European Journal of Pharmaceutical Sciences 19 (2003) 115122

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Design and evaluation of sustained release microspheres of potassium

chloride prepared by Eudragit
a a a b a,
Pao-Chu Wu , Yaw-Bin Huang , Jui-Sheng Chang , Ming-Jun Tsai , Yi-Hung Tsai *
a
School of Pharmacy, Kaohsiung Medical University, 100 Shih-Chen 1 st Road, Kaohsiung 807, Taiwan, ROC
b
Department of Neurology, Yuan s General Hospital, Kaohsiung City 80708, Taiwan, ROC
Received 8 October 2002; received in revised form 18 March 2003; accepted 19 March 2003

Abstract

The aim of the present work was to prepare and evaluate the sustained release of potassium chloride formulations. Eudragit RS and / or
RL loaded with potassium chloride microspheres were prepared by a solvent evaporation method. The effect of sustained release of
Eudragit microspheres was evaluated by an in vitro dissolution test and in vivo oral absorption study, and the results were compared to a
commercial product (Slow-K). The results showed that Eudragit microspheres loaded with potassium chloride can be easily prepared and
satisfactory results obtained considering the size distribution and shapes of microspheres by incorporating aluminum stearate. The
encapsulation efficiency and loading capacity were about 8490% and 27%, respectively. Moreover, the Eudragit RS (3045 mesh) and
Eudragit RS / RL (2030 mesh) microspheres showed a similar sustained release effect of commercial product via in vitro dissolution and
in vivo oral absorption study.
2003 Elsevier Science B.V. All rights reserved.

Keywords: Potassium chloride; Dissolution test; Eudragit; In vivo study

1. Introduction
Potassium chloride is used for the treatment of hypo-
kalemia or severe potassium loss of various etiologies
(Lacy et al., 1998). However, potassium chloride is known
for its gastrointestinal complications such as ulcerations,
hemorrhage, obstruction and perforation. In order to avoid
or minimize the adverse effects induced by potassium
chloride, the sustained release dosage form seems to be the
ideal dosage form because of the reduced possibility of a
high local concentration of potassium chloride near the
gastrointestinal mucosa (Lindstedt et al., 1991; Wu et al.,
2002).
Acrylic polymers are widely used as tablet coatings and
as retardants of drug release in sustained released formula-
tions (Goto et al., 1986; Kawata et al., 1986; Jovanovic et
al., 1997; Khanfar et al., 1997; Mehta et al., 2001). The
most interesting among acrylic polymers were high perme-
*Corresponding author. Tel.: 1886-7-3121101x2166; fax: 1886-7-
3210683.
E-mail address: pachwu@kmu.edu.tw (Y.-H. Tsai).
able Eudragit RL and low permeable Eudragit RS, both are
neutral co-polymers of poly (ethylacrylate, methyl meth-
acrylate) and trimethyl aminoethyl methacrylate chloride
and are insoluble in water and digestive juices, but both
swell and are permeable, which means that the drugs can
be released by diffusion. Therefore, the permeability of the
drug through Eudragit RS and / or RL is independent of the
pH of the digestive tract. The degree of permeability
depends on the relative proportion of quaternary am-
monium groups in Eudragit. There are some studies for
potassium chloride sustained release dosage form such as
potassium chloride tablet coated with semipermeable mem-
brane, potassium chloride matrix tablet or capsule, and
microencapsulation with mastic (Arnold et al., 1980;
Georgarakis et al., 1987, Caraballo et al., 1996, 2000; Wu
et al., 2002). In this study, Eudragit RS and RL were used
as retardants to prepare the potassium chloride micro-
spheres by a solvent evaporation method. The effect of
sustained release of potassium chloride from Eudragit has
been investigated via in vitro dissolution test and in vivo
oral absorption study and has been compared to a commer-
cial sustained release product (Slow-K).

