الفهرس 
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Abstract
This Thesis Consists Of Five Parts Which Are; General Introduction And The Other Four Parts Including An Introduction, Literature Review And Descriptive Experimental Work For The Studied Drugs In Addition To References And Summary In Arabic Language.
Part I: General Introduction
This Part Includes Definition Of Neuropathic Pain, Classification Of Neuropathic Pain, Pharmacological Treatment And Its Management Recommendations.
Part II: Quantitative Determination Of Pregabalin And Amitriptyline In Pure Form, Spiked Human Plasma And Urine
This Part Includes:
Section A: Introduction And Literature Review
This Introduction Describes The Pharmacological Action Of Pregabalin And Amitriptyline, Their Chemical Structure, Physical Properties And Literature Review Of The Published Methods For Their Analysis.
Section B: Green HPLC-DAD Method For Determination Of Binary Mixture Of Pregabalin And Amitriptyline Used For Neuropathic Pain Management
First Analytical Method Was Herein Developed For Determination Of Pregabalin (PGB) And Amitriptyline (AMT) As An Active Binary Mixture Used For Management Of Neuropathic Pain Whether In Pure Forms Or In Human Biological Fluids (Plasma/Urine). Green HPLC-DAD Was Developed After Derivatization Of PGB With Ninhydrin (NIN), On A Reversed-Phase C18 Column Using A Mobile Phase Consisting Of Ethanol: Water (97:3%, V/V) Pumped Isocratically At 0.8 Ml/Min, AMT Were Scanned At 215 Nm, While PGB-NIN Was Scanned At 580 Nm. Linear Calibration Curves Were Obtained For Human Plasma And Urine Spiked With PGB And AMT Over The Ranges Of 5-100 µg/Ml And 1-100 µg/Ml For PGB And AMT, Respectively. The Suggested Method Was Validated According FDA Guidelines For Bioanalytical Methods Validation And They Can Be Applied For Routine Therapeutic Drug Monitoring For The Concerned Drugs.
Section C: HPTLC Method For Quantitative Determination Of Binary Mixture Of Pregabalin And Amitriptyline In Pure Form, Human Plasma And Urine Samples
In This Section, PGB And AMT Were Separated On Silica Gel HPTLC F254 Plates, Using Eco-Friendly Developing System Consisting Of Ethanol: Ethyl Acetate: Acetone: Ammonia Solution, (8:2:1:0.05, By Volume). Development Of Simple And Inexpensive Derivatization Of PGB, As An Aliphatic Drug, Is Achieved By Its Reaction With Ninhydrin Reagent (NIN) Producing Purple Complex That Measured Densitometrically. AMT Peaks Were Scanned At 220 Nm Whereas PGB Peaks Were Visualized By Spraying 3% (W/V) Ethanolic NIN Solution And Scanning At 550 Nm. Linear Calibration Curves Were Obtained For Pure Form, Human Plasma And Urine Spiked With PGB And AMT Over The Ranges Of 0.2-2.5 µg/Band And 0.1-2.0 µg/Band For PGB And AMT, Respectively.
Part III: Quantitative Determination Of Pregabalin And Tramadol In Pure Form, Spiked Human Plasma And Urine Samples
This Part Includes:
Section A: Introduction And Literature Review
This Introduction Describes The Pharmacological Action Of Pregabalin And Tramadol, Their Chemical Structure, Physical Properties And Literature Review Of The Published Methods For Their Analysis.
Section B: Ecological Liquid chromatography-Electrospray Ionization-Tandem Mass Spectrometry Method As A Therapeutic Drug Monitoring Tool Of Pregabalin And Tramadol Mixture Used For Neuropathic Pain Management
A selective, Highly Sensitive, And FDA Validated High Performance Liquid chromatography-Electrospray Ionization-Mass/Mass Spectrophotometric (LC–ESI–MS/MS) Method Is Presented For Determination Of TRM And PGB Either In Pure Forms Or Human Biological Fluids (Plasma/ Urine), Using Gabapentin (GBP) As Internal Standard (IS). chromatographic Separation Was Achieved In Total Run Time Of 2.5 Min, On Phenomenex Luna® Omega 1.6 µm Polar C18 (LC 150 × 2.1 Mm) Column With A Mobile Phase Of Methanol: Water Containing 0.1% Formic Acid (70:30, V/V) At A Flow Rate Of 0.3 Ml/Min. Ionization Of The Analytes Was Performed Using Positive Electrospray Ion Mode (ESI+). MS/MS Detection Was Performed By Fragmentation Monitoring Of 263.89—>58.13 (M/Z) For TRM, 160.24—>55.09 (M/Z) For PGB And 171.95—>67.12 (M/Z) For GBP On A Mass Spectrometer Of Triple Quadrupole Mode. The Method Is Linear, Highly Sensitive, selective, And Precise. The Proposed Method Was Applied Successfully To Real Human Plasma And Urine Samples Taken from Neuropathic Patients.
