# Preparation, Characterization, and Analytical Application of Ramipril Membrane-Based Ion-Selective Electrode

Authors: Hassan Arida; Mona Ahmed; Abdallah Ali
Journal: International Journal of Analytical Chemistry
 (2009)

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## Abstract

The fabrication and electrochemical evaluation of two PVC membrane-based Ion-Selective electrodes responsive for ramipril drug have been proposed. The sensitive membranes were prepared using ramipril-phosphomolibdate and ramipril-tetraphenylborate ion-pair complexes as electroactive sensing materials in plasticized PVC support. The electrodes based on these materials provide near-Nernestian response (sensitivity of53±0.5–54±0.5 mV/concentration decade) covering the concentration range of 1.0×10-2–1.0×10-5 mol L−1 with a detection limit of 3.0×10-6–4.0×10-6 mol L−1. The suggested electrodes have been successfully used in the determination of ramipril drug in some pharmaceutical formulations using direct potentiometry with average recovery of >96% and mean standard deviation of <3% (n=5).


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## Body

## 1. Introduction

Ramipril (see Scheme1) contains not less than
98.0% of C23H32N2O5; (2S,3aS,6aS)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[d]pyrrole-2
carboxylic acid. It belongs in a class of drugs
called angiotensin converting enzyme (ACE) inhibitors which are used for
treating high blood
pressure and heart failure and for
preventing kidney
failure due to high blood pressure and
diabetes. ACE is important because it produces
the protein, angiotensin II. Angiotensin II contracts the muscles of most
arteries in the  body, including the heart, thereby
narrowing the arteries and elevating the blood pressure. In the kidney, the narrowing
caused by angiotensin II also increases blood pressure and decreases the flow
of blood. ACE inhibitors such as ramipril lower blood pressure by reducing the
production of angiotensin II, thereby relaxing the arterial muscles and
enlarging the arteries. The enlargement of the arteries throughout the body
reduces the blood pressure against which the heart must pump blood, and it
becomes easier for the heart to pump blood. The arteries supplying the heart
with blood also enlarge. This increases the flow of blood and oxygen to the
heart, and this improves further the ability of the heart to pump blood. The
effects of ACE inhibitors are particularly beneficial to people with congestive
heart failure. In the kidneys, the
enlargement of the arteries also reduces blood pressure and increases blood
flow.Figure 1
Potentiometric calibration response of ramibril-based selective electrodes.Methods in current use for the assay of ramipril,
in pharmaceutical preparation, are based on spectrophotometry [1–6], liquid
chromatography [7–12], gas chromatography [13, 14], enatioselective biosensors
[15], enatioselective membrane [16], voltammetry [17], amperometric biosensor
[18], and mass spectrometry [12]. However, most of these methods are
sophisticated, tedious, and required many manipulation steps. On the other hand,
although, ion-selective electrodes and potentiometric sensors are much simpler,
fast, and inexpensive, only one ion-selective electrode has been reported for
the determination of ramipril drug as anionic species [19].In this paper, the preparation,
characterization, and analytical application of new two ramipril cationic ion-selective electrodes based on phosphomolibdate and tetraphenylborate-ramipril
ion-pair complexes have been reported. The merits offered by the proposed
electrodes include the high cationic sensitivity of the drug in the acid media
with fast response time (<30 seconds) and long life span (2 months).


## 2. Experimental

### 2.1. Apparatus

The
potentiometric measurements were made at 25  ±  1C°, using an Orin (Model
A720) digital pH/mV meter and Orion Ross Combination pH electrode (Model 81-02)
for all pH measurements. The suggested ramipril PVC membrane-based electrode
was used for all potentiometric measurements in conjunction with a double
junction reference electrode (Orion Model 90-02) containing KNO3 (10% w/v) in the outer compartment. Perkin-Elmer (Norwalk, Conn, USA) 1430 ratio recording IR
spectrophotometer was used for structure elucidation of the ion-pair complexes.


