INTRODUCTION:
Analytical
determination of pharmaceutical compounds is a subject of high practical,
social and environmental impact [1,2]. Citrazine is (±)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1- piperazinyl]ethoxy]
acetic acid which exist in two stereoisomers (fig.-1) . It is an effective antihistamine
drug that reduces the natural chemical histamine in the body. Citrazine dihydrochloride is used for the
treatment of Kimura’s disease, which affecting the lymph nodes and soft tissues
of the head and neck. Cetirizine is also used to treat itching and swelling
caused by hives [3,4]. The selective determination of citrazine is a subject of
great importance in pharmaceutical chemistry. Few methods such as fluorimetry,
spectrophotometry [5.6], conductimetry [7], gas chromatography 8],
high-performance liquid chromatography [9, 10], liquid chromatography [11,12]
have been used for the determination pharmaceutical compounds, but these
methods required large infrastructures back up, time consuming, relatively
expensive and involve some sample manipulations. Thus a quick, convenient and
cost effective method for the selective determination of such compounds is a subject
of importance.
An analytical
technique based on electrochemical characteristics of target compound specially
suited for this purposes. Due to simple fabrication, high sensitivity, high
selectivity, wide dynamic concentration range, fast response time and low
detection limits, of electrochemical sensors makes them good alternative over
the analytical methods [13-18].
Figure 1. Structure of sterioisomers of
Citrazine dihydrochloride
A
literature survey revealed that the only two reports based on potentiometric
determination of citrazine are available for selective determination [19, 20].
The existing reports have very high response time, small dynamic rage, low
detection limit etc. The aim of this research is the
fabrication of a greatly selective and sensitive citrazine dihydrochloride
membrane sensor, based on 1,3,5-tris[(2,3-dihydroxybenzylamino)
aminomethyl]cyclohexane (L) as an ionophore for the
potentiometric measurement of the citrazine in different samples.
EXPERIMENTAL:
Reagents
and materials
Reagent
grade dibutylphthalate (DBP), ortho-nitrophenyloctylether
(o-NPOE), dibutylbutylphthalate (DBBP),
high-molecular weight polyvinylchloride (PVC), ethanol, acetone, tetrahydrofuran (THF) and sodium tetraphenyl borate (NaTPB) were obtained from
Ranbaxy, India. 1-Chloronathalene (CN), Oleic acid (OA), sodium
hydroxide (NaOH) and acetic acid (HCl) were
purchased from Cisco lab Mumbai India. To prepare
pharmaceutical sample containing cetirizine hydrochloride were obtained from
local drug stores. All solutions were prepared using doubly
distilled deionized water. The ionophore 1,3,5-tris[(2,3
dihydroxybenzylamino) aminomethyl]cyclohexane (L) was synthesized by the method
already available in literature.
Fabrication of
membrane sensor and measurement of emf
The general procedure to prepare the PVC
membrane was as followed: 2 mg of ionophore, 30 mg of
powdered PVC, 66 mg of plasticizers (o-NPOE, DBP, DBBP, OA and CN) and 2 mg of
NaTPB were dissolved in 3 mL tetrahydrofuran (THF). The solution was
mixed well. The resulting mixture was transferred into a glass dish of 2 cm
diameter, and the solvent was evaporated slowly until a concentrated mixture
remained. A Pyrex tube (3–5 mm of diameter) was dipped into the mixture for
about 30 s, in order to achieve a transparent membrane formation of about 0.5
mm in thickness. In the end, the tube was removed from the solution, kept at
room temperature for 10 hours and filled with an internal filling solution (1.0
´ 10-3 M Citrazine solution). The electrode was
conditioned for 24 h by soaking in a 1.0 ´ 10-3 M citrazine solution. The potential was
calculated by the following cell assembly:
SCE│Internal
solution││Membrane││Test solutions of drug│SCE
The performance
of the electrode was investigated by measuring the emf for the test solution
over a concentration range of 1.0 x 10-9 to 1.0 x10-2 M.
Variation in the EMF was recorded after the stabilization and the values
obtained were plotted as a function of 
(Fig. 2). The activities
were based on activity coefficient, data calculated from the modified form of
the Debye-Hückel approximations, which is applicable to any ion:
Where Z is the valency and μ is the
ionic strength. The pH of the test solutions were adjusted by using suitable
buffer solutions.