Section C: HPTLC Method For Quantitative Determination Of Binary Mixture Of Pregabalin And Tramadol In Pure Form, Human Plasma And Urine
The Presented Section Aimed To Explain FDA Validated HPTLC Method For Determination Of The Binary Mixture Of PGB And TRM, Which Is Considered One Of The Most Recommended Remedies For The Management Of Several Types Of Neuropathic Pain. In This Section, Separation Of PGB And TRM Was Achieved On Silica Gel HPTLC F254 Plates, Using Ethanol: Ethyl Acetate: Acetone: Ammonia Solution, (8:2:1:0.05, By Volume) As An Eco-Friendly Developing System. TRM Peaks Were Scanned At 220 Nm While PGB Peaks Were Visualized By Spraying 3% (W/V) Ethanolic NIN Solution And Scanning At 550 Nm. Successful Application Of The Developed Method Was Also Revealed By Determination Of PGB And TRM In Human Plasma And Urine Samples In The Range Of 0.2-2.5 µg/Band.
Part IV: Quantitative Determination Of Gabapentin, Tramadol And Amitriptyline In Pure Form, Spiked Human Plasma And Urine
This Part Includes:
Section A: Introduction And Literature Review
This Introduction Represented A Concise View About The Chemical Structure, Physical Properties, Mode Of Action And Different Published Methods For The Assay Of GBP, TRM And AMT In Pure Form, Biological Samples And Pharmaceutical Formulations.
Section B: Green GC–MS Assay Of Gabapentin, Tramadol And/Or Amitriptyline Mixtures Used For Neuropathic Pain Management; In Pure Form, Human Plasma And Urine
The Present Section Reported The First Method For Analysis Of Mixtures Of Gabapentin (GBP), Tramadol (TRM) And/Or Amitriptyline (AMT), The Most Important Combinations Used And Approved For Treatment Of Neuropathic Pain. A Novel GC–MS Method Was Developed Aiming To Achieve Simultaneous And Rapid Determination Of The Concerned Drugs Whether In Pure Forms Or Human Biological Fluids (Plasma/Urine). The chromatographic Detection Was Performed On MS Detector Applying The selected Ion Monitoring (SIM) Mode. An Agilent GC–MS With Triple Axis Single Quadrupole Detector Unit Was Used For The Analysis, Equipped With HP-5MS (5% Phenyl Methyl Siloxane) Column (Agilent) With 250 µm ID And 0.25 µm Film Thickness. Helium Was The Carrier Gas Programmed At A Flow Rate Of 2 Ml/Min. Positive Electron Impact Ionization Mode Was Used And Data Were Collected Using SIM Mode, The Principle Ions M/Z 67, 81, 110, 153 And 171; M/Z 58, 135 And 263; M/Z 57, 115, 202 And 277 Were selected For Identification Of GBP, TRM And AMT, Respectively. The Method Was Validated According To FDA Guidelines. LLOQ Was Found To Be 1, 0.1 And 0.01 µg Ml-1 For GBP, TRM And AMT, Respectively, Either In Pure Samples Or In Spiked Human Plasma And Urine.
Part V: Stability Indicating Methods For Simultaneous Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
This Part Includes:
Section A: Introduction And Literature Review
This Introduction Described The Pharmacological Action, Chemical Structure, Physical Properties, Stability And Review Of The Published Methods Developed For The Assay Of The Drug Of Interest In Pure Form, Pharmaceutical Formulations And Biological Samples.
Section B: Stability Indicating Dual Wavelength Spectrophotometric Method For Simultaneous Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
A Stressed Study On The Stability And Degradation Behavior Under ICH Forced Degradation Conditions Of Most Widely Used Antiepileptic Drug; Carbamazepine (CMZ) Is Presented In This Part. Simple And Sensitive Dual Wavelength Spectrophotometric Method Is Introduced As Stability Indicating Method For Simultaneous Determination Of CMZ And Its Degradation Product, One Of Its Reported Potential Impurities; Iminostilbene (IMS). For Best Sensitivity And selectivity, Wavelengths Of 215 And 270 Nm Were selected For The Determination Of CMZ where IMS Signified The Identical Absorption Values. By The Same Way, 258 And 307 Nm Wavelengths Were selected For The Estimation Of IMS where CMZ Showed Zero Absorbance Difference At These Wavelengths. The selectivity Of The Suggested Method Was Checked By The Analysis Of Different Laboratory Prepared Mixtures Containing Different Ratios Of IMS Down To 2.5% And Up To 50% And Good Results Were Obtained.
