الفهرس 
General Introduction and Literature ReviewOnly 14 pages are availabe for public view
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Abstract
The thesis consists of four parts
Part I: General Introduction and Literature Review
This part is divided into two sections:
Section A: Introduction
It includes a brief idea about polyionic compounds, their classification, their properties and their presence in biological and environmental matrices and pharmaceutical products.
Section B: Literature Review
It includes a review of the structures, the chemical and physical properties of the studied drugs; Therapeutic Antisense Oligonucleotides, Tianeptine sodium, Cilastatin sodium and Enoxaparin sodium. Besides, it is concerned with the different analytical methods reported in literature which aim for the determination of the chosen drugs in pure form, pharmaceutical formulations and biological fluids.
Part II: chromatographic determinations of certain polyionic drugs
This part is divided into four sections:
Section A: Degradation products characterization of Therapeutic Antisense Oligonucleotides using ultra performance liquid chromatography mass spectrometry (UPLC-MS/MS)
This section includes the application of UPLC-MS/MS for the determination of the effect of different stress conditions such as pH, temperature and hydrogen
peroxide on the chemical stability, degradation pathways, rates and kinetics of four modified therapeutic antisense oligonucleotides using C18 column (4.6 x 100.0 mm, 3.5 μm) column. The initial gradient was methanol/mobile phase A, consisting of 10.0 mM DMCHA and 25.0 mM HFIP in 10.0% methanol, (10:90, v/v) and the flow rate was 0.4 mL min-1.
The reaction kinetics for the degradation of the different oligonucleotides was studied and was found to follow pseudo-first-order kinetics.
Results showed that differences in rates exist even for oligonucleotides of similar length but consisting of different sequences.
Section B: Determination of Tianeptine sodium in tablets using LC-MS/MS
This section includes the application of LC-MS/MS for the determination of Tianeptine sodium in tablets using C18 column (2.1 x 30.0 mm, 3.0 μm) column. The initial gradient was acetonitrile/mobile phase A, consisting of 10.0 mM ammonium formate/0.1% formic acid in water, (20:80, v/v) and the flow rate was 0.3 mL min-1.
The proposed method was successfully applied for the determination of Tianeptine sodium in pure form with mean recovery percentage (101.20±1.10) and in pharmaceutical formulation (107.95±1.09).
Section C: Simultaneous determination of Tianeptine sodium and its active metabolite Tianeptine sodium MC5 in rat plasma and brain tissue using LC-MS/MS
This section includes the application of LC-MS/MS for the simultaneous determination of Tianeptine sodium and its active metabolite Tianeptine sodium MC5 in rat plasma and brain tissue using C18 column (2.1 x 30.0 mm, 3.0 μm) column. The initial gradient was acetonitrile/mobile phase A, consisting of 10.0 mM ammonium formate/0.1% formic acid in water, (20:80, v/v) and the flow rate was 0.3 mL min-1.
The proposed method was successfully applied for the determination of Tianeptine sodium and its active metabolite Tianeptine sodium MC5 in plasma with mean recovery percentages (99.59±3.16 and 100.42±3.76) and in brain homogenate (98.70±3.10, 98.80±4.82), respectively.
Section D: Simultaneous determination of Cilastatin sodium, Imipenem, Paracetamol and Caffeine using high performance liquid chromatography with diode array detector (HPLC-DAD)
This section includes the application of isocratic HPLC-DAD for the simultaneous determination of Cilastation sodium and Imipenem in their pharmaceutical formulation and for the simultaneous determination of Cilastation sodium, Imipenem, Paracetamol and Caffeine in human urine using C18 column (4.6 x 250.0 mm x 5.0 µm).The mobile phase of choice was acetonitrile:water (10:90, v/v), the flow rate was 1.0 mL min-1 and the diode array detector was set at 220.0 nm for Cilastatin sodium and Caffeine, at 290.0 nm for Imipenem and at 245.0 nm for Paracetamol.
