments reported by Espadas-Torre et al.7 demonstrated that the presence of nonionic surfactants can influence the potentiometric selectivity and the detection limits of polymeric pH electrodes containing lipophilic amines as neutral carriers for protons. Results with the pH sensors spurred these further studies to examine the effect of nonionic surfactants on several other neutral carrier-based ion sensors. These investigations were conducted with plasticized PVC membranes doped with several cation-selective carriers (I-VII) (see Figure 1) often used to fabricate sodium-, calcium-, and potassium-selective electrodes used in modern blood gas/electrolyte analyzers. Two poly(ethylene oxide)-based nonionic surfactants, Brij 35 and Triton X-100, were tested (see Figure 1). It is well-known that surfactants of this type are able to bind metal ions from the sample solution,12-14 enhancing their extraction into an organic phase. For example, Triton X-100, a surfactant with a noncyclic polyether moiety, has been reported to roll alkaline ions like a turban within the organic phase via its extended polyether chain.14 Nonionic surfactants can disturb the performance of neutral carrier-based polymeric ISEs in two ways. First, surfactant extraction into the organic membrane can change the membrane chemistry and thus the sensor’s ion selectivity.7 Second, surfactant extraction into the polymeric film and back-extraction into the sample solution can result in a transient shift of the EMF when samples are repeatedly changed from ones containing surfactant to ones without surfactant, and vice versa. To verify the above theoretical model, polymeric membranes doped with potassium, sodium, and calcium neutral carriers, as well as blank membranes (of the same composition except for the absence of neutral carrier), were investigated. To predict the effect of nonionic surfactants on ISE response in accordance with eq 21, some knowledge of the surfactant’s ability to partition into the plasticized PVC membrane phases and of complex formation constants of the primary ion carrier and nonionic surfactant with various cations in the membrane phase is needed. Unfortunately, values for cation binding to only a few of the ionophores/ surfactants examined in the present study are reported in the literature. In fact, the only values for complex formation constants in PVC/DOS polymeric membranes were determined by Bakker et al.15,16 for valinomycin-K+, valinomycin-Na+, BME-44-K+, BME44-Na+, ETH 1001-Ca2+, and ETH 129-Ca2+ complexes. More often, complex formation constants have been measured in bulk organic solvents (e.g., methanol, dichloromethane). The loga(12) Jaber, A. M. Y.; Moody, G.; Thomas, J. D. R. J. Inorg. Nucl. Chem. 1977, 39, 1689-96. (13) Hamon, R. F.; Khan, A. S.; Chow, A. Talanta 1982, 29, 313-26. (14) Kikuchi, Y.; Takahashi, N.; Suzuki, T.; Sawada, K. Anal. Chim. Acta 1992, 256, 311-18. (15) Bakker, E.; Willer, M.; Lerchi, M.; Seiler, K.; Pretsch, E. Anal. Chem. 1994, 66, 516-21. (16) Bakker, E.; Pretsch, E. J. Electrochem. Soc. 1997, 144, 125-27.

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Table 1. Complex Formation Constants Measured in Bulk Organic Solutions or Plasticized PVC Membranes stability constants (log βLM) ligand valinomycin

BME-44 monensin methyl ester calix[4]arene ethyl ester Triton X-100 Brij 35 ETH 1001 ETH 129

solvent

K+

MeOH EtOH CHCl3/C6H5NO2/picrate DOS/PVC DOS/PVC DOS/PVC MeOH CH2Cl2/picrate MeOH MeCN MeOH CH2Cl2/picrate MeOH DOS/PVC DOS/PVC

4.87 6.02 12.4 9.3 7.9 7.8 5.0 2.4 4.5 3.07 3.84 2.45

Na+

Ca2+

Ba2+

6.4 5.5 5.0 2.48 7.2 5.0 5.8 3.8 2.54 2.08

2.44 19.9 23.8

2.56

ref 17 17 18 15 15 16 17 19 20 20 17 13 17 16 16

Figure 3. Dynamic response profiles of electrodes with blank polymeric membrane of the composition KTpClPB/DOS/PVC (no ion-selective carrier) upon addition (at time ) 2 h) of 5 × 10-5 M nonionic surfactant (Brij 35 or Triton X-100) in stirred 0.1 M KCl solution (0.05 M Tris/HCl buffer, pH 7.4).

