Determination of Some Beta Using Different Spectroscopic and Electrochemical Techniques

A Thesis Presented by Marwa Mohamed Abdelmonem Sakr B. Pharm. Sci. (2002) Faculty of Pharmacy, Helwan University M. Pharm. Sci. (2010) Faculty of Pharmacy and Biotechnology, German University in Cairo Submitted for The Degree of Doctor of Philosophy in Pharmaceutical Sciences (Pharmaceutical Chemistry)

Supervised by Professor Dr. Samir Mohamed El-Moghazy Professor of Pharmaceutical Chemistry Faculty of Pharmacy Cairo University Professor Dr.Hala Sultan Al-Easa Professor of Organic Chemistry Faculty of Arts and Sciences Qatar University Dr.Marwa Ahmed Fouad Associate Professor of Pharmaceutical Chemistry Faculty of Pharmacy Cairo University Dr.Rasha Sayed Hanafi Associate Professor of Pharmaceutical Chemistry Faculty of Pharmacy and Biotechnology German University in Cairo

Faculty of Pharmacy Cairo University 2018 Abstract CHAPTER ONE I. INTRODUCTION In this section, a detailed description of three fluoroquinolones and their types as well as their pharmacological mode of action is defined.. CHAPTER TWO II. LITTERATURE SURVEY It delineates the chemical and physical characteristics, pharmacological actions as well as the techniques of analysis that were previously reported for the determination of norfloxacin, levofloxacin and lomefloxacin. CHAPTER THREE III. EXPERIMENTAL, RESULTS, DISCUSSIONS AND CONCLUSIVE REMARKS III.I. Spectrophotometry III.I.A. Spectrophotometry Experimental It encompasses the materials, reagents, instruments, software used as well as the experimental techniques applied. III.I.B. Spectrophotometry Results and Discussions The interaction of the three fluoroquinlones with lanthanides based on the antenna effect theory was verified and spectrofluorimetrically. III.I.C. Spectrophotometry Conclusive Remarks It entitles a general outline about results obtained in the spectrofluorimetry section. III.II. Spectrofluorimetry III.II.A. Spectrofluorimetry Experimental It includes the materials, reagents, instruments, software used as well as the experimental techniques instigated. III.II.B. Spectrofluorimetry Results and Discussions This section provides a comprehensive enlightenment about the obtained chemometric determination of the spectrophotometrically analyzed complexes. III.II.C. Spectrofluorimetry Conclusive Remarks It provides a general conclusion on the results obtained in the spectrophotometric section. III.III. Potentiometry III.III.A. Potentiometry experimental It presents the materials, reagents and instruments as well as the experimental techniques applied for the determination of norfloxacin, levofloxacin and lomefloxacin III.III.B. Potentiometry Results and discussion Electrodes were prepared and investigated for norfloxacin, levofloxacin and lomefloxacin based on the incorporation of the Tetraphenyl borate (TPB) as an ion- exchanger in PVC matrix using DOP as plasticizer III.III.C. Potentiometry Conclusive Remarks This section ends with a conclusion on the obtained potentiometric results. The thesis ends with 416 references that were of great help to the authoress.

INTRODUCTION

Adrenergic drug agonists

Adrenergic drugs are crucial sympathomimetic agents that serve as analogues of epinephrine (), (noradrenaline) and hormones secreted by the adrenal gland. They resemble these hormones not only in terms of pharmacological actions but also due to their possession of the vital catecholamine functional group. The term adrenergic literally means closely associated with adrenaline (epinephrine) and/or noradrenaline (norepinephrine) .

The principle role of the stated hormones is to adapt the body to stressful conditions . When circulating in the blood, their half-life lasts for few minutes, after which they are metabolized either by catechol-O-methyl transferases or by monoamine oxidase .In other words, the pharmacological impacts exhibited by adrenergic drug agonists contributes to the effectual activation of adrenergic receptors.

Adrenergic receptors are divided into two categories α and β (α1, α2, β1, and β2 receptors) by which adrenergic drugs exert their pivotal effects. α –receptors are mainly activated by norepinephrine while β receptors are primarily activated by epinephrine, however epinephrine may also activate α receptors.

Adrenergic drug agonists are divided into three classes: direct acting, indirect acting, and dual acting .

