Separation and Kinetic-Spectrophotometric Determination of

Ketoconazole from Formulations Using SDS-Coated Al

2
O
3
and KMnO
4
in
Alkaline-SDS Micellar Medium
Khalil Farhadi* and Hossein Sheikhloei Bonab
Department of Chemistry, Urmia University, Urmia, Iran
A kinetic method for the accurate and sensitive determination of Ketoconazole (KC) has been described.
The method is based on the alkaline oxidation of KC with KMnO
4
in micellar SDS medium. At a fixed time of
8 min, the formed manganate ion is spectrophotometrically measured at 610 nm. The determination of KC by
the fixed-concentration and rate constant methods is feasible with the calibration equation obtained, but the
fixed time method proves to be more applicable. The proposed method was successfully used for the quantita-
tive determination of KC in formulations after the complete separation of KC using SDS-coated Al
2
O
3
as a
suitable solid-phase extraction system in comparison to liquid-liquid extraction using poisonous organic sol-
vents. Beers law was obeyed from 0.4 to 28 mg mL
-1
and the RSD% values for tablet, cream and shampoo
samples were 1.8, 1.4 and 2.3, respectively. The results obtained agreed with those obtained by the USP
method.
Keywords: Ketoconazole; Kinetic-Spectrophotometry; SDS-Coated alumina.
INTRODUCTION
A variety of direct spectrophotometric methods for the
determination of drugs based on redox reactions in biological
fluids or formulations require an initial separation step prior
to the performing of original procedures. In most cases, a sol-
vent extraction has been suggested for this purpose. There-
fore, the development of new separation methods based on
sorption and desorption of analytes from sorbents without us-
ing toxic organic solvents requires considerable attention.
The ability of surfactants to dissolve organic com-
pounds, which are insoluble or only slightly soluble in water,
is described by incorporation of a solubilized compound into
a hydrocarbon environment in the interior of micelles. In fact,
a micellar phase plays the same role as the organic solvent in
ordinary liquid-liquid extractions.
1
On the other hand, it is
well known that similar aggregates such as hemimicell or
admicell can be formed on solid surfaces such as alumina.
2
For example, sodium dodecyle sulfate (SDS) is easily sorbed
on the protonated alumina surface by coulombic attraction to
form surfactant aggregates.
2
The SDS-coated alumina sor-
bents were successfully applied for the collection of trace
heavy metals such as non-ionic complexed forms from vari-
ous samples.
3,4
Therefore, it may be expected that the SDS-
coated alumina can be used as a suitable sorbent for the sepa-
ration of lipophilic molecules from aqueous solutions.
Ketoconazole (KC), cis-1-acetyl-4-[4-[2-(2,4-dichlo-
rophenyl)-2-(1H-imidazole-1-yl methyl)-1,3-dioxolan-4-
yl]methoxy piperazine, is an antifungal agent of the imid-
azole class which contains two nitrogen atoms in the five
membered azole ring. The primary mechanism of action of
KC and azoles, in general, is the inhibition of sterol 14-a-di-
methylase, a microsomal cytochrome P-450 dependent en-
zyme system.
5
Thus, due to the vital importance of determi-
nation of this drug in pharmaceutical preparations and bio-
logical fluids, several spectroscopic,
6-13
high performance
liquid chromatographic,
14-18
electrochemical
19-23
and titri-
metric
24
methods for the assay of KC have been reported in
the literature.
We have recently studied the electrooxidation of KC in
aqueous and non-aqueous media.
20-22
Based on the electro-
chemical results obtained, in the following step, we investi-
gated the chemical oxidation of KCin solution and developed
a new spectrophotometric method for the determination of
KC based on the oxidation with Iron(III) in acidic citrate
buffer solutions.
25
The present work represents the first at-
tempt in the kinetic study of the reaction between KC and po-
tassium permanganate in alkaline solutions in order to de-
Journal of the Chinese Chemical Society, 2004, 51, 743-750 743
* Corresponding author. E-mail: kh.farhadi@mail.urmia.ac.ir
velop a kinetic-spectrophotometric method for the determi-
nation of KC. Since KC was practically insoluble in water,
we used SDS micellar solutions as a suitable medium for the
complete dissolving of this drug. The reaction is followed up
spectrophotometrically at 610 nm, and the fixed time method
is used for the analytical determination purposes. Moreover,
a new method has been developed for the complete separa-
tion of KC from pharmaceuticals using SDS-coated alumina.