rithms of the relevant binding constants reported in the literature for various experimental conditions are summarized in Table 1. While many of the values listed may not be indicative of the exact formation constants of ionophores within the membrane phases of the ISEs tested here (see complex formation constants for (17) Inoue, Y.; Liu,Y.; Hakushi, T. Thermodynamics of Cation-Macrocycle Complexation: Enthalpy-Entropy Compensation. In Cation Binding by Macrocycles; Inoue, Y., Gokel, G. W., Eds.; Dekker Inc.: New York, 1990; pp 1-110. (18) Rakhman’ko, E. M.; Yegorov, V. V.; Gulevich, A. L.; Lushchik, Y. F. Sel. Electrode Rev. 1991, 13, 5-111. (19) Brunink, J. A. J. Sodium-selective CHEMFETS, Ph.D. Thesis, University of Twente, Enschede, The Netherlands, 1993. (20) Schwing, M. J.; McKervey, A. M. Selective Receptors for Monovalent Cations. In Calixarenes. A Versatile Class of Macrocyclic Compounds; Vicens, J., Bohmer, V., Eds.; Kluwer Academic Publishers: Dordrecht, 1991; pp 15172.

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valinomycin-K+), they can, nonetheless, be used for comparison purposes to obtain relative cation binding information under somewhat similar experimental conditions, and this can be useful when correlating measured vs predicted selectivities (see below). Membranes without Neutral Carriers. As mentioned previously, the influence of nonionic surfactants can be explained by their partitioning into the organic polymeric matrices, and the ∆EMF values measured at the maximum observed shift in EMF after addition of the surfactant can be used to compare the relative ability of a given surfactant to partition into the membrane phase and bind cations (expressed as βSJP).7 Figure 3 shows the EMF change for PVC/DOS (1:2) membranes formulated with lipophilic tetraphenylborate derivative (KTpClPB) only upon the addition of nonionic surfactant (Brij 35 or Triton X-100) to a test solution

Figure 4. Dynamic response profiles of sodium-selective polymeric membrane electrodes upon addition (at time ) 2 h) of 5 × 10-4 M nonionic surfactant Triton X-100 in stirred 140 mM NaCl, 5 mM KCl, and 2 mM CaCl2 solution (0.05 M Tris/HCl buffer, pH 7.4) and then (at time ) 18 h) again in the solution without surfactant for sodium ionophores: (O) I, (0) II, and (4) III.

containing 0.1 M KCl in 0.05 M Tris/HCl buffer, pH 7.4. Analogous behavior has been observed for membranes containing NPOE as a plasticizer.7 The initial rapid positive EMF change proves the enhanced extraction of cations from the sample solution into the membrane induced by the presence of surfactants. After a given time, the EMF reaches a maximum, and finally it begins to reverse toward the initial EMF value. This gradual decrease in EMF starts to occur when surfactant reaches the internal membrane/internal solution interface via diffusion through the membrane (solutions on both sides of the membrane are of the same ionic composition). The reponse profile of KTpClPB-based membranes for other cations in the presence of Brij 35 and Triton X-100 was also investigated. Experimental results indicate that, for blank PVC/ DOS (1:2) membranes, the sequence of the extraction of cations, in the presence of both surfactants, is K+ > Ba2+> Na+ > Ca2+. However, DEMF values observed for Triton X-100 were at least 10 times greater than those for Brij 35 (data not shown), suggesting, in conjunction with the data reported in Table 1, both an enhanced cation binding as well as an enhanced partition coefficient into the membrane for Triton vs Brij. The extraction of nonionic surfactants into the KTpClPB-based membrane greatly influences the membrane’s potentiometric response to test cations and causes the membranes to become much more responsive toward K+ and Ba2+ ions. Under such circumstances, both Brij 35 and Triton X-100 are able to behave as weak neutral carriers. The new selectivity sequence is in good agreement with the solvent extraction results (water/dichloromethane) published for poly(ethylene oxide)-based nonionic surfactants14 and the complexation data reported in Table 1 above. In effect, the presence of the surfactant enhances extraction of potassium and barium ions relative to sodium and calcium ions,