### 2.2. Reagents and Materials

All chemicals were of analytical reagent
grade unless otherwise stated and doubly distilled water was used throughout.
Poly (vinyl chloride) powder (PVC) of high molecular weight (10 000) and dioctyl
phthalate plasticizer of purity 98% were obtained from Aldrich chemical company,
Inc. (Milwaukee, Wis, USA).
Tetrahydrofuran (THF) with a purity of 99% containing 0.025%
butylatedhydroxytoluene inhibitor was used as solvent.Ramipril
stock solution (10−2 mol L−1) was prepared by dissolving 0.4165 g in a minimal
volume of acetic acid with continuous stirring and then diluted to 100 mLLwith
distilled water. The resulting clear solution of pH 3 was obtained by the addition
of small aliquots of 10−2 mol L−1 HCl. Standard phosphomolibdate
and tetraphenylborate solutions (0.2 mol L−1) were individually prepared
by dissolving appropriate weight of sodium phosphomolibdate and tetraphenylborate,
respectively, in a minimum volume of distilled water followed by filtration then
completed to 100 mL with distilled water.


### 2.3. The Ramipril Membrane-Based Ion-Selective Electrodes

Ramipril-phosphomolibdate and ramipril-tetraphenylborate
ion-pair sensing materials were individually prepared by mixing 30 mL aliquot
of 10−2 mol L−1 ramipril solution with a 30 mL aliquot
of 10−2 mol L−1 aqueous phosphomolibdate and tetraphenylborate solutions, respectively in l00 mL beaker. The obtained precipitates were filtered using a G4 sintered
glass crucible, washed thoroughly with distilled water,  and dried at room
temperature.Two
PVC master membranes based on the suggested sensing materials containing 0.01 g ion-pair complex, 0.350 g dioctylphthalate
(DOP), and 0.190 g of poly (vinyl chloride) were individually prepared. Each membrane contents
were thoroughly mixed, dissolved in 6 mL aliquot of THF, and transferred to a
glass Petri dish (3 cm diameter). The Petri dish was covered with a filter paper
and left to stand overnight to allow slow evaporation of the solvent at room
temperature. The membranes were sectioned with a cork borer (10 mm diameter) and attached
to a length of polyethylene tubing (3 cm length, 8 mm i.d) by using THF.A home
-made electrode body was used, which consists of a glass tube, to one end of
which the poly ethylene tubing was attached and filled with an equimolar
mixture of 10−2 mol L−1 of potassium chloride and
ramipril as the internal reference solution. An Ag/AgC1 internal reference wire
electrode (1.0 mm diameter) was immersed in the internal solution. This assembly
was used in the potentiometric characterization of the electrodes and the
subsequent determination of the drug.


### 2.4. Electrochemical Evaluation of the Electrodes

In
order to calibrate the suggested electrodes, aliquots (10 mL) of aqueous
ramipril solutions (1.0× 10−2–1.0 × 10−7 mol L−1)
were transferred into 50 mL beakers, and the PVC membrane electrode, in
conjunction with a double junction Ag/AgCl reference electrode, was immersed in
the solution. Alternatively, the drug PVC membrane electrode in conjunction
with a double junction Ag/AgC1 reference electrode was immersed in a 50 mL
beaker containing a l0 mL aliquot of water. Aliquots (1 mL) of 10−2–10−6 mol L−1 pure drug solution were successively added.
The solutions were gently stirred during the measurements and the potential
recorded after stabilization to ±0.2 mV and the e.m.f plotted on semilogarithmic
paper as a function of the drug concentration. The calibration graphs were used
for subsequent determination of unknown concentration of the drug.The
potentiometric selectivity coefficient indicates the extent to which a foreign
ion B interferes with the response of the electrode to its primary drug ion  A.
The potentiometric selectivity coefficientsKA,Bpot
for the suggested electrodes were measured by
separate solutions method SSM [20]. In this method, the potential responses of
the electrode in 10−2 mol L−1 solution of the
interferents were measured and recorded. The potential response of the
electrode for the drug was separately, obtained in a similar manner at the same
concentration level. The selectivity coefficient values were calculated using
the simplified form of Eisemnan Nicolsky equation:(1)KA,Bpot=E1−E2S+(1−1Z2)loga1, where E1  and E2 are the potential readings of the electrode in separate
solutions of the same concentration of the drug and interferants, respectively,
S is the slope of the drug calibration graph (mV/concentration decade), a1 is the activity of the drug, and  Z2 is the charge number of the
interfering ion.The
effect of pH of the test solution on the potential reading of the suggested
drug electrodes was studied by immersing a Ross combination glass electrode
(Orion model 81-02), PVC membrane electrode, and a double junction Ag/AgC1
reference electrode in 50 mL beakers containing 30 mL aliquots of 10−3 and 10−4 mol L−1 drug solutions. The pH of each solution
was gradually increased and decreased by adding small aliquots of dilute sodium
hydroxide and hydrochloric acid, respectively. The potential at each pH value
was recorded. The mV-pH profile at each drug concentration was plotted for
the two electrode systems.