The proposed method is not only more sensitive than the
non-aqueous titrimetric methods adopting USP and BP but
also is very fast, simple and inexpensive in comparison to
various reported methods such as HPLC.
EXPERIMENTAL
Reagents
All of the chemicals used in this study were of the high-
est purity available from Merck or Fluka and used without
further purification. Triply distilled water was used through-
out. Reagent grade KC and its tablet, cream and shampoo
samples containing 200 mg and 2% of the drugs were ob-
tained fromBehvazan Pharmaceutical Company, Rasht, Iran.
Apparatus
A LKB model 4054 UV-Vis recording spectrophoto-
meter with 10-mm matched silica cells was used for all spec-
tral measurements. The pH values were determined with a
digital WTW Multilab 540 Ionalyzer (Germany) pH/mV me-
ter using a combined electrode. A COOLNICS THERMO-
BATH model CTE-21 was used for the temperature adjust-
ment, and a shaker model Heidolph PROMAX2020 was used
for mixing of reactants.
Standard Drug Solution
Stock solution of 100 mg mL
-1
of KC was prepared by
dissolving 10 mg of pure drug in 100 mL of water containing
a few drops of 1 M hydrochloric acid. This solution is stable
for at least 24 hours when kept in the refrigerator (about 4
C).
General Recommended Procedures
Kinetic-Spectrophotometric Determination of KC
Transfer 6 mL of 0.1 M potassium permanganate and 1
mL of 10 M sodium hydroxide solution and 4 mL of 0.01 M
SDS, into 25 mL volumetric flasks. Add accurate volumes of
KC stock solution containing suitable amounts of the drug
(see Table 1). Complete to volume with distilled water and
mix well. Then, allow to stand for a fixed time of 8 min at
room temperature. Measure the absorbance of solutions at
610 nm against a blank sample. Construct the calibration
graph by plotting the final concentration of the drug against
the absorbance values measured at a fixed time of 8 min. Al-
ternatively, derive the corresponding regression equation.
Separation of KC Using SDS-Coated Alumina
Purified alumina particles (g-type)(1.5 g) were sus-
pended in 50 mL of water and mixed with 100 mg of SDS.
The suspension was acidified to pH 2.5-3 with 0.5 M hydro-
chloric acid and mixed for 15 min with a mechanical shaker.
The formed SDS-coated alumina was separated and washed
with distilled water three times. Then, 10 mL of sample solu-
tion containing appropriate amounts of KC(0.5-100 mg mL
-1
)
adjusted to pH 2.5 was mixed with prepared SDS-coated alu-
mina in a suitable flask, and the resulting mixture was shaken
mechanically for 15 min. After this time, the liquid phase was
removed and the solid phase was washed with two 2 mL por-
tions of distilled water. Then, the resulting solid phase was
treated with 6 mL of 0.5 M HCl for 5 min. Finally, solid phase
744 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 Farhadi and Bonab
CH
3
C N N O
..
CH
2
O
CH
2
N
N
O
O
..
..
Cl
Cl
Ketoconazole
Table 1. Analytical data for the kinetic determination of KC
Parameter Value
Volume of 0.1 M KMnO
4
(mL) 6
Volume of 0.01 M SDS (mL) 4
Volume of 10 M NaOH (mL) 1
Temperature (C) 25
Reaction time (min) 8
Concentration range (mg mL
-1
) 0.4 28
Molar absorptivity 26466.6
Regression equation (n = 7) A = 0.0189 + 0.0483 C
Correlation coefficient 0.9964
S
y/x
0.715
S
a
0.088
S
b
0.004
RSD% for Tablets, Cream and
Shampoo, respectively
1.85, 10.43, 2.3
was removed by filtration and washed completely with dis-
tilled water. The filtrate and washing solutions were col-
lected into a 25 mL volumetric flask and diluted to mark and
the recommended kinetic - spectrophotometric procedure for
the determination of KC was followed on appropriate
amounts of this solution.