when compared to that in the plasticized polymer phase alone. Based on these results, specific test cations (monovalent, potassium vs sodium ion, and divalent, barium vs calcium ion) were further chosen for experiments regarding surfactant-induced loss of selectivity for membranes doped with neutral carriers. Sodium Ion-Selective Electrodes. For sodium sensors, the effect of surfactants on the EMF response of membranes prepared with ionophores 4-tert-butylcalix[4]arenetetraacetic acid tetraethyl ester (I), monensin methyl ester (II), and bis[(12-crown-4)methyl] dodecylmethylmalonate (IV) was evaluated. These ionophores differ in the type of functional groups/structure present that complex cations. As such, they represent an excellent model set to assess how varying the primary and interference cation complexation influences the degree of the surfactant effect on membrane performance. For membranes containing a given sodium carrier and anionic lipophilic sites (KTpClPB), the nonionic surfactant induces response profiles over time similar to those observed for the blank membranes described above. However, in contrast to membranes with KTpClPB alone, much smaller shifts in the cell EMF values are observed. Figure 4 illustrates the behavior with time of the three different sodium-selective membranes after addition of Triton X-100 solution (final concentration, 5 × 10-4 M) to a stirred solution containing 5 mM KCl, 2 mM CaCl2, and 140 mM NaCl (in 0.05 M Tris/HCl buffer, pH 7.4). Also shown is the behavior observed when this test solution is replaced again by a fresh solution without surfactant. To clearly show how the surfactantinduced EMF changes depend on the exact nature of the ionophore employed within the polymeric membrane, Triton X-100 was used at higher concentrations than in most subsequent selectivity experiments, but still below its critical micelle concenAnalytical Chemistry, Vol. 70, No. 8, April 15, 1998

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Table 2. Composition of Sodium-Selective Membranes [2 wt % of Ionophore, PVC/Plasticizer (1:2)] and Their Potentiometric Properties in the Absence and Presence of Nonionic Surfactants

membrane

KTpClPBa (mol %)

calix[4]arene (I)

10

50

monensin (II)

10

50

III

10 50

conditions no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond no surfactant Brijc Tritond

slopeb (mV/decade) 61.3 61.3 61.3 61.3 61.2 61.3 58.3 58.3 52.3 58.7 56.1 40.9 59.8 59.8 57.4 58.1 56.7 52.8

f log Kpot Na,J

K+

Ba2+

Ca2+

-2.13 -1.98 -1.7 -1.00 -2.13 -1.89 -1.50 -0.71 -0.50 -0.49 -0.16 +0.56 -0.50 -0.41 +0.26 +0.95 -1.71 -1.51 -1.15 -1.47 -1.15 -0.56

-4.00 -3.60 -3.30 -2.92 -4.00 -3.10 -2.80 -2.48 -2.80 -2.40 -2.03 -1.50 -2.80 -2.13 -1.70 -1.07 -3.86 -3.73 -3.43 -3.25 -2.87 -2.34

-3.89 -3.87 -3.74 -3.67 -3.90 -3.78 -3.57 -3.47 -3.30 -3.30 -3.27 -3.10 -3.05 -3.00 -4.13 -4.12 -4.07 -3.96 -3.88 -3.51

a Mol % relative to ionophore. b Slopes recorded for background solution of physiologial level of potassium (5 mM) and calcium (2 mM) ions and at the sodium activity range 20-200 mM, with addition of the following: c 5 × 10-5 M Brij 35; d 5 × 10-5 M Triton X-100; e 5 × 10-4 M Triton 9 X-100. f Potentionetric selectivity coefficients (log Kpot Na,J) were determined according to the fixed interference method (FIM) using 0.1 M solutions of the interfering ion.

tration.21 From the dynamic response pattern shown in Figure 4, it is clear that surfactant partitioning into the organic film is a reversible process that induces EMF shifts when sample solution is changed from one void of surfactant to one with surfactant present, and vice versa. In the case of sodium-selective electrodes, these changes reach values of (9 mV for ionophore II, while they are much smaller for ionophore I under the same experimental conditions ((1 mV). By decreasing the concentration of the surfactant to 5 × 10-5 M, these EMF changes can be significantly reduced. However, except for ionophore I (for which changes no larger than (0.2-0.3 mV are observed in the presence of 5 × 10-5 M Triton X-100), EMF shifts were still larger than (1 mV for each of the other three neutral carrier systems. By replacing Triton X-100 with Brij 35 (5 × 10-5 M), the observed shifts in EMF values are eliminated for ionophore I and become even smaller for membranes doped with the other three ionophores (i.e., (0.3 mV). However, taking into account the requirements for EMF stability of cation-selective electrodes for whole blood, plasma, and serum applications, these instabilities are unacceptable when the recommended limits of (0.12 mV for sodium measurements are imposed.22 As can be seen in Figure 4, fluctuations of the measured EMF values depend on the specific sodium ionophore incorporated into the membrane. The sequence of the observed surfactant-induced EMF instabilities is ionophore II > ionophore III > ionophore I. Such behavior can be explained by the complex formation ability of these ionophores. For example, the complex formation constants (log βLM) for methyl monensin (II), Brij 35, and Triton

