MICROCHEMICAL JOURNAL 45, 232-247 (1992)

Flow-Injection Potentiometry for the Assay of Potassium in

Biological Fluids

Research Group for Technical Analytical Chemistry of the Hungarian Academy of Sciences,
Institute for General and Analytical Chemistry, Technical University of Budapest, GellCrt Tkr 4.,
H-l 11I Budapest, Hungary
Received February 10, 1992; accepted February 19, 1992
The performance characteristics (selectivity, slope of the electrode response, response
time) of polyvinyl chloride and modified polyvinyl chloride based solvent polymeric, po-
tassium selective membrane electrodes were evaluated in relevance to the analysis of ionic
constituents in biological samples. A flow-injection system incorporating a macro wall-jet
potentiometric detector was designed and its utility for the potassium assay in undiluted
urine samples was evaluated. Analytical data obtained by flow methods for the potassium
content of patients’ blood serum and urine samples had been correlated with flame atomic
emission spectrometric data. 0 1992 Academic press, IN.

INTRODUCTION
Flow analysis with on-line detection offers a modern approach to automation of
analytical procedures that find utility in clinical, pharmaceutical, and environmen-
tal analyses, as well as in process monitoring. Electrochemical detection in flow
analysis has become important in two aspects; namely the rapidly developing flow
analytical techniques need selective and sensitive detectors in order to reduce the
complexity of the analysis system, while electrochemical sensors in general ex-
hibit improved performance characteristics under hydrodynamically controlled
conditions (Z-3).
The special features of solvent polymeric membrane electrode-based ion-
selective potentiometry (e.g., the sensor size and geometry can easily be adapted
to the analytical task, the interfering effect of biochemicals on ionophore-based
plasticized polyvinyl chloride membranes can be minimized by membrane tech-
nology) made its use in clinical chemistry attractive and competitive by the ex-
tensively used flame photometry (4-6).
If ionophore-based solvent polymeric membrane electrodes are to be used for
the assay of ionic constituents in biological fluids it should be considered that the
analysis will be performed in extremely complex but more or less well-defined
matrices of naturally occurring and/or therapeutic samples. The conditions in
blood and urine samples are defined in certain respect by distinct physiological
concentration ranges. Thus, due to the special nature of the sample matrix the
requirements for the performance characteristics of the sensors can be predicted
(4).

’ To whom correspondence should be addressed.

232
0026-265x/92 $1.50
Copyright 0 1992 by Academic Press. Inc.
All rights of reproduction in any form reserved.
 FLOW-INJECTION ASSAY OF F’OTASSIUM 233
The demand for the analysis of ionic constituents of electrolytes of biological
origin on a large scale prompted the automation of analysis in clinical chemistry.
Since the appearance of ionophore-based solvent polymeric membrane elec-
trodes, continuous flow methods with flow-through ion-selective detection have
become more and more popular and relatively less work has been devoted to the
use of the dynamic flow-injection technique for the assay of biological fluids.
The purpose of this contribution is to demonstrate the importance of ion-
selective membrane technological optimization for clinical analysis as well as to
explore the analytical value of a flow-injection potentiometry with a macro wall-
jet detector cell for the assay of potassium in biological samples.

MATERIALS AND METHODS

Reagents
All chemicals were of p.a. grade.
For membrane preparation BME-44 (2,2’-bis[3,4-( 15-crown-5)-2-nitropenyl-
carbamoxymethyll-tetradecane; (7) TU-Budapest) ionophore, PVC (polyvinyl
chloride); Fluka 81392, Fluka AG. Buchs, Switzerland) or PVC-COOH (PVC with
1.8 wt% COOH groups; Aldrich 18,9553, Aldrich GmbH. Steinheim, Germany)
membrane support materials, DOS (bis(2-ethylhexyl)sebacate; Fluka 84811) soft-
ener and KTpClPB (potassium tetrakis(p-chlorophenyl)borate; Fluka 60591) ad-
ditive salt as well as tetrahydrofuran (Fluka 87368) were used.
For modeling the presence of proteins naturally occuring in biological samples,
7 wt% solution of bovine serum albumin (BSA) purchased from Reanal (Budapest,
Hungary) was used. All electrolyte solutions were prepared with doubly quartz
distilled water and salts of p.a. grade.