0928-0987 / 03 / $ see front matter 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016 / S0928-0987(03)00069-1
116 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122
2. Materials and methods
2.1. Materials
Potassium chloride, cesium chloride, potassium standard
solution, aluminum stearate and sodium chloride were
purchased from E. Merk (Germany). Eudragit RS and RL
were purchased from Rohm Pharma GMBH Weiter Stadt
(Germany). Slow-K tablet (Norvatis) was purchased from
a local market. All other chemicals and solvents were of
analytical reagent grade.
2.2. Preparation of microspheres
Two grams of Eudragit was dissolved completely in 50
ml of acetone in a glass vessel. The aluminum stearate
(0.251.0 g) and 2 g potassium chloride were dispersed
into the Eudragit solution. The mixture was stirred at 250
rpm in a water bath at 10 8C over 20 min, and then poured
into 100 ml liquid paraffin previously cooled to 10 8C. The
emulsion was heated to 35 8C with a constant temperature
and was continually stirred at 250 rpm until the acetone
was removed completely by evaporation. Then, 30 ml of
n-hexane was added to the suspension of microspheres.
After 10 min, the microspheres were separated by filtra-
tion, washed twice with 50 ml n-hexane and dried at room
temperature in a desiccator under reduced pressure over-
night.
2.3. Scanning electron microscopy
The surface characteristics were examined by means of
a scanning electron microscope. The microspheres were
coated with platinum / palladium alloy using an ion coater
(Eiko Engineering counter) under vacuum, and then sam-
ples were examined with a scanning electron microscope
(Hitachi S-450).
2.4. Sieve analysis
Separation of the microspheres into various size frac-
tions was carried out using a mechanical sieve shaker
(Sieving machine, Retsch, Germany). A series of five
standard stainless steel sieves (20, 30, 45, 60 and 80 mesh)
were arranged in the order of decreasing aperture size. Five
grams of drug loaded microspheres were placed on the
upper-most sieve. The sieves were shaken for a period of
about 10 min, and then the particles on the screen were
weighed. The procedure was carried out three times for
each product.
2.5. Drug content determination
Microspheres were pulverized and dispersed in a 100-ml
flask with 25 ml acetone. After shaking for 10 min, 50 ml
of deionized water was added and was continually shaken
for 30 min. The deionized water layer was diluted and
determined by atomic absorption spectrophotometry (Var-
ian, 875 series with a lamp capable of measuring the
absorbance of potassium at its secondary wavelength of
766.5 nm). The loading capacity was calculated using the
equation:
loading capacity
5 actual potassium content / theoretical potassium content
3 100
2.6. In vitro dissolution test
Dissolution tests were performed in 900 ml deionized
water using the basket method with a rotation speed of 100
rpm at 3760.5 8C. At fixed time intervals (15, 30, 60, 90,
120, 150, 180, 240, 300 and 360 min), 5-ml samples were
withdrawn and replaced with the same volume of dissolu-
tion medium. The potassium contents in the dissolution
samples were measured by atomic absorption spectro-
photometry (Varian, 875 series with a lamp capable of
measuring the absorbance of potassium at its secondary
wavelength of 766.5 nm). The dissolved amount of drug at
each time was expressed as a percentage of the dose.
2.7. Data analysis
Three kinetic models including the zero-order release
equation (Eq. (1)), Higuchi equation (Eq. (2)) and first-
order equation (Eq. (3)) were applied to process the in
vitro data to find the equation with the best fit (James et
al., 1997; Wu et al., 2002).
Q 5 k1t (1)
Q 5 k 2std 0.5 (2)
2k3t
Q 5 100s1 2 e d (3)
where Q is the release percentage at time (t). k 1 , k 2 and k 3
are the rate constant of zero-order, Higuchi and first order
model, respectively.
Statistical comparisons between data were made using
ANOVA analysis. Subgroup comparisons were made using
the NewmanKeuls multiple comparisons.
2.8. In vivo absorption study
Male New Zealand white rabbits (1012 weeks old,
2.02.5 kg) were used and fasted 12 h prior to the
experiment. During the study, 8 ml of deionized water was
supplied hourly for 12 h after treatment to ensure adequate
urine flow. The first day was the control day for the
treatment on the second day. Potassium chloride (600 mg)
of experimental formulations or commercial product was
 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122 117

orally administered with 10 ml deionized water. All urine The volume of each collection was recorded, and a sample
voided was collected hourly up to the 12th hour and was centrifuged and analyzed for its potassium content by
pooled from 12 to 24 h by Nelaton Catheter tube No. 3. an atomic absorption spectrophotometer.