### 2.5. Analytical Application of the Ramipril Electrodes

In
order to investigate the reliability of the proposed electrodes, they have been
applied in the determination of the drug using direct potentiometry and
potentiometric titration. In the direct potentiometry study, a PVC membrane-based
ramipril electrode in conjunction with a double junction reference electrode
was immersed in a l0 mL of the appropriate drug solutions of unknown
concentration. The potential readings were recorded after stabilization to ±0.2 mV and compared with the calibration graph. The solutions were stirred during
measurements, and the electrodes were thoroughly washed with distilled water
between measurements.In the
potentiometric titration of ramipril, aliquots (2–6 mL) of 10−3 mol
L−1 of ramipril solution were transferred to 50 mL beakers and
diluted to 10 mL with distilled water. The solution was stirred and titrated
with a standard 10−3 mol L−1 sodium tetraphenylborate
solution using the suggested ramipril membrane electrode in conjunction with a
double junction Ag/AgC1 reference electrode. The electrode potential (E) was
recorded as a function of the titrant volume (v) added, (E versus v) curves were
plotted. The end point was calculated from the maximum slope  ΔE/Δv versus
v.Moreover,
different forms and dosages of pharmaceutical preparations were assayed to
determine ramipril in different formulations. In this study, aliquot of  5 mL of
the drug was transferred to 25 mL beaker containing 15 mL of deionised water, and
the pH of the solution was adjusted to pH 3 with a drop of dilute HC1 solution.
The solution was then transferred to 25 mL volumetric flask, completed to the
mark, shaken well, and transferred to a 100 mL beaker for ISE measurement. For
the assay of tablet formulations, 10 tablets were finely powdered, mixed, and an
accurate weight equivalent to 0.1% of the tablet was transferred into 50 mL
beakers containing 20 mL of deionized water, the pH of the solution was
adjusted to pH 3 with a drop of dilute HC1 solution, and transferred to 25 mL
volumetric flask, completed with water to the mark, shaken well. The suggested
ramipril-based membrane electrode was immersed in conjunction with a double
junction Ag/AgC1 reference electrode into the solution. The potential was
measured after a stable reading was obtained and compared with that on a
calibration graph previously constructed for standard solutions.


## 2.1. Apparatus

The
potentiometric measurements were made at 25  ±  1C°, using an Orin (Model
A720) digital pH/mV meter and Orion Ross Combination pH electrode (Model 81-02)
for all pH measurements. The suggested ramipril PVC membrane-based electrode
was used for all potentiometric measurements in conjunction with a double
junction reference electrode (Orion Model 90-02) containing KNO3 (10% w/v) in the outer compartment. Perkin-Elmer (Norwalk, Conn, USA) 1430 ratio recording IR
spectrophotometer was used for structure elucidation of the ion-pair complexes.


## 2.2. Reagents and Materials

All chemicals were of analytical reagent
grade unless otherwise stated and doubly distilled water was used throughout.
Poly (vinyl chloride) powder (PVC) of high molecular weight (10 000) and dioctyl
phthalate plasticizer of purity 98% were obtained from Aldrich chemical company,
Inc. (Milwaukee, Wis, USA).
Tetrahydrofuran (THF) with a purity of 99% containing 0.025%
butylatedhydroxytoluene inhibitor was used as solvent.Ramipril
stock solution (10−2 mol L−1) was prepared by dissolving 0.4165 g in a minimal
volume of acetic acid with continuous stirring and then diluted to 100 mLLwith
distilled water. The resulting clear solution of pH 3 was obtained by the addition
of small aliquots of 10−2 mol L−1 HCl. Standard phosphomolibdate
and tetraphenylborate solutions (0.2 mol L−1) were individually prepared
by dissolving appropriate weight of sodium phosphomolibdate and tetraphenylborate,
respectively, in a minimum volume of distilled water followed by filtration then
completed to 100 mL with distilled water.