Membrane Preparation and Electrode System

Ion-selective solvent polymeric membranes were prepared as suggested by
Craggs et al. (8). The composition of the membranes was 1 wt% ionophore, 33
wt% PVC or PVC-COOH, and 66 wt% DOS. Occasionally the ion-selective mem-
branes incorporated a lipophilic salt additive, like KTpClPB in 75 mol%, to the
ionophore (Fig. 1).
Discs of the membranes (7 mm diameter) prepared on this way were cut and
mounted into a commercially available Philips IS-560 electrode body (Philips
N.V. Gloeilampenfabriken, Eindhoven, The Netherlands), using 10e3 M KC1
inner reference electrolyte.

Steady-State Calibration Data and Selectivity Factors

The concentration sensitivity and the detection limit of the electrodes were
evaluated with KC1 pure solution, but also in blood serum (BSE) and urine like
(ULE) electrolytes (BSE (9), 140 mM NaCl; 24 mM NaHCO,; 0.6 mit4 MgCl,; 1.1
mM CaCl, and ULE (ZO), 130 rniW MgCl,; 24.8 mM tris(hydroxymethyl)ami-
nomethane, pH 8, adjusted by 0.1 M HCl).
The selectivity coefficients were determined by the separate solution method
234 JENEY ET AL.

N4
W-COO-c-ooc-H

BME-44

KTpClPE

-O-Or
0
DOS
FIG. 1. Membrane constituents.

(SSM) at the 0.1 M concentration level of the relevant chloride salts (II), by
considering theoretical slope values.
The mean activity coefficients of the electrolytes were calculated with the
Debye-Htickel equation (6) while the liquid junction potentials were estimated
with the help of the Henderson formation (6).
The double junction reference electrode used, Ag; AgCl, KC1 (1 iU) 1
CHJOOLi (1 M), was a Radelkis model (Budapest, Hungary). The EMF mea-
surements were carried out at room temperature with a six-channel electrode
switch (Orion Model 605, Orion Research Inc., Cambridge, MA) coupled to a
Radiometer pHM 64 (Radiometer Copenhagen, Denmark) digital pH-mV meter.
Reproducibility Test
The stability of the sensor is characterized in terms of the reproducibility of the
potential data measured between two alternating standards samples of different
concentration and/or composition (4). For the reproducibility test the electrodes
were immersed alternately in 10e2 M KC1 in BSE, then in low3 M KC1 in BSE,
or 10e3 M KC1 in BSE + 7 wt% BSA, at least 10 times, and the potential readings
were taken 120 s after each immersion. Between the measurements the electrodes
were washed with distilled water and wiped with tissue paper.
 FLOW-INJECTION ASSAY OF POTASSIUM 235
Response Time Measurements
Dynamic response curves were recorded in a computer-controlled, switched
wall-jet measuring arrangement (12) with an activity perturbation. The switching
time was 7 ms. Eight preset scan rates were available, ranging from 0.661 to 147.6
ms time resolution, corresponding to total data acquisition times of 1 s to 4 min.
FTIR-ATR Measurements
The effect of albumin on ex situ conditioned ion-selective membranes of differ-
ent compositions was followed by FTIR spectroscopy using the ATR technique.
All membranes were treated in 1 M KC1 + 7 wt% BSA solution for 30 min and
rinsed for an instant with distilled water. The details and the capability of the
FTIR-ATR technique are described in (1.3).
Flow-Injection Measurements
An LKB pump (12000 Varioperpex, LKB-Produkter AB, Bomma, Sweden)
with a variable flow rate option was used to adjust the carrier stream. Samples
were introduced into the flow system by means of a six-port manual injector
(Rheodyne 7125, Cotati, CA) provided with loops of different volumes. A macro
wall-jet cell was located as a detector at the end of the analysis channel.
The injector and the macro wall-jet detector cell are connected to the flow-
system with Teflon ferrules. All connections and the analysis channel were made
of Teflon tubing (i.d., 0.5 mm; o.d., 1.8 mm).
Depending on the analytical task, the geometry of the analysis channel could
easily be altered by the incorporation of a dispersion coil, mixing chamber, or
straight-line tubes of different volumes (14). Coil reactors of different lengths were
constructed by wrapping the teflon tubing around a chart paper cardboard tube
(o.d., 17 mm).
Potential measurements were carried out with a Radelkis OP 208/l pH-mV
meter (Budapest, Hungary), and recorded with an Omniscribe DSOOO(Huston
Instrument Div., Gistel, Belgium) strip chart recorder.