X-100 with sodium cations, as measured in methanol, are of similar strength. For the calix[4]arene ethyl ester (I)-Na+ complex, however, log βLM is greater by more than 2 log units than those for the methyl ester of monensin (II), Brij 35, and Triton X-100 (see Table 1). In contrast, their respective complexes with potassium ions differ by only 0.5 unit. These data can then explain why the surfactant effect for ionophore II, observed in solutions of physiological composition, is so much greater than that for ionophore I. Unfortunately, there is no literature information available on the actual complex formation constants with cations for ionophore III in organic solvents. However, the bis-crown ether derivative III possesses the same type of coordinating atoms (ether oxygen) as present in methyl monensin (II), as well as in Brij 35 or Triton X-100 (neutral surfactants with polyether chains). From this fact, it can be expected that the complex formation ability of ionophore III should be similar to that of methyl monensin (II), with slightly higher selectivity due to intramolecular sandwich-type complexes between Na+ and the bis-crown ether derivative III.23 Indeed, as shown in Figure 4, the effect of surfactant on membranes formulated with ionophore III is quite significant; in fact, it is of nearly the same magnitude as that observed for methyl monensin (II). The experimental values for the potentiometric selectivity coefficients, given as log Kpot Na,J, for membranes doped with the four sodium ionophores and two levels of lipophilic anionic sites (10 and 50 mol %) in the absence and presence of surfactants are tabulated in Table 2. It can be seen that the addition of nonionic

(21) Jones, D. L.; Moody, G. J.; Thomas, J. D. R. Analyst 1981, 106, 439-47. (22) Oesch, U.; Ammann, D.; Simon, W. Clin. Chem. 1986, 32, 1448-59.

(23) Shono, T.; Okahara, M.; Ikeda, I.; Kimura, K.; Tamura, H. J. Electroanal. Chem. 1982, 132, 99-105.

1484 Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

Figure 5. Typical potentiometric response curves of polymeric membrane sodium electrodes based on sodium ionophores I, II, and III, respectively as inscribed on the graphs, in background solutions containing physiological levels of potassium (5 mM) and calcium (2 mM) cations in the absence of surfactant (]) or after addition of either Brij 35 (0) or Triton X-100 (4) to a final concentration of 5 × 10-5 M. Table 3. Composition of Potassium-Selective Membranes [2 wt % of Ionophore, PVC/DOS (1:2)] and Their Potentiometric Properties in the Absence and Presence of Nonionic Surfactants membrane ionophore BME-44 (IV)

KTpClPBa [mol %] 10

50

valinomycin (V)

10

50

f log Kpot K,J

conditions

slopeb (mV/dec)

Na+

Ba2+

Ca2+

no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond Tritone no surfactant Brijc Tritond Tritone

58.1 57.8 58.0 54.7 57.9 57.5 57.7 53.3 58.8 58.7 58.8 58.7 58.7 58.8 58.7 58.6

-3.62 -3.29 -3.46 -2.83 -3.58 -3.15 -3.26 -2.61 -4.20 -4.10 -4.12 -3.82 -4.22 -4.06 -4.14 -3.70

-4.26 -4.00 -4.00 -3.63 -4.30 -3.96 -4.10 -3.68 -4.24 -4.12 -4.21 -4.08 -4.27 -3.80 -4.10 -3.85