I.II. Classification of β – Adrenergic drug agonists

I.II.A. β1-Receptor activating drugs Due to their prevalence in the heart muscle and kidney, β1- are largely associated with the conducting system (e.g., pacemaker) and the ventricular musculature. They are also abundant in sweat and salivary glands. Epinephrine or norepinephrine cause excitatory responses in these tissues. Activation of β1 receptors in the heart has a positive inotropic effect leading to an increase in the force of contraction, thus improving cardiac performance.

I.II.B. β2 –Receptor activating drugs

β2 Receptors are mostly present in bronchial smooth muscle and blood vessels of skeletal muscle. They can also be found in arterioles, heart, lung, uterus, and liver.

Therapeutic applications of β2 stimulation are restricted to the lungs and the uterus.

The key role of β2-adrenergic drug agonists, is to cause smooth muscle relaxation in the lung promoting bronchodilation , thus relieving or preventing attacks. Accordingly, these drugs serve as suitable candidates for the treatment of bronchial asthma, chronic bronchitis, emphysema and in cases of premature labor for relaxing uterine smooth muscle. An example of a β2-receptor activating drug is hexoprenaline

Trivalent Lanthanides and Lanthanide-catecholamine complexes

Owing to their extraordinarily high sensitivity and selectivity , as reported by literature, lanthanide III metals were known to play fundamental roles as luminescent probes in many pharmaceutical and bioanalytical applications. Lanthanide-sensitized luminescence present wide Stokes shift , narrow emission bands along with extended luminescence lifetimes . Owing to their strong emission peaks (<10 nm full width at half-maximum) in the visible and near-infrared region under UV excitation , lanthanide complexes’ luminescence has gained a lot of attention in the past decade . Attributable to their photo-transfiguration properties, these complexes are also pertinent in many other diverse fields . Aim of work

Applying a multivariate approach, a chemometric-assisted spectrofluorimetric and spectrophotometric techniques were executed for the determination of (DOB), Hexoprenaline (HEX) and (ISO) catecholamine drugs in their pure and pharmaceutical dosage forms. Predicated on the existent “antenna” interaction between the catecholamine drugs and the designated lanthanide metals, nine new chemosensors were modeled for the analysis. Lanthanum, Samarium and Terbium metals were selected for the attainment of the designated models through their complexation reactions with DOB, HEX and ISO. Four continuous factors were screened namely, reaction time (RT), metal volume (MV), temperature (T) and pH by aid of Plackett-Burman Design. Optimization for the screened factors was carried out by means of Box-Behnken Design and Central Composite Design for spectrofluorimetric and spectrophotometric techniques, respectively.

The present work also aimed to offer three new ion-selective electrodes of the plastic membrane type for the determination of dobutamine hydrochloride (DOB), hexoprenaline sulphate (HEX) and isoprenaline hydrochloride (ISO) in pure and pharmaceutical dosage forms. These electrodes depend mainly on the incorporation of the ion- exchangers of the above mentioned drugs with phosphomolybdic acid (PMA) in a PVC matrix. Electrodes’ performance characteristics were tested by investigating the effects of membrane composition, soaking, temperature and pH. Selectivity of the three electrodes towards their respective ions was also examined in presence of various cations and sugars.

Review Spectrofluorimetric Analysis Spectral characteristics

Using the spectrofluorimetric technique, maximum fluorescence intensity was detected for the formed complexes. Ln complexes were produced at λex/λem= 312 /455 for DOB-Ln, 310/455 for HEX-Ln and 315/455 for ISO-Ln. For Sm, complexes were obtained at λex/λem= 312 /450 for DOB-Sm, 310/450 for HEX-Sm and 315/450 for ISO-Sm. Tb complexes were produced at λex/λem= 312 /550 for DOB-Tb, 310/550 for HEX-Tb and 315/550 for ISO-Tb. Thus, signifying the antenna effect phenomena through interaction between the catecholamine ligands and the three lanthanides [396]. In order to avoid direct excitation of lanthanide metals, it is worth noting that excitation peaks were carefully chosen at these given wavelengths. Figs. 6-8 demonstrates the excitation and emission spectra for the three blank catecholamines and their spectra after complexation with Ln3+, Sm3+, Tb3+, respectively.