Wall-Jet Cell
After the introduction of the voltammetric wall-jet detector (e.g. (15, 26)) into
liquid chromatography this cell arrangement became more widely used with other
types of detectors as well as in different fields of analytical chemistry (17-19). The
characterization of an ion-selective electrode wall-jet detector for flow-injection
analysis has been reported recently (20).
In our work a potentiometric wall-jet cell arrangement with small effective
volume and a macro ion-selective electrode was also designed and elaborated for
flow-injection analysis (Fig. 2). A Philips IS-560 electrode body (ISE, 1) and a
Radelkis OP-830 calomel electrode (REF, 3) with a bottom-ceramic frit were fitted
into the cell body made of plexi (poly(methylmethacrylate)). The reference elec-
trolyte (4) flowed continuously around the reference electrode frit, forming a thin
solution film around the ISE then entered a reservoir (6). The streaming carrier
solution was directed directly onto the ion-selective membrane surface (2) through
236 JENEY ET AL.

3 6

FIG. 2. Potentiometric wall-jet cell arrangement. 1, ISE; 2, ion-selective membrane; 3, reference

electrode; 4, bore for continuously streaming reference electrolyte; 5, jet; 6, outlet.

the variable diameter jet (5). The jet-nozzle-electrode membrane distance could
be varied by adjusting the nozzle. The wall-jet cell can be positioned both hori-
zontally and vertically. Since air bubbles occasionally exist in the carrier solution
and/or in the sample solution, positioning the wall-jet arrangement horizontally is
more advantageous.

RESULTS AND DISCUSSION

The major application of ionophore-based plasticized PVC membranes is in
clinical chemistry and neurophysiology for the serial analysis or in situ monitoring
of ionic constituents.
In earlier work it was demonstrated that the highly lipophilic bis(crown-ether)
(BME-44)-based potassium sensor of optimized membrane composition is excel-
lent for the analysis (29) as well as for the in vivo monitoring (21) of the potassium
content of biological samples. In recent years there has been a trend toward using
modified membrane support materials in ion-selective liquid membrane technol-
ogy with the aim of eliminating the interfering effect of biochemicals, reducing the
electrical resistance, and improving the adsorption properties of the membranes
to solid support in thin film electrode production (22, 23).
The analytically important performance characteristics of the BME-44-based
membranes of different compositions (including the use of modified PVC), being
most relevant to biological application, are compiled in Tables 1 and 2. The
thorough comparison of the sensor characteristics corresponding to ion-selective
potassium sensors incorporating different membrane support materials proves
that the analytically significant parameters coincide with each other.
Among sensor characteristics, the response time is of utmost importance if
ion-selective electrodes are incorporated in continuous flow techniques, particu-
larly in transient techniques like flow-injection analysis. A slow electrode re-
sponse can seriously affect the analytical signal as well as the sample through-put
(3).
Detailed studies (24) on the dynamic response characteristics of plasticized
polyvinyl chloride membrane electrodes in a switched wall-jet system proved that
the response time values of the liquid membrane electrodes (tWO) were in the
 FLOW-INJECTION ASSAY OF POTASSIUM 237
TABLE 1
Characteristics of Potassium Selective Membranes Based on PVC and PVC-COOH
Membrane composition
BME44
BME44 PVC BME44
PVC DOS PVC-COOH
Analytical data DOS KTpClPB DOS
Slope value (mV/d) (10-‘-10-4 M KCl) 58.48 59.36 58.89
Detection limit (lga) (in KCl) -5.5 -5.5 -5.5
t 90% (msec)” (lo-’ + 10e3 M KCI;
background, 0.1 M NaCl) 43.6 31.1 35.0
I 90% (msec)’ (lo-’ + 10m3M KCl;
background, 0.1 M NaCl) 38.4 28.1 52.9

a Unconditioned membranes (Fig. 3a).

