الفهرس 
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Abstract
This Thesis Contains Three Separate Parts, Which Contain Different Analytical Methods For Quantitative Determination Of Some Pharmaceutical Compounds Containing Aza Heterocyclic group In Raw Materials And In Their Pharmaceutical Formulations.
Part I: Determination Of Azelastine Hydrochloride And Its Genotoxic Impurity
This Part Is Focused On Investigating Accurate, Sensitive, And Specific Methods For Determination Of Azelastine (AZL) And Its Impurity, Benzohydrazide (BHZ) Which Is Genotoxic And Carcinogenic Compound. Two Different Spectrophotometric Methods And Two selective chromatographic Methods Were Described In This Part. These Methods Were The First Developed Ones For Simultaneous Determination Of The Studied Drug Along With Its Toxic Impurity.
This Part Includes Four Sections:
Section A: Introduction And Literature Review
This Section Includes An Introduction About The Pharmacological Actions Of Azelastine (AZL) And Benzohydrazide (BHZ), Their Chemical Structures, Physical Properties And Summary Of The Published Methods Developed For Their Analysis.
Section B: Determination Of Azelastine Hydrochloride And Its Genotoxic Impurity By Different Spectrophotometric Methods.
In This Section, Different Spectrophotometric Methods; First Derivative Spectrophotometry (1D), First Derivative Of Ratio Spectra (1DD), And Mean Centering Of Ratio Spectra (MCR) Spectrophotometric Method, Were Developed For Determination Of Both AZL And Its Genotoxic Impurity (BHZ).
In The Developed Spectrophotometric Methods, AZL Was Determined By 1D Spectrophotometric Method At 321nm While BHZ Was Analyzed By 1DD Method Using The Amplitudes At 268.4nm. On The Other Hand, The Drug And Its Impurity Were Determined By Mean Centering Of Ratio Spectra Method (MCR) Using The Mean Centered Amplitudes At 293 And 247nm For AZL And BHZ, Respectively. The Developed Spectrophotometric Methods Were Used For Analysis Of The Studied Components In Laboratory Prepared Mixture And Also For Determination Of AZL Concentration In Its Available Dosage Form where No Interference from Excipient (Benzalkonium Chloride) Was Observed.
Section C: Simultaneous Determination Of Azelastine Hydrochloride And Its Genotoxic Impurity By UPLC Method.
In This Section, A selective, Sensitive, And Fast Ultra-Performance Liquid chromatographic (UPLC) Method Was Developed And Validated To Separate AZL, Its Carcinogenic Impurity (BHZ) And Benzalkonium Chloride On C18 Column (50 X 2.1 Mm I.D., 1.9 µm) Using Acetonitrile And (0.1%W/V) Sodium Lauryl Sulfate (Ph=5 With Phosphoric Acid)(55: 45,V/V) As A Mobile Phase. The Injection Volume Was 5 µl, And Detection Was Carried Out At 215 Nm. The Column Temperature Was Maintained At 50°C. The Flow Rate Was 1.2 Ml/Min And The Overall Run Time Was 2 Min. Linear Calibration Curves Were Constructed Over Concentration Ranges Of (1-50 Μg/Ml) For AZL And (5-35 Μg/Ml) For BHZ. The Investigated Method Was Successfully Applied To Dosage Form And Method Validation Has Been Carried Out. The Results Obtained By Applying This Method Were Analyzed And Compared With Reported One And No Significant Difference Was Obtained Regarding Both Accuracy And Precision.
Section D: Simultaneous Determination Of Azelastine Hydrochloride And Its Genotoxic Impurity By Capillary Electrophoretic Method.
In This Section, AZL, BHZ, And Benzalkonium Chloride Were Separated Using CE Method. Separation Was Performed On A Standard Bare Fused-Silica Capillary (75 µm I.D., 50 Cm Effective Length) Using 40mm Potassium Dihydrogen Phosphate Buffer. A Diode-Array UV Detector Was Set At 225 Nm With A Bandwidth Of 10 Nm. The Capillary Temperature Was Kept Constant At 25°C And A Voltage Of 30 KV Was Applied. The Injection Volume Was 50 Nl And The Run Time Was 6 Min. The Linearity Of The Developed CE Method Was Evaluated By Analyzing Series Of Different Concentrations Of AZL And BHZ In The Range Of 5–50 And 5-40 µg/Ml, Respectively. Additionally, The Method Was Applied To Marketed Eye Drops And Synthetic Mixtures And All The Obtained Results Were Within Acceptable Limits.
Part II: Baclofen Impurities: Facile Synthesis And Novel Environmentally Benign TLC And UPLC Methods For Their Simultaneous Determination In Baclofen.
This Part Is Focused On Developing Simple, Accurate, Sensitive, And selective chromatographic Stability- Indicating Methods For Determination Of Baclofen (BAC) And Its Synthesized Impurities; [Impurity A(IMA) And B (IMB)]; In Pure Form And In Laboratory Prepared Mixtures. The Most Important Advantage Of This Work Is That The Developed Methods Are The First Developed Ones For Simultaneous Determination Of BAC And Its Pharmacopeial Impurities. They Have Short Analysis Time, Hence Low Solvents Consumption And Low Environmentally Hazardous Effects. The Greenness Profile Of The Developed Methods Was Evaluated.
This Part Includes Four Sections:
Section A: Introduction And Literature Review
This Section Includes An Introduction About The Pharmacological Actions Of BAC, The Chemical Structures Of BAC, IMA, And IMB, And Summary Of The Published Methods Developed For Analysis Of BAC.