RESULT
AND DISCUSSIONS:
The polarity of plasticizer plays an important role
in the complexation between ionophore and target species, because an effective
plasticizer provides the best electrochemical responses of the sensor [21-24].
Thus five different membranes were prepared by using different plasticizers.
The best results were obtained with membrane composition of 3 % of ionophore, 30 % PVC, 66 % plasticizers (o-NPOE, DBP,
DBBP, OA and CN) and 1 % NaTPB (fig.2). All the components were added in weight
percentage. The result presented in figure 2 clearly indicates that the
best result in terms of concentration range and detection limit was obtained by
using o-NPOE as plasticizer. The response charaterstics of optimized membrane
with different plasricizers are presented in table-1.
The membrane sensor (no. 7) without ionophore shows
very response towards citrazine in the concentration range of 2.3 x 10-3
to 1.0 x 10-2 M solution, this is due to the bonding between
additive and drug in the solution, while the response of membrane (no. 6) with
ionophore in absence of o- NPOE give batter results in terms of working
concentration range (table 1). The membrane no. 1 with o-NPOE as plasticizer is
best in terms of working concentration range and detection limit of sensor
assembly. Experimental data indicates that the detection limit of membrane
sensor follows the order of 2.0 x 10-8 (o-NPOE), 1.0 x 10-7
DBP, 1.5 x 10-7 (DBBP), 1.8 x 10-7, 5.6 x 10-7
(CN), 6.4x 10-7 (OA), which is in good agreement with the dielectric
constant of the plasticizers. The addition of lipophilic anions (NaTPB) in
membrane electrodes not only diminishes the ohmic resistance, but also in poor
extraction capacities, increases the sensitivity and selectivity of the
membrane electrodes [25-27].
Figure 2. Calibration curve of citrazine
selective electrodes with different plasticizers
Potentiometric
selectivity
The membrane gives the response towards variety of
target species in solution, although it can be more responsive to the primary
target species than other species. Thus, to assess the performance of an
electrode in presence of other ions, the term ‘selectivity coefficient’ has
been introduced. It shows the ability of the sensor for the preferential uptake
of the determinant ion (primary ion) in the presence of other interfering ions
[28, 29]. In the present study the selectivity coefficients were calculated by
Separate Solution Method (SSM) using equation 1 by keeping the concentration of
citrazine and interfering ions 1.0 x 10-3 M (IUPAC recommendation),
and the results are summered in table 2.
……………………..(1
Where, 
and 
are the activities of
citrazine and interfering ions, 
and 
are their charges
respectively.
Table 2. Selectivity Coefficient values
calculated by SSM method
|
Interfering
Ion
|
Selectivity
Coefficient 
|
|
This
work
(SSM
- method)
|
Reference
No. 20
(SSM
-method)
|
|
Glucose
|
3.42
|
2.14
|
|
Fructose
|
3.44
|
3.42
|
|
Lactose
|
3.32
|
3.26
|
|
Maltose
|
2.83
|
-
|
|
Glycine
|
2.94
|
3.26
|
|
Tyrosine
|
2.51
|
2.48
|
|
Histidine
|
2.34
|
2.12
|
|
Cysteine
|
2.67
|
2.32
|
|
Pyrogallate
|
3.56
|
3.55
|
|
Resorcinolate
|
2.45
|
2.23
|
|
Tartarate
|
2.45
|
-
|
|
Malonate
|
4.3
|
4.3
|
|
Na+
|
5.65
|
5.70
|
|
Al3+
|
4.9
|
-
|
|
K+
|
5.89
|
5.88
|
|
Mg2+
|
5.52
|
5.56
|
The selectivity coefficient of proposed electrode
was also compared with the best previously reported electrode [30, 31]. The
data presented in table 1 clearly indicates the high selectivity of proposed
citrazine selective sensor with o-NPOE as plasticizer. Due to the high
selectivity the sensor based on ionophore 1,3,5-tris[(2,3-dihydroxybenzylamino)
aminomethyl]cyclohexane as ionophore and o-NPOE as plasticizer was chosen for
the further studies.
Response time and life time
The time in which the membrane sensors attain a
static potential is known as response time of the sensor assembly [32 - 35]. In
the present work the static time of the membrane sensor was found to be less
than 10 s for Cityrazine concentration 1.0 x 10-3 M (fig. 3). The
membrane electrode will perform at least around 10 months without any
considerable divergence in potentials. After this period, the slope and
detection limit (always decrease with time) of sensor will decrease or increase
due to loss of plasticizer and/or ion-carrier from the polymeric membrane
resulting in the leaching of the membrane into the aqueous solution (sample) is
the primary reason for the limited life time of the carrier-based sensor [36,
37].