b Conditioned in 1O-3 M KC1 for 5 days (Fig. 3b).

millisecond range and only slightly affected by the nature of the ionophores or the
plasticizers with relevant lipophilicity values above log P 2 5. In this experimental
work the effect of mobile or fixed ion-exchanger sites incorporated in the ion-
selective membranes on the dynamic response characteristics was evaluated with
the aim of selecting the best membrane system for assay of biological fluids in the
flow-injection operation mode (Fig. 3).
The comparison of the response time curves relevant to different membrane
compositions, including the use of carboxylated PVC, demonstrates in accor-
dance with earlier findings (25, 26) that the increase in the site concentration of
ion-selective membranes reduces the response time (twS) of the sensor. More-
over, in contrast to the use of nonderivatized polyvinyl chloride, the conditioning
time in aqueous electrolyte solution increases significantly the response time of
ion-selective membranes incorporating carboxylated PVC, probably due to the
water uptake and the development of a hydrated surface gel-layer. This fact can
seriously limit the application of carboxylated PVC as a membrane support.
In respect to the application of plasticized polyvinyl chloride-based ion-
selective membrane electrodes in clinical chemistry, the problem associated with
the influence of proteins on the electrode response function has been disputed in
several publications (5, 23). The drift of the potentiometric cell incorporating
liquid membrane electrodes has been ascribed to protein adsorption, and it was
claimed that its effect can be overcome by membrane technology, e.g., by the use
of vinyl chloride-vinyl alcohol copolymers.
In the present work the nature of the protein-liquid membrane interaction was
studied in the function of PVC-types used for membrane preparation by the mo-
lecular specific FTIR spectroscopy using the ATR technique (1.9, in parallel with
electrochemical studies.
In contrast to expectation (23), the spectroscopic data relevant to potassium-
selective ionophore (BME-44)-based liquid membranes of different nature and
composition, being conditioned in 7 wt% BSA containing 1 M KCl, showed that
the protein deposition at the membrane surface was pronounced even at mem-
238 JENEY ET AL.

TABLE 2
Selectivity Properties of the BME-44 Ionophore-Based Potassium Sensors

BME 44 BME 44 BME 44

lIj

u -- K -K -__ K

__ NH4

-3 1 __ Na
~ No -H
-H
- Ll
-H
Li

-4
- co
1
- co CO

-5 ’

branes incorporating carboxylated PVC (Fig. 4). To follow the membrane-protein

interaction the absorption band at 1660 cm- ‘, corresponding to the v - C = 0
vibrations of the amide group in the polypeptide chain, was monitored.
Electrochemical steady-state calibration data carried out in KC1 standard solu-
tions at 7 wt% BSA background demonstrate that BSA has an effect on the
electrode potential response only below 10v3 M, which is far below the physio-
logical concentration range for potassium in blood serum samples. Accordingly,
reproducibility and response time measurements, aimed at studying the influence
 FLOW-INJECTION ASSAY OF POTASSIUM 239

Time (msec)

50.--

-30-

-500 I I I I I
“t om “N
4 8 w
lime (msec)

FIG. 3. Dynamic response characteristics of potassium sensors based on PVC and PVC-COOH in
two diierent time domains. (-) BME-44, PVC, DOS; (+ + +) BME-44, PVC, DOS, KTpClPB; (---)
BME-44, PVC-COOH, DOS. (A) Recorded with unconditioned membranes, (B) recorded with mem-
branes conditioned in 10m3M KC1 for 5 days. Concentration step: lo-* M KC1 -+ 10e3 M KC1 in 0.1
M NaCl background electrolyte.
240 JENEY ET AL.