Tablet, Cream, and Shampoo Sample Solutions
An accurately weighed amount of KC shampoo or
cream or finely powdered KC tablet was dissolved in water
containing a few drops of 1 M Hydrochloric acid. The excipi-
ents were separated by filtration and the filter paper was
washed three times with water. The filtrate and washing solu-
tions of the tablet or cream or shampoo samples were trans-
ferred quantitatively into a 100 mL calibrated flask and di-
luted to the mark with water, and the recommended proce-
dures for the separation and determination of KC were fol-
lowed.
RESULTS AND DISCUSSION
Kinetics and Optimization
The possibility of the reaction between KC and alkaline
potassium permanganate in micellar SDS medium was stud-
ied spectrophotometrically. The visible absorption spectra of
2.4 10
-3
M KMnO
4
in the presence of KC at room tempera-
ture with different time values are shown in Fig. 1. As seen,
the absorption values of KMnO
4
in the 480-560 nm decrease
slowly with time whereas the intensity of 610 nm band corre-
sponding to the green color of manganate species increases
until the end of the reaction. On the other hand, we have al-
ready found that all products resulting from the electrooxida-
tion of KC in high pH values (pH > 10) are completely color-
less,
20
so, no spectral interference is observed in the detecting
of manganate ion. As a result, the product species that ab-
sorbs at 610 nm was found to depend on time and the concen-
tration of both reactants and useful to elaborate a kinetically
based method for the determination of KC. Therefore, the re-
action was investigated under various conditions of reagent
concentration by changing each variable in turn, while keep-
ing all others constant.
The effect of potassiumpermanganate concentration on
the reaction rate and maximum absorbance was studied over
the range of 4 10
-4
- 2.8 10
-3
M of KMnO
4
and three se-
lected concentrations of KC (Fig. 2). As is seen, the absorb-
ance values increase with increasing KMnO
4
concentration
and level off at 2.0 10
-3
M. Therefore, 2.0 10
-3
M KMnO
4
was chosen as the most suitable concentration.
The ability of surfactants to dissolve organic com-
pounds, which are insoluble or slightly soluble in water, is a
distinctive feature of solubilization. The usual explanation
offered for this phenomenon suggests that the solubilized
compounds are incorporated into a hydrocarbon environment
in the interior of micelles.
26
Therefore, in this study, we used
micellar solution as a suitable medium for the complete dis-
solving of KC. For this purpose, several anionic, cationic,
and non-ionic surfactants were tested. Among the tested sur-
factants in alkaline mixture of KC, the obtained micellar so-
lutions using SDS were completely transparent, so, all KCso-
Kinetic Determination of Ketoconazole J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 745
Fig. 1. Absorption spectra for KMnO
4
(2.4 10
-3
M) in
the presence of KC (8 mg mL
-1
) and NaOH (0.4
M): A, KMnO
4
alone; B-F, immediately after
mixing with a time interval of 5 min.
0
0 . 2
0 . 4
0 . 6
0 . 8
1
0 1 0 2 0 3 0
[ K M n O
4
] 1 0
4
A
b
s
.
A
B
C
Fig. 2. Effect of potassium permanganate concentra-
tion on the reaction product of (A) 0.4, (B) 8 and
(C) 28 mg mL
-1
KC measured at room tempera-
ture after 8 min.
lutions were prepared in alkaline SDS micellar medium. The
effect of various concentrations of SDS on absorbance inten-
sity at different amounts of KC is shown in Fig. 3. As it is
seen, in all cases, a maximum absorbance was obtained for
solutions containing 1.6 10
-3
M of SDS. Therefore, the opti-
mum concentration of SDS was selected to be 1.6 10
-3
M in
further experiments.
The influence of NaOH concentration on the reaction
rate was studied between 0.16-0.8 M, and the obtained results
are shown in Fig. 4. As is seen, the absorbance of reactants in-
creases in alkaline medium up to 0.4 M sodium hydroxide
and remains nearly constant for concentrations higher than
0.4 M. Therefore, 0.4 M NaOH was chosen as the most suit-
able concentration.