Fig. 1. Scanning electron micrographs of potassium chloride (a) and Eudragit RS microspheres containing potassium chloride (b): 1: the SEM graph of
2030 mesh microspheres at 100 times of amplification; 2: the SEM graph of 3045 mesh microspheres with 100 times of amplification; 3: the SEM graph
of 4560 mesh microspheres with 200 times of amplification; 4: the SEM graph of 6080 mesh microspheres with 200 times of amplification; 5: the SEM
graph of 2030 mesh microspheres with 2000 times of amplification; 6: the SEM graph of 3045 mesh microspheres with 2000 times of amplification; 7:
the SEM graph of 4560 mesh microspheres with 2000 times of amplification; 8: the SEM graph of 6080 mesh microspheres with 2000 times of
amplification.
118 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122
3. Results and discussion
3.1. In vitro study
According to earlier studies (Kawata et al., 1986; Goto
et al., 1986), aluminum stearate was found to be a useful
additive for microencapsulation using the Eudragit series
in terms of the reduction of the interfacial tension and
prevention of electrification and flocculation in the mi-
croencapsulation dispersion system and thus improve the
yield ratio and the shape and internal structure of micro-
spheres. In this study, different amounts of aluminum
stearate (0.251.0%) were used to prevent flocculation and
aggregation of microspheres in all studied systems and to
enable the isolation of final products. The surface mor-
phologies of potassium chloride and different particle size
of Eudragit RS microspheres containing potassium chlo-
ride with 1002000 times of amplification are shown in
Fig. 1a,b, respectively. The shape of potassium chloride
crystal was irregular. The Eudragit RS microspheres were
quite spherical in shape except for large size particles
(2030 mesh) (Fig. 1b14), indicated that spherical
solid microspheres could be prepared by adding a small
amount of aluminum stearate. In comparison the surface of
microspheres at 2000 times amplification (Fig. 1b58),
smaller particles had a smoother and closer surface struc-
ture than that of lager particles. The encapsulation ef-
ficiency of these formulations was about 8490%. Fig. 2
illustrates the size distribution of Eudragit microspheres
incorporated with various amounts of aluminum stearate.
The result indicated that the added amount of aluminum
Fig. 2. The size distribution of Eudragit RS microspheres containing different amounts of aluminum stearate.
stearate had no significant effect on the size distribution of
microspheres and more than 58% of particles were
gathered up between 30 and 60 mesh. The loading capacity
of potassium was about 27%.
The dissolution profiles of potassium chloride from
various Eudragit microspheres into deionized water are
shown in Fig. 3. It was observed that the release rate of
potassium from Eudragit microspheres increased in the
following order of Eudragit RS,Eudragit RS / RL,
Eudragit RL. The release of potassium from Eudragit RL
microspheres was remarkably faster than from Eudragit
RS. It could be explained considering the chemical struc-
ture of Eudragit. The Eudragit RL and RS are synthesized
from acrylic and methacrylic esters with high and low
content of quaternary ammonium groups (1 / 20 and 1 / 10)
and result in microspheres with different water permeabili-
ty. The effect of particle size on drug release rate was also
investigated. As depicted in Fig. 3, except for the Eudragit
RL microspheres, the release rate of microspheres in-
creased in the following order: 6080 mesh,4560
mesh,3045 mesh52030 mesh. The release rates of
larger microspheres were faster than that of smaller
microspheres and had a burst effect in the initial period. In
contrast, the release rate of the smallest microspheres
(Eudragit RS6080 mesh or Eudragit RS / RL 6080 mesh)
were slower and had a lag time of about 6090 min.
Moreover, from the SEM graphs of Eudragit RS micro-
spheres (Fig. 1b, the other graphs of Eudragit RS / RL and
RL microspheres were not shown), the surfaces of the
larger microspheres were rougher. Therefore, it might be
proposed that the very small amount of potassium chloride
 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122 119

Fig. 3. Dissolution profiles of potassium chloride Eudragit microspheres and the commercial product (Slow-K) in deionized water (n56, mean6S.D.).

was aggregated on the surface of microspheres and / or comparison to the dissolution patterns with the commercial
some individual microspheres coagulated together to form product, it showed that the dissolution pattern of Eudragit
larger size microspheres in the evaporating process. In RS (3045 mesh), RS / RL (2030 mesh) and RS / RL
120 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122