0.25

TU-WIEN IFS 113

DATE 21/01/91
TIME 19:41:47

ATR KRSS
TRANSMISSION APT=I.2

FLS=JKRSIOS
0.0 ‘1 1 FLR=JKRSlOI
2000 1500 I( 3oc
)
WAVENUMBER CM-I NSS=IOO
RES=4.0
VEL=IO
SMF=O
FIG. 4. FIIR-ATR spectrum of BME-44, PVC-COOH, DOS membrane treated in 7 wt% BSA
containing 1 M KC1 solution.

of the presence of proteins on the characteristics of potentiometric electrodes,

were designed and carried out at potassium levels bracketing the physiological
concentration range of potassium in blood serum.
The reproducibility of the potassium sensor-based potentiometric cell arrange-
ments was studied in the absence and in the presence of bovine serum albumin.
The relevant data are exhibited in Fig. 5, indicating in accordance with expecta-
tion that the presence of albumin in this potassium concentration range has no
significant effect on the reproducibility of the potentiometric cell.
Under the very same conditions response time measurements were also per-
formed in the switched wall-jet system. The response time curves corresponding
to the potassium concentration decrease at the electrode surface when changing
from an aqueous to a protein containing electrolyte reflect surface sorption-
desorption processes, but steady-state conditions are achieved in about 500 ms
(Fig. 6). This fact needs to be taken into account when designing flow analytical
methods for the analysis of electrodes in blood samples.
By considering the foregoing electrochemical data, the most favorable mem-
brane composition, i.e., BME-44-based plasticized polyvinyl chloride membranes
with added mobile sites (e.g., Fig. 7), was selected and tested in a continuous flow
analyzer (SERA-210) for measuring the potassium content of individual patents’
blood serum samples without dilution. The potassium concentration data deter-
mined by ion-selective potentiometry in continuous flow operation mode using
aqueous calibration standards were correlated with flame atomic emission spec-
trometric data (FAES) (Fig. 8). The potassium values determined in serum sam-
ples by ISEs were found to be somewhat higher than those obtained by FEAS due
to the volume displacement by, e.g., excessive proteins (5).
With the continuous analyzer (SERA-210), samples such as whole blood, se-
rum, and plasma can be analyzed without dilution with the sampling rate of 48
samples per hour. This means that analysis time is 76 s, including one point
calibration between samples.
 FLOW-INJECTION ASSAY OF POTASSIUM 241
BME44,PVC,DOS BME44,PVC,DOS
E (mV) E (mVt
210
‘““6

BME44,PVC,DOS,KTpCIPB BME44,PVC,DOS,KTpCIPB
E (mV)
*M)
wx2o

BME44,PVC-COOH,DOS BME44,PVC-COOH,DOS
E (mV) E hV)
260 210 -

*-0.23 s-o.17
2w- 100

a-O.26
110- , r-0.24
l 160. + +

100 2 ,w
0 2 lo u 0 1 10 I?
Nb. of m&u,.me”f Nb. Of mc:w,.,n:.
A B
FIG. 5. Reproducibility study corresponding to BME-44based ion-selective membranes of diierent
compositions. Measurements were carried out alternately in (A) lo-* M KC1 (0) and 10m3M KC1 (+)
containing BSE (B) 10 -* M KC1 (0) and 10e3 M KC1 + 7 wt% BSA (+) containing BSE.

Since almost all continuous analyzers require the predilution of urine samples,
the flow-injection analysis approach with controlled dispersion has advantages,
like short contact time with the interfering sample solution, self cleaning proper-
ties due to the alternating measuring-conditioning nature of the technique, in situ
dilution, etc., for the analysis of undiluted urine samples.
242 JENEY ET AL.

I--
50 - A

30’-* x

E +
S
10 -
6
J
5
+
cf -10 -
xt+++++
x ++++
2 I I x K x x I .:+++
xx.::: ;:++++++++++
xxxxxxxxxx
-30 -

Time (msec)

Time (msec)
FIG. 6. Dynamic response curves recorded with potassium membranes with fixed and mobile ion
exchanger sites in two different time domains. (+) BME-44, PVC-COOH, DOS; (x) BME-44, PVC,
KTpClPB, DOS. Concentration step: 10W2M KCI + lo-’ M KC1 + 7 wt% BSA in 0.1 M NaCl
background electrolyte.