-4.41 -4.30 -4.35 -4.20 -4.37 -4.29 -4.31 -4.15 -4.50 -4.41 -4.48 -4.28 -4.50 -4.36 -4.42 -4.28

a Mol % relative to ionophore. b Slopes recorded for background solution of physiological level of sodium (140 mM) and calcium (2 mM) ions and at the potassium activity range 1-5 mM, with addition of the following. c 5 × 10-4 M Brij 35; d 5 × 10-5 M Triton X-100; e 5 × 10-4 M Triton 9 X-100. f Potentiometric selectivity coefficients (log Kpot K,J) were determined according to the fixed interference method (FIM) using 0.1 M solutions of the interfering ion.

surfactants always decreases the selectivity of sodium electrodes. The extent of the decrease in membrane selectivity is greater for samples containing Triton X-100 than for those with Brij 35 and increases with surfactant concentration. It can also be seen that the amount of tetraphenylborate derivative (10 or 50 mol %) incorporated into the membrane does not appreciably change the selectivity of membranes when surfactants are not present in the sample phase. However, in the presence of surfactant, the tetraphenylborate derivative content plays a major role in the observed changes of membrane selectivity. Indeed, the values for selectivity coefficients toward potassium and barium increase more dramatically for membranes with 50 mol % than for those fomulated with only 10 mol % of borate relative to the neutral carrier. These results (especially for ionophores I and II) are consistent with the effect of anionic site concentration as predicted by eqs 20 and 21, above. The relatively small effect of surfactant on the selectivity for sodium over calcium in all three sodium sensors is explained by the fact that the ability of Triton X-100 or Brij 35 to

complex and extract calcium ion into the membrane phase is much lower compared to that for potassium and barium ions. Surfactant-induced loss of selectivity over potassium cations can have significant consequences when attempting to use polymer membrane sodium electrodes for blood Na+ measurements. The required selectivity coefficient for Na+ over K+ (log pot KNa,K ) for blood measurements should be lower than -0.6.22,24 As shown in Table 2, the presence of nonionic surfactants in the sample solution, especially Triton X-100, can cause several of the Na+-selective membrane formulations tested to provide less than adequate selectivity for such measurements. Figure 5 shows experimental sodium calibration curves, with and without surfactant, obtained in test solutions containing physiological levels of potassium and calcium ions. It is evident that the presence of surfactant diminishes the linear concentration domain of calibration curve. Table 2 reports experimental slope (24) Bakker, E.; Meruva, R. K.; Pretsch, E.; Meyerhoff, M. Anal. Chem. 1994, 66, 3021-30.

Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

1485

Figure 6. Dynamic response profiles of potassium-selective polymeric membrane electrodes upon addition (at time ) 2 h) of 5 × 10-4 M nonionic surfactant Triton X-100 in stirred 140 mM NaCl, 5 mM KCl, and 2 mM CaCl2 solution (0.05 M Tris/HCl buffer, pH 7.4) and then (at time ) 18 h) again in the solution without surfactant for potassium ionophores: (4) IV and (O) V. Table 4. Composition of Calcium-Selective Membranes [2 wt % of Ionophore, PVC/Plasticizer (1:2)] and Their Potentiometric Properties in the Absence and Presence of Nonionic Surfactants membrane ionophore plasticizer

KTpClPBa (mol %)

ETH 1001 (VI) NPOE

70

ETH 1001 (VI) DOS

70

ETH 129 (VII) NPOE

70

ETH 129 (VII) DOS

70

e log Kpot Ca,J

conditions

slopeb (V/decade)

K+

Ba2+

Na+

no surfactant Brijc Tritond no surfactant Brijc Tritond no surfactant Brijc Tritond no surfactant Brijc Tritond

29.9 29.8 29.8 25.3 24.4 23.3 28.7 28.4 27.9 29.0 28.9 28.0

-3.55 -3.20 -2.60 -2.73 -2.10 -0.87 -3.62 -3.2 -2.5 -3.50 -3.10 -2.41

-3.27 -3.26 -3.20 -3.18 -2.93 -2.81 -3.46 -2.98 -2.93 -3.36 -3.24 -3.11

-3.45 -3.34 -3.23 -2.61 -2.51 -2.34 -3.73 -3.56 -3.50 -3.46 -3.16 -3.06

a Mol % relative to ionophore. b Slopes recorded for background solution of physiological level of potassium (5 mM) and sodium (140 mM) ions and at the calcium activity range 0.2-20 mM, with addition of the following. c 5 × 10-5 M Brij 35; d 5 × 10-5 M Triton X-100. e Potentiometric 9 selectivity coefficients (log Kpot Ca,J) were determined according to the fixed interference method (FIM) using 0.1 M solutions of the interfering ion.