The proposed method was successfully applied for the determination of Cilastation sodium, Imipenem, Paracetamol and Caffeine in pure form with mean recovery percentages (100.23±1.14, 100.39±1.20, 99.98±1.13 and 99.64±1.26), in laboratory prepared mixtures (99.74±1.45, 100.57±1.63, 100.08±0.64 and 100.56±1.11) and in human urine (104.10±0.36, 105.03±0.65, 99.47±2.23 and 99.23±2.43), respectively. Also, the method was applied for the determination of Cilastatin sodium and Imipenem in pharmaceutical formulation with mean recovery percentages (103.83±0.70 and 104.50±1.11), respectively.
Part III: Spectrophotometric and chemometric determinations of certain polyionic drugs
This part is divided into two sections:
Section A: Extended derivative ratio technique for the determination of Cilastatin sodium, Imipenem, Ciprofloxacin hydrochloride, Dexamethasone sodium phosphate and Paracetamol in human urine
This section includes an introduction to the extended derivative ratio technique.
The use of the derivative ratio technique has been extended to be used for the simultaneous determination of the five studied drugs. Each component in the mixture of these drugs was determined using a mixture of the other four compounds as divisor. Linear correlation was obtained between the derivative ratio signal and the corresponding concentration in each case. Cilastatin sodium, Imipenem, Ciprofloxacin hydrochloride, Dexamethasone sodium phosphate and Paracetamol were measured at 221.0, 293.0, 284.0, 276.0 and 257.0 nm, respectively.
This method was applied for determination of Cilastatin sodium, Imipenem, Ciprofloxacin hydrochloride, Dexamethasone sodium phosphate and Paracetamol in pure form with mean recovery percentages (99.91±1.18, 100.79±0.90, 99.64±1.07, 99.91±1.21 and 100.20±1.38), in laboratory prepared mixtures (101.11±1.24, 101.34±0.60, 100.95±0.80, 99.95±1.43 and 100.76±1.51) and in human urine (102.35±1.25, 102.68± 0.93, 104.00±2.00, 101.65± 3.43 and 103.78± 0.91), respectively.
Section B: Partial least square and principal components regression chemometric determinations of Cilastatin sodium, Imipenem, Ciprofloxacin hydrochloride, Dexamethasone sodium phosphate and Paracetamol in human urine
This section includes an introduction to the partial least square and the principal component regression chemometric techniques.
Experimental design was used for constructing twenty five mixtures of the five studied compounds (eighteen samples for the calibration and seven samples for the validation set). The optimum number of factors (eight factors) was selected for each compound to obtain an appropriate calibration of the five drugs.
Part IV: selective molecularly imprinted polymer-based potentiometric determination of Enoxaparin sodium
This part describes the theory, the different types and the assembly of ion selective electrodes. Yet, it mainly focuses on the use of molecular imprinting as a promising polymerization technique and its outstanding applications in potentiometric sensors.
Molecularly imprinted and non imprinted based polymer coated graphite electrodes (representing sensors 1 and 2, respectively) were fabricated for Enoxaparin sodium determination in pure form and pharmaceutical formulation using acrylamide as a functional monomer, divinyl benzene as a cross-linking agent and benzoyl peroxide as an initiator.
Molecularly imprinted and non imprinted based polymers were characterized using Fourier-transform infra-red spectroscopy, scanning electron microscope and binding experiments.
The performance of the proposed electrodes was assessed according to the IUPAC recommendations and showed that they had fast, stable and nernstian response. Response time, effect of pH and temperature on the response, selectivity and stability of the electrodes were studied to determine the optimum conditions for the determination of Enoxaparin sodium in pure form and in its pharmaceutical formulation.
Sensors 1 and 2 showed linear responses in the concentration range of 10-8 to 10-5 M and 10-7 to 10-5 M with mean recovery percentages of pure drug (99.53±0.82 and 99.64±0.97), respectively. The proposed method was successfully applied for the determination of Enoxaparin sodium in pharmaceutical formulation with mean recovery percentage (101.33±0.58 and (102.67±1.15) for sensors 1 and 2, respectively.
This thesis contains 354 references, 75 figures, 38 tables and ends with Arabic summary.