Experimental Designs Screening step using Plackett-Burman Design (PBD) In the current work, four chief factors were studied by using a Plackett-Burman Design (PBD) with the aim of constructing the design and screening a set of experiments [87].The design included two levels for each factor with their upper (+) and lower (-) limits being adjusted. Examination of the four factors, namely reaction time (RT), metal volume (MV), temperature (T) and pH for DOB, HEX and ISO lanthanide complexes was carried out and the resultant responses were measured as maximum fluorescence intensity for each model. It’s worth noting, that the selection of the experimental factors was based on literature review as these factors were known to might affect the responses of the proposed models. This design was customized to comprise 16 runs and 4 added central points. The design analyzes the input data, and hence determines the substantial factors exhibiting significant effects on the anticipated responses. Based on the Pareto chart, an assessing quality tool and analysis of variance (ANOVA) testing at 95% confidence, only factors which proved significant post-screening, were considered for further analysis in the optimization phase. Optimization step using Box-Behnken design (BBD) Factors found to be significant in the screening phase were fine tuned to encompass tighter ranges using a BBD. One of the superlative assets of this design is its independent scrutiny of data, and hence being uninfluenced by the preliminary proposals derived from the screening phase. Two tables were elucidated according to the results obtained from PBD; three factors (15 experiments) and four-factors (31 experiments) optimization tables. To sum up, upper and lower limits for each factor of the proposed models were tailored as follows: RT was tested from 0-15 min, MV from 0.1 -0.5 mL, while pH was kept between 5.00 to 7.00. For temperature whenever significant (four-factors optimization table) was tested in the range between 25 to 40. UV-Visible Spectrophotometric Analysis Spectral characteristics

The proposed procedure for the designated models is principally dependent on the complexation reaction between the drug moiety(ligand) and lanthanide (metal) where maximum absorbance of the formed complexes was attained at λ=299, 298, and 295 for DOB, HEX and ISO complexes. The absorption spectra for the three blank catecholamines before and after their complexation with Ln, Sm, Tb, respectively, is illustrated by Figs. 51-53. Experimental Designs Screening step using Plackett-Burman Design (PBD) A Plackett-Burman Design (PBD) was exploited for designing the layout and scanning a set of experiments. Four main variables were selected for the analysis. Factorial upper (+) and lower (-) limits of the two leveled design were adjusted for each variable. Examination of the four factors, namely reaction time (RT), metal volume (MV), temperature (T) and pH for DOB, HEX and ISO lanthanide complexes was carried out and the resultant responses were measured as maximum absorbance for each of the proposed complexes. The selection of the experimental variables, that were believed to exhibit probable influence on the anticipated responses was cited from literature. This design included 16 runs with 4 added central points. Upon implementing this design, determination of significant variables and their impacts on the anticipated responses was achieved. Consequently, and according to the results attained by mean of Pareto charts as well as analysis of variance (ANOVA) testing at 95% confidence, only significant variables were fine-tuned for further assay at the optimization level. Optimization step using Central-Composite design (CCD) Levels of variables that were proved significant post-screening were tailored to comprise narrower ranges that satisfies the experimental specifications. A central composite design was employed for this purpose. According to the experimental results, Tables obtained from CCD were constructed to include; three factors (20 experiments). Overall, Upper and lower limits for each variable of the designated models were tuned as follows: RT was tested from 5-20 min, MV was examined from 0.15 -0.5 mL, while pH was kept between 5.00 to 7.00 For temperature whenever significant (four-factors optimization table) was tested in the range between 25 to 40. Potentiometric Analysis

Preparation of the Ion-Exchanger

The ion-exchangers dobutamine phosphomolybdate, (DOB-PMA) , hexoprenaline phosphomolybdate (HEX-PMA) and isoprenaline phosphomolybdate (ISO-PMA) were prepared by the addition of 150 ml of 1.0x10-2M DOB, HEX and ISO drug solution to 50 mL of 1.0x10-2M of phosphomolybdic acid (PMA).

The resulting precipitates were left in contact with their mother liquor overnight to assure complete coagulation, filtered and washed with DDW, and left to dry at room temperature for at least 48 hrs. The formation and purity of ion- exchangers (DOB-PMA, HEX-PMA and ISO-PMA) were checked by elemental analysis for carbon, hydrogen, nitrogen at the Organic Microanalysis Section, National Research Center, Cairo as shown in table 32.

Preparation of Membranes

Membranes of different compositions were prepared for DOB-PMA, HEX- PMA and ISO-PMA by mixing the required amounts of ion-exchangers, PVC and plasticizers , namely, DOP, DBS (on testing effect of plasticizers) of total weight 0.35 g in a 5.0 cm (diameter) Petri-dish containing 10mL tetrahydrofuran (THF).

To obtain homogeneous and uniform thickness, the amount of solvent was kept constant and the membranes were left covered to dry in air (not less than 48 hr).