## 2.3. The Ramipril Membrane-Based Ion-Selective Electrodes

Ramipril-phosphomolibdate and ramipril-tetraphenylborate
ion-pair sensing materials were individually prepared by mixing 30 mL aliquot
of 10−2 mol L−1 ramipril solution with a 30 mL aliquot
of 10−2 mol L−1 aqueous phosphomolibdate and tetraphenylborate solutions, respectively in l00 mL beaker. The obtained precipitates were filtered using a G4 sintered
glass crucible, washed thoroughly with distilled water,  and dried at room
temperature.Two
PVC master membranes based on the suggested sensing materials containing 0.01 g ion-pair complex, 0.350 g dioctylphthalate
(DOP), and 0.190 g of poly (vinyl chloride) were individually prepared. Each membrane contents
were thoroughly mixed, dissolved in 6 mL aliquot of THF, and transferred to a
glass Petri dish (3 cm diameter). The Petri dish was covered with a filter paper
and left to stand overnight to allow slow evaporation of the solvent at room
temperature. The membranes were sectioned with a cork borer (10 mm diameter) and attached
to a length of polyethylene tubing (3 cm length, 8 mm i.d) by using THF.A home
-made electrode body was used, which consists of a glass tube, to one end of
which the poly ethylene tubing was attached and filled with an equimolar
mixture of 10−2 mol L−1 of potassium chloride and
ramipril as the internal reference solution. An Ag/AgC1 internal reference wire
electrode (1.0 mm diameter) was immersed in the internal solution. This assembly
was used in the potentiometric characterization of the electrodes and the
subsequent determination of the drug.


## 2.4. Electrochemical Evaluation of the Electrodes

In
order to calibrate the suggested electrodes, aliquots (10 mL) of aqueous
ramipril solutions (1.0× 10−2–1.0 × 10−7 mol L−1)
were transferred into 50 mL beakers, and the PVC membrane electrode, in
conjunction with a double junction Ag/AgCl reference electrode, was immersed in
the solution. Alternatively, the drug PVC membrane electrode in conjunction
with a double junction Ag/AgC1 reference electrode was immersed in a 50 mL
beaker containing a l0 mL aliquot of water. Aliquots (1 mL) of 10−2–10−6 mol L−1 pure drug solution were successively added.
The solutions were gently stirred during the measurements and the potential
recorded after stabilization to ±0.2 mV and the e.m.f plotted on semilogarithmic
paper as a function of the drug concentration. The calibration graphs were used
for subsequent determination of unknown concentration of the drug.The
potentiometric selectivity coefficient indicates the extent to which a foreign
ion B interferes with the response of the electrode to its primary drug ion  A.
The potentiometric selectivity coefficientsKA,Bpot
for the suggested electrodes were measured by
separate solutions method SSM [20]. In this method, the potential responses of
the electrode in 10−2 mol L−1 solution of the
interferents were measured and recorded. The potential response of the
electrode for the drug was separately, obtained in a similar manner at the same
concentration level. The selectivity coefficient values were calculated using
the simplified form of Eisemnan Nicolsky equation:(1)KA,Bpot=E1−E2S+(1−1Z2)loga1, where E1  and E2 are the potential readings of the electrode in separate
solutions of the same concentration of the drug and interferants, respectively,
S is the slope of the drug calibration graph (mV/concentration decade), a1 is the activity of the drug, and  Z2 is the charge number of the
interfering ion.The
effect of pH of the test solution on the potential reading of the suggested
drug electrodes was studied by immersing a Ross combination glass electrode
(Orion model 81-02), PVC membrane electrode, and a double junction Ag/AgC1
reference electrode in 50 mL beakers containing 30 mL aliquots of 10−3 and 10−4 mol L−1 drug solutions. The pH of each solution
was gradually increased and decreased by adding small aliquots of dilute sodium
hydroxide and hydrochloric acid, respectively. The potential at each pH value
was recorded. The mV-pH profile at each drug concentration was plotted for
the two electrode systems.