values determined for the four different sodium electrodes in the absence and presence of surfactant (tested over the range of 20200 mM). For membranes doped with 50 mol % of KTpClPB to sodium ionophore, slopes toward sodium ion activity generally decrease to ∼50 mV/decade, except for membranes formulated with the calixarene ionophore I. Clearly, the best sodium ionophore, in terms of resistance to surfactant effects, appears to be the calix[4]arene derivative I. Potassium Ion-Selective Electrodes. From a group of known potassium ionophores, only 2-dodecyl-2-methyl-1,3-propanediylbis[N-5′-nitro(benzo-15-crown-5)-4′-yl)carbamatel (BME44) (IV) and valinomycin (V) were tested, owing to their high selectivity relative to sodium ion. 1486 Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

Membranes doped with valinomycin (V), the most popular potassium-selective neutral carrier, along with 10 or 50 mol % of KTpClPB and PVC/DOS (1:2), do not exhibit any significant change in performance in the presence of either Brij 35 or Triton X-100. Even in the presence of 5 × 10-4 M levels of surfactant (see Table 3), the changes of potentiometric selectivity coefficients are not larger than 0.6 and remain below required values22,24 for accurate blood measurements of potassium. In contrast, much greater changes of the selectivity coefficients, caused by the presence of surfactant, are observed for membranes formulated with BME-44 (IV), especially in the case of sodium ion (see Table 3). Initial selectivity, measured in sample solutions without surfactant, is just about at the required level for blood

pot measurements (log KK,Na ) -3.6).22,24 The addition of nonionic surfactant to sample solution causes the membrane to exhibit insufficient selectivity toward K+ over Na+ for biomedical applications.22 This interference becomes greater in the presence of Triton X-100 than in the presence of Brij 35. As is shown in Table 3, slopes recorded for background solution of physiological level of sodium (140 mM) and calcium (2 mM) ions and at the potassium activity range 3.5-5.0 mM also decrease to ∼53-55 mV/decade when Triton X-100 is added at 5 × 10-4 M concentration. From Figure 6, it can be seen that the fluctuation of the measured EMF values observed for valinomycin-based membranes, when the sample solution is changed from one containing surfactant to one without surfactant, and vice versa (even for 5 × 10-4 M Triton X-100), is smaller than the recommended limit of (0.46 mV22 for potassium measurements in whole blood, plasma, or serum. In the case of membranes with BME-44 (IV), such a requirement is achieved only for Brij 35 at a concentration no higher than 5 × 10-5 M. The presence of surfactants in the sample phase does not dramatically affect the performance of the valinomycin-based membranes, apparently because of the relatively high complex formation constants of complexes of primary and interference ions with valinomycin (see Table 1) in the membrane phase. Such complexation constants in the membrane are likely to be greater than those for cation binding with Brij 35 or Triton X-100 and thus do not allow nonionic surfactants to compete effectively with valinomycin for complexation with cations in the membrane phase. These results are in good agreement with those of previously reported studies regarding the effect of nonionic surfactants on the response of valinomycin-based electrodes.5 The lower formation constant of the sodium ion complex with BME-44 (by 0.9 log unit; see Table 1) reflects greater changes of selectivity coefficients as predicted by eq 21 above. Calcium Ion-Selective Electrodes. The calcium ionophores ETH 129 (VII) and ETH 1001 (VI) are both highly selective carriers, but the latter forms complexes with calcium ions that are 4 orders of magnitude weaker, as measured in PVC/DOS membrane15 (see Table 1). PVC membranes with 70 mol % of KTpClPB relative to these ionophores and NPOE or DOS as plasticizer were examined for their potentiometric response in the absence and presence of the nonionic surfactants. Table 4 gives the selectivity coefficients determined for these membranes under various experimental conditions. As can be seen (Table 4), nonionic surfactants do not change membrane selectivities significantly toward calcium ions over sodium and barium ions for each of the membranes tested. However, a very pronounced decrease in selectivity over potassium ions is observed, even at relatively low surfactant concentations. Again, Triton X-100 more strongly influences the changes in Ca2+/K+selectivity compared to Brij 35. Except for the membrane containing ETH 1001 (VI) and DOS, in the presence of 5 × 10-5 M Triton X-100, most of the membranes evaluated still provide sufficient selectivity to be used for blood measurements in the presence of either surfactant.22 Indeed, as illustrated in Figure 7a, the calibration curves for electrodes with membranes based on ETH 1001 (VI) in a PVC/NPOE matrix in a sample background consisting of 140 mM NaCl and 5 mM KCl do not