Factors affecting the performance characteristics of the Electrodes

Effect of Plasticizer on the Performance Characteristics of the Electrodes The performance characteristics of DOB-PMA, HEX-PMA and ISO-PMA membrane sensors was studied by using two different plasticizers exhibiting different physical properties, namely, Dioctyl phthalate (DOP) and Dibutyl sebacate (DBS) with plasticizer to PVC ratio 1:1.

Effect of Soaking

The investigated electrodes, DOB-PMA, HEX-PMA and ISO-PMA were soaked in 1.0x10-3M of their corresponding drug solution at 25±1°C. A calibration graph was constructed for each electrode after different time intervals until the slope of the calibration graph deviated largely from the Nernstian value and the electrode become out of use.

Effect of Temperature on the Electrode Potential

To study the thermal stability of DOB-PMA, HEX-PMA and ISO-PMA electrodes, calibration graphs were constructed at different test solution temperatures covering the range of 25-60°C. Heating was carried out by means of a circulating thermostat. The slope, usable concentration range and response time of the electrodes corresponding to each temperature were reported.

Effect of pH on the Electrode Potential

For measurements obtained in this section, the effect of pH of the test solution on the potential values of DOB-PMA, HEX-PMA and ISO-PMA electrodes in solutions of different concentrations containing (1.0x10-4, 1.0x10-3 and 1.0x10-2M) of DOB, HEX and ISO was studied. Aliquots of each drug (50 ml) were used and the pH of the solutions was varied within the range 1.00-14.00. The variation in potential with pH change was followed by the addition of small volumes of HCl and/or NaOH solution (0.1- 1.0 M of each). The potential was recorded and thus the potential-pH curves were constructed.

Analytical applications

For the determination of DOB, HEX and ISO in pure powder and pharmaceutical dosage forms, the standard additions method was instigated [414], in which a known incremental change is made through the addition of standard solution of the sample. This was achieved by adding known volumes of DOB, HEX and ISO 1.0x10-2M to 50 ml DDW containing different amounts of each drug in its pure state and in its corresponding pharmaceutical preparation Dobier® ampoules (250mg /5mL), Gynipral® tablets (0.5 mg) and Isuprel® ampoules( 0.2mg/mL). The change in mV reading was recorded for each increment and used to calculate the concentration of each drug in sample solution using the following equation:

n(E ) VS S VX 1 CX  CS ( )[10  ] VX VS VS VX

Summary

This thesis outlines the determination of three catecholamine drugs, namely, Dobutamine, Hexoprenaline and Isoprenaline upon employing three different techniques. This is achieved by means of two different approaches. First, is interaction of the examined drugs with three selected lanthanides, namely, samarium, terbium and lanthanum and chemometrically detecting the formed complexes by spectrofluorimetric and spectrophotometric techniques. This methodology implements a multivariate strategy for the determination of the optimal factorial combination affecting the formed complexes. This is was applied by first constructing the model (screening and optimization), then by verification and validation of the proposed models. Based on independent factor analysis, a second approach was used for the fabrication potentiometric sensors for the designated catecholamine drugs based on molding of phosphomolybic acid ion-exchanger and DOP as plasticizer into a PVC polymeric matrix. The performance characteristics of the three selected electrodes were prudently scrutinized. This thesis comprises four chapters: CHAPTER ONE I. INTRODUCTION In this section, a detailed description of agonists and their types as well as their pharmacological mode of action is defined. The second part highlights the theoretical basis of the antenna interaction between the three catecholamine drugs with trivalent lanthanides. Elaboration on chemometric- assisted spectroscopic techniques and their applications in diverse areas is also comprehended. The section finally provides insights about the three different techniques (spectrofluorimetric, spectrophotometric and potentiometric) employed for the analysis of dobutamine, hexoprenaline and isoprenaline. CHAPTER TWO II. LITTERATURE SURVEY II.I. Dobutamine It delineates the chemical and physical characteristics, pharmacological actions as well as the techniques of analysis that were previously reported for the determination of dobutamine. Various techniques have been applied for the determination of dobutamine. These include, spectrophotometric, spectrofluorimetric, HPLC, voltammetric and several potentiometric techniques. II.II. Hexoprenaline It describes the chemical and physical characteristics of hexoprenaline , its pharmacological uses as well as literature reports elaborating on a number of methods applied for the assay of hexoprenaline. These procedures comprise, spectrophotometric, spectrofluorimetric, HPLC and other potentiometric methods. II.III. Isoprenaline It outlines the chemical and physical characteristics of Isoprenaline as well as its pharmacological actions. Reports provided by literature encompasses the different techniques applied for the analysis of Isoprenaline via spectrophotometric, spectrofluorimetric, HPLC, polarographic as well some potentiometric techniques. CHAPTER THREE III. EXPERIMENTAL, RESULTS, DISCUSSIONS AND CONCLUSIVE REMARKS III.I. Spectrofluorimetry III.I.A. Spectrofluorimetry Experimental It encompasses the materials, reagents, instruments, software used as well as the experimental techniques applied. A detailed description regarding the general reaction procedure, optimized reaction procedure for the preparation of Sm, Tb and Ln complexes, as well as procedure for dosage forms is also given. Furthermore, construction of the experimental design was defined via its two phases, Firstly, Plackett-Burman Design (PBD) for screening of the factors, followed by optimization phase exploiting Box-Behnken Design. III.I.B. Spectrofluorimetry Results and Discussions In this section, a full description of results and discussion is revealed, that can be summarized as follows: The interaction of the three catecholamines with lanthanides based on the antenna effect theory was verified and spectrofluorimetrically. The obtained excitation and emission spectra were recorded