## 2.5. Analytical Application of the Ramipril Electrodes

In
order to investigate the reliability of the proposed electrodes, they have been
applied in the determination of the drug using direct potentiometry and
potentiometric titration. In the direct potentiometry study, a PVC membrane-based
ramipril electrode in conjunction with a double junction reference electrode
was immersed in a l0 mL of the appropriate drug solutions of unknown
concentration. The potential readings were recorded after stabilization to ±0.2 mV and compared with the calibration graph. The solutions were stirred during
measurements, and the electrodes were thoroughly washed with distilled water
between measurements.In the
potentiometric titration of ramipril, aliquots (2–6 mL) of 10−3 mol
L−1 of ramipril solution were transferred to 50 mL beakers and
diluted to 10 mL with distilled water. The solution was stirred and titrated
with a standard 10−3 mol L−1 sodium tetraphenylborate
solution using the suggested ramipril membrane electrode in conjunction with a
double junction Ag/AgC1 reference electrode. The electrode potential (E) was
recorded as a function of the titrant volume (v) added, (E versus v) curves were
plotted. The end point was calculated from the maximum slope  ΔE/Δv versus
v.Moreover,
different forms and dosages of pharmaceutical preparations were assayed to
determine ramipril in different formulations. In this study, aliquot of  5 mL of
the drug was transferred to 25 mL beaker containing 15 mL of deionised water, and
the pH of the solution was adjusted to pH 3 with a drop of dilute HC1 solution.
The solution was then transferred to 25 mL volumetric flask, completed to the
mark, shaken well, and transferred to a 100 mL beaker for ISE measurement. For
the assay of tablet formulations, 10 tablets were finely powdered, mixed, and an
accurate weight equivalent to 0.1% of the tablet was transferred into 50 mL
beakers containing 20 mL of deionized water, the pH of the solution was
adjusted to pH 3 with a drop of dilute HC1 solution, and transferred to 25 mL
volumetric flask, completed with water to the mark, shaken well. The suggested
ramipril-based membrane electrode was immersed in conjunction with a double
junction Ag/AgC1 reference electrode into the solution. The potential was
measured after a stable reading was obtained and compared with that on a
calibration graph previously constructed for standard solutions.


## 3. Results and Discussion

### 3.1. The Nature and Composition of Ramipril-Based Membranes

Ramipril—phosphomolibdate and ramipril—tetraphenylborate ion-pair complexes have been
prepared and examined as new electroactive ionophores in PVC matrix membranes
responsive to ramipril cation. In acid media, ramipril cations readily react
with phosphomolibdate and tetraphenylborate anions to form stable water insoluble
ion association complexes. The IR studies confirm that the formation of 1:1
ramipril:anion ion-pair association. The potentiometric response
characteristics of the proposed electrodes were evaluated, according to IUPAC
recommendations [20] using the following electrochemical cell:Ag/AgCl|10−2molL−1KC110−2molL−1ramipril|PVCmembrane||Ramipriltestsolution||10%KC1|AgC1/Ag