After the optimization of chemical variables, the influ-
ence of temperature over the range of 25-55 C was exam-
ined. The signal increased slightly with increasing tempera-
ture and no considerable improvement in linear concentration
range and sensitivity occurred in comparison to roomtemper-
ature, so, 25 C was selected as the optimum temperature
(Fig. 5). Under the optimal physicochemical conditions, the
absorbance-time signals were recorded at l
max
= 610 nm be-
tween 0 and 40 min. for solutions containing different amounts
of KC over the range 0.4-28 mg mL
-1
and constant amounts of
KMnO
4
, SDS and NaOH (Fig. 6). It is clear from the graphs
shown in Fig. 6 that the rate increases as the KC concentra-
tion increases, indicating that the reaction rate obeys the fol-
lowing equation:
Rate = k[KC]
n
(1)
where k is the pseudo-first-order rate constant, n is the order
of the reaction and [KC] is the molar concentration of KC.
Apparently, the reaction proceeds in two steps (see Fig.
6). The first step being fast and the second slow. The latter,
being the rate-determining step, could be estimated as
DA/Dt,
27
where A is the absorbance and t is the time in sec-
onds. Taking logarithms of rates and concentrations (Table
746 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 Farhadi and Bonab
Fig. 3. Effect of sodium dodecyl sulfate concentration
on the reaction product of (A) 0.4, (B) 8 and (C)
28 mg mL
-1
KC measured at room temperature
after 8 min.
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
[NaOH]
A
b
s
.
Fig. 4. Effect of sodium hydroxide concentration on
the reaction product of 8 mg mL
-1
KC measured
at room temperature after 8 min.
0.2
0.3
0.4
0.5
0.6
0.7
0.8
15 25 35 45 55
T (
o
C)
A
b
s
.
Fig. 5. Effect of temperature on the reaction between 8
mg mL
-1
KC with alkaline potassium permanga-
nate in the presence of SDS.
0
0.5
1
1.5
2
0 20 40 60
t(min)
A
b
s
.
0.4ppm
4ppm
8ppm
12ppm
16ppm
20ppm
24ppm
28ppm
Fig. 6. Absorbance versus time graphs for the reaction
between KC and KMnO
4
at 25 C.
2), Eq. 1 is transformed into:
log (rate) = logDA/Dt = log k + n log[KC] (2)
Regression of log (rate) versus log [KC] by the least square
method gave the regression equation:
log (rate) = 1.0017 + 0.9457 log [KC]; R
2
= 0.9978
Hence k = 10.16 s
-1
and the reaction is pseudo first order (n @
1) with respect to KC.
The reaction stoichiometry was studied via the molar
ratio method
28
and was found to be 1:1. Therefore, the fol-
lowing scheme can be suggested for the reaction between KC
and KMnO
4
in alkaline SDS micellar solutions:
KC + MnO
4
- NaOH SDS -
KC
+
+ MnO
4
2-
where KC
+
is the cation radical produced from the first oxi-
dation step of KC. This process agrees well with our results
regarding the electrochemical studies of KC.
20-22
It is note-
worthy that the electrochemical studies showed that the only
possibility in the oxidation of KC to KC
+
is the loss of one
electron from the methoxy group.
20,21
Complementary exper-
iments showed that the resulting colored cation radical de-
cays gradually in acidic medium and quickly decomposes to
various products in alkaline solutions.
Evaluation of the Kinetic Methods
Initial-rate Method (Pseudo-Zero-Order method)
In this method, the graphs of rate (at the beginning of
the reaction) versus KC concentration were not easy to ob-
tain, because the first step of the reaction is not rate determin-
ing and is too fast to follow, so tangents to the curves at zero
time are not easy to draw. This method was therefore aban-
doned.
Rate-Constant Method
Graphs of log (absorbance) versus time for KC concen-
tration in the range of 0.4-28 mg mL
-1
were plotted and all ap-
peared to be rectilinear. Pseudo-first-order rate constants (K)
corresponding to different KC concentrations, C, were calcu-
lated from the slopes multiplied by -2.303 and are presented
in Fig. 7. Regression of K versus C gave the equation:
K = -50644 C + 2.1025 (R
2
= 0.9483)
The poor linearity is probably due to change in the rate con-
stant (K) with the inevitable slight changes in the elevated
temperature of the reaction.