Four continuous factors were designated for study. Preliminary investigation of factors was screened by means of Plackett- Burman Design followed by optimization assessments upon employing Box-Behnken Design. ANOVA testing confirmed the results as well as the linearity obtained in the regression plots. Factorial interactions were also highlighted by construction of 2-D contour and 3- D surface plots. The optimal factorial blend for factors was described in terms of pH values, metal volume of the three employed lanthanides, reaction time and optimal temperature conditons.These were demonstrated by means of optimization plots. III.I.C. Spectrofluorimetry Conclusive Remarks It entitles a general outline about results obtained in the spectrofluorimetry section. III.II. Spectrophotometry III.II.A. Spectrophotometry Experimental It includes the materials, reagents, instruments, software used as well as the experimental techniques instigated. General reaction procedure was described followed by the optimized reaction procedure for the preparation of Sm, Tb and Ln complexes for authentic and pharmaceutical preparations. Furthermore, experimental design for factors that might affect the anticipated response was attained through two stages, Firstly, Plackett-Burman Design (PBD) for screening of the factors, followed by tweaking of the factors’ upper and lower limits before optimization was carried out by using a Central Composite Design. III.II.B. Spectrophotometry Results and Discussions This section provides a comprehensive enlightenment about the obtained chemometric determination of the spectrophotometrically analyzed complexes. In conclusion, a full description of the interaction of Dobutamine, Hexoprenaline and Isoprenaline with the three selected lanthanides is presented. Four continuous factors were selected for study in the screening phase by means of a Plackett- Burman Design, where temperature factor was excluded for being non-significant and the other factors as metal volume, pH and reaction time were optimized by Central Composite Design. III.II.C. Spectrophotometry Conclusive Remarks It provides a general conclusion on the results obtained in the spectrophotometric section. III.III. Potentiometry III.III.A. Potentiometry experimental It presents the materials, reagents and instruments as well as the experimental techniques applied for the determination of dobutamine, hexoprenaline and isoprenaline. Details descriptions concerning constitution of the ion selective membranes, construction of the calibration curves and examination of the effect of soaking, changing plasticizers, temperature and pH on the performance characteristics of the electrodes are conversed in this section. Methods of evaluation of the electrode selectivity and determination of the studied drugs in pure solutions and pharmaceutical preparations are also defined. III.III.B. Potentiometry Results and discussion This section is involved with the results and discussion and can be summarized as following: Electrodes were prepared and investigated for Dobutamine, Hexoprenaline and Isoprenaline based on the incorporation of the phosphomolybdic acid (PMA) as an ion- exchanger in PVC matrix using DOP as plasticizer. The optimum compositions of the membranes were achieved with 5.0 % DOB-PMA, ISO-PMA and 7.0 % HEX- PMA. These compositions revealed the best Nernstian slopes and hence have been used to carry out all the subsequent studies. The electrodes are characterized by a wide usable concentration range of 1.0x10-5 - 1.0x10-2 at 25°C. The change in pH did not affect the potential readings of the studied electrodes within the pH range 2.00-6.00 for DOB-PMA , 2.00-7.00 for HEX-PMA and 2.00-6.50 for ISO-PMA. The study of the effect of temperature change on the potential response of the electrodes indicated that the three selected electrodes are thermally stable over a wide temperature range (25-60°C). The isothermal temperature coefficients of the electrodes 1.550 x 10-3, 1.497 x 10-3and 1.509 x10-3 V/ºC for DOB-PMA, HEX- PMA and ISO-PMA electrodes, respectively, indicating that the electrodes exhibit high thermal stability within the usable temperature range. Furthermore, the study showed that the three electrodes are highly selective in the presence of some inorganic cations, sugars and urea. Low LOD, LOQ values were obtained as well as excellent precision and accuracy for inter, and intra- day determinations. III.III.C. Potentiometry Conclusive Remarks This section ends with a conclusion on the obtained potentiometric results. The thesis ends with 430 references that were of great help to the authoress.