### 3.2. Electrochemical Evaluation of Ramipril Electrodes

The potentiometric
response characteristics of the investigated ramipril PVC membrane-based electrodes
were evaluated from the data collected from four assemblies for each membrane
electrode. The results are summarized in (Table1). The responses of ramipril
electrode systems are linear over the concentration range 1 × 10−2–1 × 10−5 mol L−1. The slopes
of the calibration plots (Figure 1) are typically 53 ± 0.5 mV and 54 ± 0.5 per concentration decade for ramipril—phosphomolibdate
and ramipril—tetraphenyle
borate membrane electrode, respectively. Deviation from the ideal Nernstian
slope (59.2 mV/concentration
decade) stems from the fact that most potentiometric drug sensors respond to
the activity of the drug cations rather than the concentration.Table 1
Response characteristics of ramipril membrane-based
selective electrodes.
ParameterRamiprilRamiprilphosphomolibdatetetraphenylborateSlope, mV/decade53 ± 0.554 ± 0.5Linear range, mol L−11×  10−2–1 × 10−51× 10−2–1 ×  10−5Lower limit of detection,4.0× 10−63.0×  10−6mol L−1Response time, (s)<20<15Life time, (d)6050Working pH range1–3.81–4The response time and stability of the membranes have been
investigated. In these studies, the
time required for ramipril poly (vinyl chloride) membrane electrodes to reach a
value of ±1 mV from the final equilibrium potential in the same day after
successive immersion in different ramipril solutions was measured. The results
obtained (Figure2) show thats the electrode attain stable potential values
within 20 seconds. In addition, the potentials displayed by the electrode in
the linear concentration range of ramipril in the same day do not vary by more
than ±0.5 mV. The stability of the potential reading for the ramipril-based
electrodes is within ±2 mV during the lifetime (2 months) of the electrodes.Figure 2
Potentiometric dynamic response of ramipril-phosphomolibdate membrane electrode.The
effect of pH on the potential readings of the proposed electrode was also examined
by recording the e.m.f. of ramipril test solutions (10−3 and  10−4 mol L−1) at various pH values, which were obtained by the addition
of very small volumes of hydrochloric acid and/or sodium hydroxide solutions 10−1 mol/L of each. The e.m.f. -pH plots presented in Figures 3 and 4 revealed that
the potential readings are insensitive to pH changes in the ranges 1.0–3.8 and 1.0–4.0 for the
ramipril-phosphomolibdate and ramipeil-tetraphenylborate, respectively. The shape of mV-pH profile depends
on the stability of the ion-pair in the membrane as a function of pH, the
nature of the drug (protonation or complexation equilibrium) in the test
solution, and the sensitivity of the membrane to either [H+] or  [OH−]
at low or high pH values, respectively. It was observed that ramipril ion-pair
complexes deteriorate in alkaline media causing severe potential shift. At relatively
higher pH values, the e.m.f decreased this is probably due to deprotonated
species in test solution.Figure 3
Effect of pH on the potentiometric response of ramipril-phosphomolibdate
PVC membrane electrode.Figure 4
Effect of pH on the potentiometric response of the ramipril-tetraphenylborate PVC membrane electrode.The
selectivity coefficients of the investigated electrodes were evaluated using
separate solution method (SSM). In this study, the performance of the ramipril
electrodes in the presence of some tested organic and inorganic cations was studied.
The selectivity coefficient values (KA,Bpot) are calculated and presented in Table
2. As can be seen, the electrode offers a reasonable selectivity for the ramipril
cation over most of the tested species.Table 2
Potentiometric
selectivity coefficients (KA,Bpot) for the ramipril phosphomolibdate and
ramipril-tetraphenylborate selective electrodes.
Interfering species, BRamipril-phosphomolibdateRamipril-tetraphenylborateelectrodeelectrodeRamipril11NH4+8.8×  10−39.1×  10−3Co2+8.7× 10−38.8× 10−3Cd2+8.8× 10−38.7× 10−3Ni2+8.8× 10−38.7× 10−3Cr3+4.2× 10−24.3× 10−2Cu2+6.6× 10−39.0× 10−3Ca2+4.6× 10−34.8× 10−3Mg2+9.8× 10−39.8× 10−3Sn2+5.1× 10−25.3× 10−2K+8.8× 10−38.6× 10−3Na+8.1× 10−38.5× 10−3Fe3+8.8× 10−38.8× 10−3Glycine7.8× 10−38.1× 10−3Phenyl hydrazine3.2× 10−23.2× 10−2Hydroxylamine2.2× 10−22.7× 10−2