Fixed-Concentration Method
Reaction rates were recorded for different KC concen-
trations in the range of 12-20 mg mL
-1
. Apre-selected value of
the absorbance was fixed and the time was measured in sec-
onds. The reciprocal of time versus the initial concentrations
of KC was plotted and the following equation of the calibra-
tion graph was obtained:
1/t = 491.02 C - 0.0109 (R
2
= 0.9441)
The range of KC concentrations giving the most acceptable
calibration graph with the above equation was very limited
and showed poor linearity, which could be a disadvantage.
Fixed-time Method
Reaction rates were measured for different concentra-
Kinetic Determination of Ketoconazole J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 747
Table 2. Logarithms of the rates for different concentrations of
KC at constant concentrations of 2.4 10
-3
M KMnO
4
,
1.6 10
-3
M SDS and 0.4 M NaOH at room temperature
log (DA/Dt) log (KC/M)
-4.8 -6.12
-3.8 -5.12
-3.56 -4.82
-3.4 -4.65
-3.3 -4.52
-3.19 -4.42
-3.06 -4.34
-3.07 -4.28
y = - 0.0506 x + 2.1025
R
2
= 0.9483
0
0.5
1
1.5
2
0 10 20 30 40
[KC] 10
6
K
'
Fig. 7. Values for K calculated from slopes of log
(Abs.) versus t (s) graphs multiplied by -2.303
for different concentration of KC at constant
concentration of 0.4 M NaOH, 2.4 10
-3
M
KMnO
4
and 1.6 10
-4
SDS at room tempera-
ture.
tions of KC, and the corresponding calibration graphs were
obtained at fixed times 2, 4, 6, 8, 10 and 12 min with the cali-
bration equations shown in Table 3. It is clear that both the
slopes and intercepts increase with time. The best correlation
coefficient (indicated by higher absorbance reading as shown
in Fig. 6) were obtained for a fixed time of 8 min. Therefore, 8
min was chosen as the most suitable time for measurements.
Linearity
The kinetic curves obtained at different concentrations
of KC, under the optimized conditions, were processed by the
fixed time method.
29
Calibration graph of absorbance versus
initial concentration of KC was established at different
fixed-time intervals. It was found that the slopes increase
with time and the most acceptable values of the correlation
coefficient (R
2
) and the intercept were obtained at a fixed-
time of 8 min that was, therefore, chosen as the most suitable
time intervals for measurement. The calibration graph was
linear over the concentration range of 0.4-28 mg mL
-1
. Re-
gression analysis indicated a linear relationship with negligi-
ble intercept. Table 1 presents the analytical parameters, mo-
lar absorpitivity, and the results of the statistical analysis of
the experimental data regression equation calculated from
calibration graphs along with standard deviation of the slope
(S
b
) and intercept (S
a
) on the ordinate and the standard devia-
tion of residuals (S
y/x
). The high values of the correlation co-
efficient of regression equations indicate good linearity and
conformity to Beers law. The detection and quantification
limits were 0.152 and 0.502 mg mL
-1
for KC, respectively.
Accuracy and Precision
Five replicate determinations at different concentration
levels of KC were carried out to test the precision and accu-
racy of the proposed method. The relative standard deviation
(RSD%) is shown in Table 1. The figures obtained point to
the good accuracy and repeatability of the method.