Figure 3. Response time curve for
Citrazine selective sensor
Influence
of pH
The selectivity and sensitivity of PVC based
membrane sensors have been strongly influenced by changing the pH of the test
solution [38, 39]. So it is necessary to study the effect of pH and favorable
working range of pH of the membrane electrode for accurate measurements. In
this study the pH dependence of the electrode potential was tested over the
range 0 – 9 with in the concentration of 1.0×10-3, 1.0×10-4
and 1.0×10-5 M of citrazine solution, and the results are shown in
Fig. 4. The pH of the solutions was adjusted by the addition of acetic acid or hexamine - HCl buffer solution. It is clear from
Fig. 4 that the potentials remain constant in pH range of 2 – 6.5. It might be
due to the doprotonation of citrazine in strongly acidic medium and
deprotonation of citrazine at higher pH.
Figure 4. Effect of pH on Citrazine
selective sensor no. 1
The performance of proposed citrazine selective
electrodes was compared with the previously reported electrodes (Table 3). The
data presented in table 2 indicates the superiority of the proposed electrode
with existing electrodes.
Table
3. Comparison of response characters of roposed electrode with previously
reported electrodes
|
Response
Character
|
This
work
|
Ref.
no. 19
|
Ref.
no. 20
|
|
Concentration
range (M)
|
5.0
x 10-8 – 1.0 x 10-2
|
3.1
x 10-5 – 1.0 x 10-3
|
5.0
x 10-6 – 1.0 x 10-1
|
|
Detection
limit (M)
|
2.0
x 10-8
|
7.0
x 10-5
|
7.0
x 10-7
|
|
Slope
(mV/
decay)
|
61.1
|
66.8
|
60.2
|
|
pH
range
|
2.0
– 6.5
|
1.5
- 2.8
|
2
– 4
|
|
Response
time (sec)
|
10
|
-
|
15
- 30
|
Analytical
applications
The proposed membrane sensor no. 1 was also used for
the determination of citrazine in different pharmcutical samples. The solution
of citrazine was prepared by dissolving a definite amount of citrazine tablet
purchased from local medical stores of Ghaziabad city in 20 mL of acetic acid
buffer solution (pH =3.8). The solution is further diluted up to 50 ml at
constant pH. The 10 mL of dilute solution of each sample was used for the
studies using proposed citrazine selective sensor. The obtained value was
compared with the standard values of drug sample (Table 4).
In addition the proposed electrode sensor was also
used for the potentiometric determination of citrazine in spiked water sample
and human urine sample. The values obtained were quite comparable with the
values obtained by UV-visible spectrophotometry (Table 5), and thus illustrate
the practical utility of the membrane sensor. An aqueous solution of citrazine
(0.1 to 0.0001M) was used to prepare these spiked samples.
Table 5. The values obtained by
UV-visible spectrophotometry
|
Sample
|
Amount
of citrazine
taken
(mg
/mL)
|
Recovered
By
sensor no. 1
|
Recovered
By
UV-Vis
|
Standard
deviation
|
|
Water
sample
|
2.5
5.0
7.5
10
|
2.53
5.13
7.60
10.12
|
2.51
5.12
7.54
10.12
|
1.20
2.60
1.13
1.20
|
|
Urine
sample
|
2.5
5.0
7.5
10
|
2.54
5.10
7.72
10.15
|
2.53
5.12
7.71
10.15
|
1.60
2.00
2.29
1.20
|
CONCLUSION:
In this work we have explain the high selectivity of
PVC based membrane sensor based on 1,3,5-tris[(2,3-dihydroxybenzylamino)
aminomethyl]cyclohexane (L) as ionophore for the potentiometric determination
of citrazine. The effect of various plasticizers on the response characters of
the fabricated sensor was studied. The results indicates the membrane sensor in
the composition of 30% PVC, 66% o-NPOE, 3% ionophore and 1% NaTPB works
satisfactorily within the concentration range of 5.0 x 10-8 – 1.0 x
10-2 M, with detection limit of 2.0 x 10-8 M, and has
fast response time of about 10s. The proposed sensor was used for the selective
determination of citrazine in different synthetic as well as real sample, and
can be used within the pH range of 2.0 – 6.5.
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