Figure 7. Potentiometric response curves of polymer membrane calcium electrodes based on ETH 1001 ionophore in background solutions of physiological level of potassium (5 mM) and sodium (140 mM) cations in the absence of surfactant (]) or after addition of either Brij 35 (0) or Triton X-100 (4) to a final concentration of 5 × 10-5 M.

change appreciably when low levels of surfactant are present. Electrodes prepared with membranes containing ETH 129 (VII) and DOS or NPOE perform like the ETH 1001/NPOE system (data not shown in Figure 7). In contrast, electrodes with ETH 1001 (VI) in a PVC/DOS matrix should not be used in the presence of nonionic surfactants since, as shown in Figure 7b, there is a significant shift in the EMF values for these membranes within the physiological range of ionized calcium values. In this case, the presence of surfactant diminishes the linear calcium measurement range by increasing the detection limit. Furthermore, within the physiological range of calcium activity, the slope becomes sensitive to both potassium and surfactant concentration. Moreover, larger fluctuations of the measured EMF value for such Ca2+ electrodes, (0.6-1 mV for Brij 35 and (4-5 mV for Triton X-100 (5 × 10-5 M final concentration), were recorded when the sample solution, of physiological composition, was changed from Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

1487

one containing surfactant to one without surfactant and vice versa (data not shown). Because of the very narrow physiological range of ionized calcium concentration in blood (1.0 -1.2 mM), these EMF fluctuations are much higher than the required (0.12 mV EMF stability suggested by Oesch et al. for Ca2+ sensors.22 Clearly, when surfactants are present, membranes composed of ETH 129 or ETH 1001 with NPOE as the plasticizer are the preferred sensing films for measurement of calcium without significant degradation in selectivity. It should be pointed out that by using metal ion-buffer solutions25 as test samples, the changes in selectivity coefficients measured in the presence and absence of surfactant may be greater than those presented in Table 4. However, similar experiments for potassium and sodium electrodes are not possible, since no buffer system for these ions exists, and hence such experiments with metal ion-buffer solutions were not performed. CONCLUSIONS In summary, based on results obtained for model electrolyte solutions of composition close to that of blood serum, it can be predicted that the selectivity of several polymeric membrane ISE systems now used within commercial instruments to assay sodium, potassium, and calcium levels in undiluted blood samples can be influenced by the presence of nonionic surfactants (specifically Brij and Triton X-100) in the sample phase. Although not present in biological samples, these surfactants can be present (25) Sokalski, T.; Maj-Z˙ urawska, M.; Hulanicki, A. Mikrochim. Acta 1991, I, 28591.

1488 Analytical Chemistry, Vol. 70, No. 8, April 15, 1998

in calibrating, rinsing, and quality control solutions. A theoretical model predicts that the loss in sensor selectivity is dependent on the partition coefficient of the surfactant into the ion-selective polymer membrane, the relative binding constants of primary and interference ions with the surfactant and neutral carrier ionophore, respectively, the concentration of lipophilic anionic sites present in the membrane, and the concentration of surfactant that is present at one time or another in samples/calibrating/rinsing solutions that are brought in contact with the sensors. Experimental results confirm that the loss in selectivity for several sodium, potassium, and calcium membrane formulations is sufficient to cause significant errors in the measurement of these ions when Brij or Triton X-100 are present. The model and experimental data presented herein should be of interest to those involved in the development of ISE-based clinical analyzers and may help guide the appropriate choice of membrane components and sample phase surfactant additives to optimize the analytical performance of such ISEs in clinical chemistry analyzers. ACKNOWLEDGMENT E.M. gratefully acknowledges the State Committee for Scientific Research (11/164/96 and 8T10C01913) for partial support of this work. MEM gratefully acknowledges the National Institut of Health (GM 28882) for partial support of this work.

Received for review July 15, 1997. Accepted November 24, 1997. AC970761T