In the present work a flow-injection system incorporating a macro wall-jet, easy

handling detection system was optimized for FIA studies of undiluted urine sam-
ples on the basis of the design and operational parameters.
In the function of the volume injected, the flow rate of the streaming solution,
 FLOW-INJECTION ASSAY OF POTASSIUM 243
EMF (mV)
300,

- SME 44 (KC11
250 - + BME 44 (KCIIBSE)
+ BME 44 (KCMJLE)
200 -

150 -

100 -

50

I I I I I I I
-50’
-6 -7 -6 -5 -4 -3 -2 -1 0

log a
FIG. 7. EMF vs log uk response in different electrolyte solutions. Membrane composition: 2 wt%
BME-44, 34 wt% PVC, 63.3 wt% DOS, 0.7 wt% KTpClPB.

and the length of the analysis channel, respectively, the variation of the signal
corresponding to 10 injections is shown in Fig. 9. For selecting the most favorable
parameters, a fast, reagent saving method with desired dispersion was also con-
sidered.

5.
“L Y - A + Ex / I

Y 3.

5.5

K CFlamd mmol/l

FIG. 8. Correlation study for the potassium concentrations of 50 blood serum samples.
244 JENEY ET AL.

*s (mV)
- 20 ul - 60 ul -1ooul -2oou1
*) _.,...._...... I.

,. .,., 1.0 m..

1 2 8 4 6 0
flow rate (mlhnid

04

0
0 1 2 a 4 6 0 7
flow rate (ml/mid

2.~1..1~

-0 1 2 3 4 8 0 7
flow ‘rate (ml/mid
FIG. 9. Optimization of the parameters of the FIA manifold.
 FLOW-INJECTION ASSAY OF POTASSIUM 245

For urine analysis the system parameters were:

-dispersion tube of 2 m of coiled Teflon tube (i.d., 0.5 mm),
-injection volume of 50 ~1,
-flow rate of 1.6 mYmin.
In order to achieve good stability, sensitivity, and response time for the ion-
selective electrode-based potentiometric detector system, the carrier solution
contained a primary ion relevant to the sensor, in a relatively low, constant
concentration (26, 27).
Accordingly, keeping in mind the above and the total ionic strength of urine
samples, the following carrier solution (ULE) composition was selected (20): 1
m&f KCl, 130 n&f MgCl,, 24.8 rSt4 tris(hydroxymethyl)aminomethane, pH 8,
adjusted by 0.1 M HCl.
The calibration standards were: 10, 20, 40, 80, and 100 mM KC1 in ULE,
respectively. The sample concentrations were evaluated on the basis of the peak
height correlating to the maximum concentration detected.

batch mode
wC(potroaium) mM
r-0.34
4S-

10 12 14 16 18 20
No: of mearurement8

flow-through mode
,~~

2 4 6 8 10 12 14 18 18 20
No. of mearurementr

flow-injection mode
;;,

2 4 6 8 10 12 14 16 18 20
No. of merrurementr
FIG. 10. The within run precision of the analytical data (n = 15).
246 JENEY ET AL.

150
Y - A + Bx
A - 1.2 125 ! Y - A + 9x
B - 0.95 A - -2.96
rsd.- 5. 6
0.95
y 100 t-l - 0.927 100i rsd.- 4.9
- 0.975
2
I

P
75
6
Y
2% 50

0
SO 100 1 0

K [Flame1 mmol/l K CSERAI mmol/l

B
A

FIG. 11. Correlation study for the potassium ion concentrations in urine samples. (A) HORIBA
SERA-210 Ion analyzer vs FAES. (B) Flow-injection analysis vs HORIBA SERA-210 Ion analyzer.

The within run precision of the analytical data relevant to urine samples, per-
formed by the optimized flow-injection system, is exhibited in Fig. 10 in compar-
ison with data obtained by the batch operation mode and by the commercial
SERA-210 Ion analyzer, respectively.
The potassium concentration data of undiluted urine samples of individual pa-
tients determined by the flow-injection analysis technique were correlated to
those obtained with the continuous flow method (SERA-210) as well as with
FAES (Fig. 11).
The correlation presented proves the value of the FIA method as well as the
macro wall-jet cell arrangement with a commercially available potassium ion-
selective membrane electrode of optimized composition, for the analysis of bio-
logical samples of microliter volumes with a rate of 100 samples per hour.
ACKNOWLEDGMENTS
The authors thank Prof. Dr. R. Kellner for the helpful discussion on FTIR-ATR investigations and
the Hungarian Academy of Sciences for providing financial support for this research (OTKA 421/88).

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