Conclusion

Applying Placket-Burman Design (PBD) with the purpose of screening of variables and Box –Behnken (BBD) design for optimization of the scanned variables, the determination of dobutamine, hexoprenaline and isoprenaline complexed with lanthanum, samarium and terbium, respectively, was conducted by employing spectrofluorimetric technique. Initial screening of the four key variables was performed (reaction time, metal volume, temperature and pH), after which the optimization procedure was designed to exclude the insignificant factors defined by the screening procedure. No transformation was required as the residual plots for the proposed models substantiated normal distribution of data. Construction of 2-D Contour and 3-D Surface plots as well as factorial optimization plots reflected that the detection of responses can be conveniently carried out without running a massive number of experiments and hence confirming the validation of the designated models and their intensive efficiency in conserving time and effort. Additionally, Analysis of variance (ANOVA) assessments were performed for both screening and optimization stages to assent that the obtained results were statistically validated. Findings obtained from the validation procedure of the assessed factors comprising accuracy, precision linearity specificity, ruggedness and robustness, confirmed the superiority of the proposed models upon employing chemometric-assisted spectrofluorimetry. Moreover, the proposed procedure was successfully applied for their determination in pure powder as well as pharmaceutical preparation. With the aim of screening and optimization of four studied variables, a Plackett- Burman design of experiments and a Central Composite response surface methodology were implemented. A spectrophotometric method was applied for the determination dobutamine, hexoprenaline and isoprenaline lanthanide complexes in authentic and pharmaceutical formulations. Preliminary scanning of the selected variables was performed (reaction time, metal volume, pH and temperature). A central composite optimization procedure was then exploited include only the three substantial factors as per the screening phase outcomes. Due to its insignificant effects, temperature was not considered for the optimization phase. Box-Cox transformation was applied for the designated models with an attempt to achieve normal distribution of data in residuals. 2-D Contour plots and 3-D surface plots, in addition to the assayed desirability plots were analyzed to indicate that the desired responses can be attained with a reduced number of experiments. Thus, validating the designated models for their high efficiency in saving time and effort. Furthermore, and subsequent to all these findings, Analysis of variance (ANOVA) tests were performed consequent to the screening and optimization stages. The achieved data confirmed the statistical significance of the proposed models. Superiority of the proposed models’ used for the spectrophotometric determination of the proposed models in authentic and pharmaceutical dosage forms, was endorsed by the results obtained from the validation procedure of the assessed factors comprising accuracy, precision linearity specificity, ruggedness and robustness. The present work offers three new ion-selective electrodes of the plastic membrane type for the determination of Dobutamine, hexoprenaline and isoprenaline. These electrodes depend mainly on the incorporation of the ion- associates of the above mentioned drugs with phosphomolybdic acid (Drug-PMA) in a PVC matrix. The DOB-PMA, HEX-PMA and ISO-PMA electrodes are characterized by a wide usable concentration range of (1.0x10-5–1.0x10-2) The change in pH does not affect the potential reading of the studied electrodes within the range 2.00 -6.00, 2.00-7.00 and 2.00-6.50, for DOB-PMA, HEX-PMA and ISO-PMA electrodes, respectively. In these ranges, the electrodes can be used safely for determination in pure and pharmaceutical dosage forms. Additionally, the electrodes exhibited high selectivity towards a variety of inorganic cations, and neutral molecules. It is clear from the obtained data that, the presented electrodes have nearly the same usable concentration, temperature and pH range, selectivity and can be applied to the determination of their respective drug with nearly the same precision and accuracy. The investigated drugs were determined in their pure and pharmaceutical preparations and the results were accurate and precise as indicated by the recovery values and relative standard deviation.