Table 1
The kinetic parameters for release of potassium chloride in deionized water
Polymers Zero-order model Higuchi model First order model
r k r k r k
RS 2030 mesh 0.9403 0.1709 0.9856 4.1609 0.8604 0.0033
RS 3045 mesh 0.8793 0.1513 0.9472 3.7915 0.8002 0.0030
RS 4560 mesh 0.9827 0.1686 0.9892 3.9479 0.9050 0.0052
RS 6080 mesh 0.9502 0.1796 0.8968 3.9641 0.8940 0.0074
RS / RL 2030 mesh 0.9243 0.1843 0.9765 4.9160 0.8059 0.0046
RS / RL 3045 mesh 0.9100 0.1982 0.9605 4.8914 0.7858 0.0056
RS / RL 4560 mesh 0.9674 0.1982 0.9943 4.7380 0.8143 0.0065
RS / RL 6080 mesh 0.9756 0.1716 0.9632 3.9351 0.8345 0.0082
RL 2030 mesh 0.9111 0.1816 0.9644 4.4546 0.8382 0.0031
RL 3045 mesh 0.9738 0.2200 0.9965 5.2347 0.9211 0.0033
RL 4560 mesh 0.9469 0.2126 0.9828 5.1382 0.8916 0.0033
RL 6080 mesh 0.9175 0.2199 0.9670 5.3896 0.7994 0.0042
r, correlation coefficient; k, release rate constant.

(3045 mesh) microspheres were closer to that of the
commercial product. Therefore, these three microspheres
were used for the in vivo study
In addition, the release mechanism of potassium from
these Eudragit microspheres was also evaluated on the
basis of theoretical dissolution equations including zero-
order, Higuchi equation and first order kinetic models
(James et al., 1997), since different release kinetics are
assumed to reflect different release mechanisms. The
results are shown in Table 1. It shows that the release
pattern of potassium chloride from Eudragit microspheres
corresponded best to the Higuchi equation and diffusion
model.
3.2. In vivo absorption study
Changes in the urine potassium levels for each collec-
tion were determined by first averaging the urine potas-
sium levels for the control day for each rabbit and then
subtracting these values from the corresponding urine
potassium levels of the treatment day (Arnold et al., 1980;
Betlach et al., 1987). The cumulative amount of potassium

Fig. 4. Cumulative amount (mEq) of potassium excreted in the urine corrected for the control after oral administration of 600 mg potassium chloride in
rabbits (n56, mean6S.D.). d Significant difference between Slow-K vs. s RS 3045 mesh; n RS / RL 2030 mesh; and h RS / RL 3045 mesh
(P,0.05) at 24 h.
 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122 121

excreted in the urine over 24 h for Eudragit RS (3045
mesh), RS / RL (2030 mesh), RS / RL (3045 mesh)
microspheres and the commercial product (Slow-K) is
shown in Fig. 4. The cumulative urinary potassium values
corrected for the control (0.30.4 mEq) were equivalent to
45.4%, 49.0%, 65.8% and 41.9% of the state dose for the
Eudragit RS (3045 mesh), RS / RL (2030 mesh), RS / RL
(3045 mesh) and Slow-K, respectively. The cumulative
urinary amount of potassium of RS / RL (3045 mesh) was
higher than Slow-K. There were no significant differences
(P.0.05) among Eudragit RS (3045 mesh), RS / RL (20
30 mesh) and Slow-K, indicating that the sustained release
effect of these two Eudragit microspheres were similar to
that of Slow-K. The excretion rate curves (Fig. 5) also

Fig. 5. The curve of urinary potassium excretion rate (mEq / h) corrected for the control versus the midpoint of the collection interval after oral
administration of 600 mg potassium chloride in rabbits (n56, mean6S.D.).
122 P.-C. Wu et al. / European Journal of Pharmaceutical Sciences 19 (2003) 115122
show that the excretion rates of these Eudragit micro-
spheres were similar to that of the commercial product.
4. Conclusions
Eudragit microspheres loaded with potassium chloride
can be easily prepared by the use of solvent evaporation
and satisfactory results obtained considering size distribu-
tion and shapes of microspheres. The results of dissolution
tests showed that the various particle sizes of microspheres
had different release rates. Among these microspheres, the
Eudragit RS (3045 mesh) and Eudragit RS / RL (2030
mesh) microspheres exhibited a similar sustained release
effect of the commercial product via in vitro dissolution
and in vivo oral absorption study. Therefore, the optimal
release profile might be obtained by combining the differ-
ent Eudragit microspheres.
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