Section B: Facile Synthesis Of Baclofen Impurities
In This Section, An Easy, Efficient, Economic And High Yielding Method Was Described For The Synthesis Of Baclofen (BAC) Pharmacopoeial Impurities (Impurities A And B) Which Can Be Used For Gram Scale Synthesis. After Synthesis Of The Reported Impurities, Structural Elucidation Was Done Using MS And NMR Analyses.
Section C: Simultaneous Determination Of Baclofen And Its Pharmacopoeial Impurities By TLC-Densitometric Method.
A Novel Ecofriendly Stability Indicating TLC-Densitometric Method Was Established And Validated For The Determination Of BAC And Its Synthesized Impurities.
The Developed TLC-Densitometric Method Depends On chromatographic Separation Using Thin Layer chromatographic (TLC) Plates (60 F254) And A Green Mobile Phase Of Ethyl Acetate: Methanol: Ammonia Solution ”33%” (8:2:0.1, By Volume) With UV Scanning At 220nm.
Linearity Was Achieved In The Concentration Ranges Of 1-30, 0.5-15, And 1-15 µg/Band For BAC, IMA, And IMB, Respectively. Method Was Validated With Respect To ICH Guidelines And Then Applied For Analysis Of BAC In Its Formulated Dosage Form.
Section D: Simultaneous Determination Of Baclofen And Its Pharmacopoeial Impurities By UPLC Method.
The Established UPLC Method Was Based On Using C18 Column As A Stationary Phase And An Ecofriendly Mobile Phase Of Ethanol: 40 Mm KH2PO4 (25:75, V/V, Ph=2.5 With Phosphoric Acid) With A Flow Rate Of 2 Ml/Min And UV Detection At 220 Nm. The Method Was Linear In The Range Of 1-20, 1-10, And 1-10 µg/Ml For BAC, IMA, And IMB, Respectively. The Investigated Method Was Successfully Applied To Dosage Form And Method Validation Has Been Carried Out. The Results Obtained By Applying This Method Were Analyzed And Compared With Reported One And No Significant Difference Was Obtained Regarding Both Accuracy And Precision.
Part III: Different Spectrophotometric And chromatographic Methods For Determination Of Mepivacaine And Its Toxic Impurity
Stability Indicating Spectrophotometric, TLC- Densitometric And UPLC Methods Were Developed For The Determination Of Mepivacaine Hcl (MEP) In The Presence Of Its Toxic Impurity, 2,6-Dimethylaniline (DMA). These Methods Used To Quantify The Toxic Impurity With High Sensitivity And selectivity.
This Part Includes Four Sections:
Section A: Introduction And Literature Review
This Section Includes An Introduction About The Pharmacological Actions Of Mepivacaine (MEP) And The Chemical Structures Of MEP And Its Impurity, And Summary Of The Published Methods Developed For Analysis Of The Parent Drug.
Section B: Determination Of Mepivacaine And Its Toxic Impurity By Different Spectrophotometric Methods
In This Section, Two Spectrophotometric Methods Were Developed For Determination Of MEP And DMA. Method (1) Was Dual Wavelength Method Complementary With 0D Method. In Dual Wavelength Method, The Absorbance Difference Between 221.4 And 240 Nm Was Used For MEP Measurement, While The Absorbance At 283 Nm Was Used For Direct Measurement Of DMA In The Binary Mixture. On The Other Hand, The Second Method Was Second Derivative (2D) Spectrophotometric Method At Which The Amplitudes At 272.2 And 232.6 Nm Were Recorded And Used For Determination Of MEP And DMA, Respectively. Calibration Curves Of These Methods Were Linear Over The Concentration Ranges Of 5-30 And 3-10 µg/Ml For MEP And DMA, Respectively (Method 1), In The Range Of 3-30 µg/Ml And 1-10 µg/Ml For MEP And DMA, Respectively (Method 2). The Developed Methods where Applied To Synthetic Mixtures where Good Results Were Obtained.
Section C: Simultaneous Determination Of Mepivacaine And Its Toxic Impurity By TLC-Densitometric Method
In This Section, TLC-Densitometric Method Was Developed Which Depended On chromatographic Separation Using Silica Gel 60 F254 TLC Plates As A Stationary Phase And Methanol: Water: Acetic Acid (9:1: 0.1, By Volume) As A Developing System With UV Scanning At 230 Nm. Factors Affecting Separation Was Studied And Optimized And Also, System Suitability Parameters Were Calculated And All Values Were Within The Acceptable Limits. In The Same Way, The Method Was Applied To Available Dosage Form And Results Confirmed That Excipients Did Not Interfere.
Section D: Simultaneous Determination Of Mepivacaine And Its Toxic Impurity By UPLC Method
UPLC Method Was Developed And Validated To Determine MEP And Its Carcinogenic Impurity (DMA) At Which The Mixture Was Separated On A Reversed Phase C18 Column (50×2.1 Mm I.D., 1.9µm Particle Size) Using Acetonitrile: Water (40: 60, V/V, Ph=4 With Phosphoric Acid) As A Mobile Phase With A Flow Rate Of 0.4ml/Min And UV Detection At 215 Nm. The chromatographic Run Time Was Approximately 1.2 Minute. The Linearity Of Calibration Curve Was Evaluated By Analyzing Different Concentrations In The Range Of 3–25 And 0.9-14 µg/Ml For MEP And DMA, Respectively. The Proposed Method Was Validated With Respect To ICH Guidelines And Then Compared With A Reported One Using Student’s T And F –Tests And No Significant Difference Were Found Between Them.
The Thesis Ended With Reference And Then Arabic Summary.
The Thesis Contains 40 Figures And 63 Tables.