### 3.3. Analytical Application of Ramipril Electrodes

In order to investigate the analytical usefulness of the
proposed electrodes, they have been successfully applied in the potentiometer
determination of ramipril in aqueous samples as well as in some local pharmaceutical
formulations. In the former study, solutions of concentration in the liner
range of the tested electrode are prepared from pharmaceutical grade of
ramipril and determined by direct potentiometry and potentiometric titration
using the proposed ramipril electrodes. The
results obtained are summarized in Table3. In the later study, some local
pharmaceutical formulations have been prepared and analyzed by direct
potentiometry using the investigated ramipril electrodes. The results obtained
are summarized in Table 4. As can be seen, the two electrodes provide a good
accuracy (average recovery >96%) and high
precision (RSD <3%, n = 5) in both studies.Table 3
The accuracy and reliability of
result obtained with ramipril PVC matrix membrane electrode.
SampleConcentration, mol L−1Ramipril-phosphomolibdateRamipril-teraphenylborateFoundRecovery %FoundRecovery %11×   10−30.95× 10−395.00.95× 10−395.022× 10−31.87× 10−393.51.90×
10−395.033× 10−32.91× 10−397.02.92×
10−397.344× 10−33.94× 10−398.53.94×
10−398.555× 10−34.98× 10−399.64.93×
10−398.6Averagere covery96.796.9Table 4
Determination of ramipril in some pharmaceutical
preparations.
Sample(a)Nominal content mg/tabletRamipril-phosphomolibdateRamipril-teraphenylborateFoundRecovery
%FoundRecovery
%11.251.2398.41.2499.222.502.4397.22.4698.435.04.9599.04.9599.0Average recovery98.298.8D(a)ifferent pharmaceutical formulations (tritace;
aventis).


## 3.1. The Nature and Composition of Ramipril-Based Membranes

Ramipril—phosphomolibdate and ramipril—tetraphenylborate ion-pair complexes have been
prepared and examined as new electroactive ionophores in PVC matrix membranes
responsive to ramipril cation. In acid media, ramipril cations readily react
with phosphomolibdate and tetraphenylborate anions to form stable water insoluble
ion association complexes. The IR studies confirm that the formation of 1:1
ramipril:anion ion-pair association. The potentiometric response
characteristics of the proposed electrodes were evaluated, according to IUPAC
recommendations [20] using the following electrochemical cell:Ag/AgCl|10−2molL−1KC110−2molL−1ramipril|PVCmembrane||Ramipriltestsolution||10%KC1|AgC1/Ag


## 3.2. Electrochemical Evaluation of Ramipril Electrodes

The potentiometric
response characteristics of the investigated ramipril PVC membrane-based electrodes
were evaluated from the data collected from four assemblies for each membrane
electrode. The results are summarized in (Table1). The responses of ramipril
electrode systems are linear over the concentration range 1 × 10−2–1 × 10−5 mol L−1. The slopes
of the calibration plots (Figure 1) are typically 53 ± 0.5 mV and 54 ± 0.5 per concentration decade for ramipril—phosphomolibdate
and ramipril—tetraphenyle
borate membrane electrode, respectively. Deviation from the ideal Nernstian
slope (59.2 mV/concentration
decade) stems from the fact that most potentiometric drug sensors respond to
the activity of the drug cations rather than the concentration.Table 1
Response characteristics of ramipril membrane-based
selective electrodes.
ParameterRamiprilRamiprilphosphomolibdatetetraphenylborateSlope, mV/decade53 ± 0.554 ± 0.5Linear range, mol L−11×  10−2–1 × 10−51× 10−2–1 ×  10−5Lower limit of detection,4.0× 10−63.0×  10−6mol L−1Response time, (s)<20<15Life time, (d)6050Working pH range1–3.81–4The response time and stability of the membranes have been
investigated. In these studies, the
time required for ramipril poly (vinyl chloride) membrane electrodes to reach a
value of ±1 mV from the final equilibrium potential in the same day after
successive immersion in different ramipril solutions was measured. The results
obtained (Figure2) show thats the electrode attain stable potential values
within 20 seconds. In addition, the potentials displayed by the electrode in
the linear concentration range of ramipril in the same day do not vary by more
than ±0.5 mV. The stability of the potential reading for the ramipril-based
electrodes is within ±2 mV during the lifetime (2 months) of the electrodes.Figure 2
Potentiometric dynamic response of ramipril-phosphomolibdate membrane electrode.The
effect of pH on the potential readings of the proposed electrode was also examined
by recording the e.m.f. of ramipril test solutions (10−3 and  10−4 mol L−1) at various pH values, which were obtained by the addition
of very small volumes of hydrochloric acid and/or sodium hydroxide solutions 10−1 mol/L of each. The e.m.f. -pH plots presented in Figures 3 and 4 revealed that
the potential readings are insensitive to pH changes in the ranges 1.0–3.8 and 1.0–4.0 for the
ramipril-phosphomolibdate and ramipeil-tetraphenylborate, respectively. The shape of mV-pH profile depends
on the stability of the ion-pair in the membrane as a function of pH, the
nature of the drug (protonation or complexation equilibrium) in the test
solution, and the sensitivity of the membrane to either [H+] or  [OH−]
at low or high pH values, respectively. It was observed that ramipril ion-pair
complexes deteriorate in alkaline media causing severe potential shift. At relatively
higher pH values, the e.m.f decreased this is probably due to deprotonated
species in test solution.Figure 3
Effect of pH on the potentiometric response of ramipril-phosphomolibdate
PVC membrane electrode.Figure 4
Effect of pH on the potentiometric response of the ramipril-tetraphenylborate PVC membrane electrode.The
selectivity coefficients of the investigated electrodes were evaluated using
separate solution method (SSM). In this study, the performance of the ramipril
electrodes in the presence of some tested organic and inorganic cations was studied.
The selectivity coefficient values (KA,Bpot) are calculated and presented in Table
2. As can be seen, the electrode offers a reasonable selectivity for the ramipril
cation over most of the tested species.Table 2
Potentiometric
selectivity coefficients (KA,Bpot) for the ramipril phosphomolibdate and
ramipril-tetraphenylborate selective electrodes.
Interfering species, BRamipril-phosphomolibdateRamipril-tetraphenylborateelectrodeelectrodeRamipril11NH4+8.8×  10−39.1×  10−3Co2+8.7× 10−38.8× 10−3Cd2+8.8× 10−38.7× 10−3Ni2+8.8× 10−38.7× 10−3Cr3+4.2× 10−24.3× 10−2Cu2+6.6× 10−39.0× 10−3Ca2+4.6× 10−34.8× 10−3Mg2+9.8× 10−39.8× 10−3Sn2+5.1× 10−25.3× 10−2K+8.8× 10−38.6× 10−3Na+8.1× 10−38.5× 10−3Fe3+8.8× 10−38.8× 10−3Glycine7.8× 10−38.1× 10−3Phenyl hydrazine3.2× 10−23.2× 10−2Hydroxylamine2.2× 10−22.7× 10−2