Analytical Applications
The fixed-time method was applied to the determina-
tion of KC in pharmaceutical preparations. In preliminary ex-
periments, direct application of proposed kinetic fixed time
method for the determination of KC in formulations showed
large errors probably due to the presence of some commonly
oxidizable excipients. Therefore, the separation of KC from
the sample matrix was necessary. For this purpose, we were
interested in studying the application of SDS-coated Al
2
O
3
as
a solid-phase sorbent for separation of KC from formulation
samples (see experimental section). Preliminary experiments
showed that Al
2
O
3
in the absence of SDS is not able to collect
all of KC (20 mg) from samples at various ranges of pH, 1-6,
so that the recovery values were less than 10%. Therefore, we
fixed various amount of SDS on Al
2
O
3
by mixing 2 g of alu-
mina with different concentrations of SDS at pH 2.5
3
and
studied the efficiency of the resulting sorbents. The obtained
results demonstrated that the total of KC (20 mg, pH 2.5) can
be collected on SDS-coated Al
2
O
3
with a mean recovery of
>99.5% using about 0.15 g SDS (above CMC). The effect of
the pH of KC solutions on recovery values was also investi-
gated. The best recoveries were obtained at pH 2.5. In pH
<2.5, the recovery values diminished probably due to exten-
sive protonation of KC. On the other hand, the decrease in re-
coveries at pH > 2.5, is most probably related to poor fixation
of SDS on alumina. Therefore, pH 2.5 was selected as opti-
mum pH for desorption of adsorbed KC from sorbent before
running the kinetic-spectrophotometric method. The result
obtained using the batch method was very accurate and repro-
ducible. The mechanism of separation is probably based on
the interaction of formed hemi-micelles or ad-micelles on
solid-phase with KC. Similar phenomena have been shown in
the separation of traces of iron, cobalt, nickel, copper, cad-
mium, lead, chromium, and Hesperidin using SDS - coated
Al
2
O
3
solid-phase.
3-4
The proposed separation method is sim-
ple, fast, and inexpensive in comparison to application of liq-
uid-liquid extraction using poisonous organic solvents. The
recommended kinetic fixed time method was performed on
the elutions obtained from the proposed separation method.
The concentration of KC was calculated using the corre-
sponding regression equations at a fixed time of 8 min. The
results obtained are presented in Table 4. Statistical analysis
of the results obtained by the proposed and official meth-
ods
7,30
revealed no significant difference in the performance
of the two methods regarding accuracy and precision as re-
vealed by t-test and F-test, respectively (Table 4).
748 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 Farhadi and Bonab
Table 3. Calibration equations at different fixed times for KC
concentration in the range of 0.4-28 mg mL
-1
Time (min) Calibration equation Correlation coefficient
2 A = 0.0377x 0.0021 0.9994
4 A = 0.0419x + 0.0059 0.9965
6 A = 0.0457x + 0.0159 0.9962
8 A = 0.0483x + 0.0189 0.9964
10 A = 0.0511x + 0.0112 0.9982
12 A = 0.0528x + 0.0116 0.9981
We have also evaluated the accuracy of the proposed
method by performing experiments on the samples prepared
from dosage forms and pure drugs. The mean percent recov-
eries obtained from three replicate measurements were found
to be 99.8 with an RSD% between 1.5-2.1%.
CONCLUSION
The above results obtained from proposed kinetic fixed
time method on formulation after the separation of KC using
SDS-coated Al
2
O
3
as a suitable solid-phase showed that the
method is comparable to the official USP method (Table 4).
The proposed kinetic-spectrophotometric method is simple,
fast, and inexpensive, does not require any toxic organic sol-
vents, and is precise and accurate. This method was satisfac-
tory for the determination of KC in drug formulations such as
tablets, creams, and shampoos without considerable interfer-
ence.
The students t-test and F-test values for the 95% confi-
dence level did not exceed the theoretical values of 4.3 and
19.0 for t- and F-tests, respectively, indicating no significant
difference between the accuracy and precision of the two
methods. Therefore this makes the method applicable for the
determination of KC.
ACKNOWLEDGMENTS
Financial support from the Research Affairs of Urmia
University is acknowledged. The authors are grateful to the
Behvazan Pharmaceutical Company, Rasht, Iran, for the sup-
ply of pure drug samples.
Received June 5, 2003.
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Kinetic Determination of Ketoconazole J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 749
Table 4. Application of the proposed method to the
determination of KC in its formulation
Sampl Label % Recovery SD*
Proposed method Official method
Tablets 200 mg 197.9 3.6 mg 196.4 2.0 mg
t = 0.63, F = 3.24
Cream 2% (1.82 0.2) % (1.89 0.05) %
t = 0.59, F = 16
Shampoo 2% (1.38 0.03) % -----
* Average of three replicate measurements. Tabulated values of t
and F are 2.78 and 19.00 at 95% confidence level.
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750 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 Farhadi and Bonab