## 3.3. Analytical Application of Ramipril Electrodes

In order to investigate the analytical usefulness of the
proposed electrodes, they have been successfully applied in the potentiometer
determination of ramipril in aqueous samples as well as in some local pharmaceutical
formulations. In the former study, solutions of concentration in the liner
range of the tested electrode are prepared from pharmaceutical grade of
ramipril and determined by direct potentiometry and potentiometric titration
using the proposed ramipril electrodes. The
results obtained are summarized in Table3. In the later study, some local
pharmaceutical formulations have been prepared and analyzed by direct
potentiometry using the investigated ramipril electrodes. The results obtained
are summarized in Table 4. As can be seen, the two electrodes provide a good
accuracy (average recovery >96%) and high
precision (RSD <3%, n = 5) in both studies.Table 3
The accuracy and reliability of
result obtained with ramipril PVC matrix membrane electrode.
SampleConcentration, mol L−1Ramipril-phosphomolibdateRamipril-teraphenylborateFoundRecovery %FoundRecovery %11×   10−30.95× 10−395.00.95× 10−395.022× 10−31.87× 10−393.51.90×
10−395.033× 10−32.91× 10−397.02.92×
10−397.344× 10−33.94× 10−398.53.94×
10−398.555× 10−34.98× 10−399.64.93×
10−398.6Averagere covery96.796.9Table 4
Determination of ramipril in some pharmaceutical
preparations.
Sample(a)Nominal content mg/tabletRamipril-phosphomolibdateRamipril-teraphenylborateFoundRecovery
%FoundRecovery
%11.251.2398.41.2499.222.502.4397.22.4698.435.04.9599.04.9599.0Average recovery98.298.8D(a)ifferent pharmaceutical formulations (tritace;
aventis).


## 4. Conclusion

Two ramipril selective
electrodes have been prepared and electrochemicaly evaluated. They provide
analytical, useful sensitivity to the drug with fast response time, reliable, and
reproducible response. The proposed electrodes have been successfully applied
in the determination of ramipril in some pharmaceutical formulations with good
accuracy and high precision.Scheme 1
Structure of ramipril.



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*Source: 954083-2009-04-06.xml*