Section C: Isoabsorptive Point Spectrophotometric Method For Determination Of Carbamazepine In Presence Of Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
In This Section, A Successful Attempt Was Achieved To Estimate CMZ In Presence Of Its Degradation Product Using Isoabsorptive Point Spectrophotometric Method. Good Linearity Was Obtained For CMZ At 225 And 277 Nm (Aiso1& Iso2) In The Range Of 0.5–20 µg Ml-1. The Proposed Method Was Applied For The Determination Of CMZ In Its Pharmaceutical Formulations where The Validity Was Further Assessed By Applying The Standard Addition Technique. The Proposed Method Was Applied For Direct Determination Of CMZ In Presence Of Its Degradation Product IMS As A Stability Indicating Assay In Zero order Spectra Without Needing Any Derivatization.
Section D: Stability Indicating Second Derivative Spectrophotometric Method For Simultaneous Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
A Rapid, Simple And Low Cost Spectrophotometric Method Based Upon Measuring The Peak Amplitude Of D2 Spectrum Of CMZ At 247 Nm And IMS At 273 Nm Was Developed With Good Sensitivity, Accuracy And Without Any Interference from Each Other. The D2 Spectra Of CMZ And IMS Were Recorded At Δλ= 4 Nm And Scaling Factor= 100. Linear Correlations Were Obtained Between The Peak Amplitude Of D2 Spectrum And The Corresponding Concentration In The Range Of 0.5–30 Μg Ml-1 For CMZ And Of 0.5–14 Μg Ml-1 For IMS. The Method Achieves Sensitive Determination Of IMS In CMZ Pure Substance In Ratio Down To 2.5% Of The Drug Concentration. The Validity Of The Proposed Method Was Checked By The Analysis Of CMZ In Pharmaceutical Formulation where The Results Obtained Were Statistically Compared To The Reference HPLC Method With No Significant Difference Between Them.
Section E: Stability Indicating Ratio Difference Spectrophotometric Method For Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
The Focus Of The Present Section Was To Develop Accurate, selective And Reproducible Ratio Difference Spectrophotometric Method For Determination Of CMZ And Its Degradation Product IMS In Pure Form Or Pharmaceutical Formulations. To Run Ratio Difference Method, The Absorption Spectra Of CMZ In The Range Of 0.5–30 µg Ml-1 Were Divided By The Absorption Spectrum Of 10 µg Ml-1 Of IMS As A Divisor. Regarding IMS, The Absorption Spectra Of IMS In The Range Of 0.5–14 µg Ml-1 Were Divided By The Absorption Spectrum Of 10 µg Ml-1 Of CMZ. Good Linearity Was Achieved For Determination Of CMZ And IMS By Measuring Differences In The Amplitude Of Ratio Spectra At 285, 258 Nm And 258, 285 Nm, Respectively. The Suggested Method Was Then Successfully Applied For Determination Of CMZ In Its Pharmaceutical Formulations.
Section F: Stability Indicating First Derivative Of Ratio Spectra Spectrophotometric Method For Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
In This Section, Simple, Sensitive And selective First Derivative Of Ratio Spectra Method (1DD) Was Proposed For The Quantitative Determination Of CMZ And IMS In Their Binary Mixture To Resolve Their Interfering Spectra. The Absorption Spectra Of CMZ In The Range Of 0.5–30 µg Ml-1 Were Divided By The Absorption Spectrum Of 10 µg Ml-1 Of IMS, While The Absorption Spectra Of IMS In The Range Of 0.5–14 µg Ml-1 Were Divided By The Absorption Spectrum Of 10 µg Ml-1 Of CMZ. The Obtained Ratio Spectra Were Differentiated With Respect To Wavelength Using Δλ= 4 Nm And Scaling Factor = 10. Peak Amplitude Values Of 1DD Spectra Showed Good Linearity For Determination Of CMZ And IMS By Measuring Peak Amplitudes At 280.5 Nm And 253 Nm, Respectively In Their Concentration Ranges. The Method Was Validated And Showed That It Can Be Used For The Regular Quality Control Testing Due To Its Simplicity And Wide Range Of Applicability.
Section G: Stability Indicating Mean Centering Of Ratio Spectra Spectrophotometric Method For Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form And Pharmaceutical Formulations
The Mean Centering Of Ratio Spectra Method (MCR) Was Developed For Quantitative Determination Of CMZ And IMS In Their Binary Mixture Without Previous Separation. The Recorded Absorption Spectra Of CMZ In The Range 200–330 Nm Were Divided By The Absorption Spectra Of 10 µg Ml-1 Of IMS. Thus The Resulted Ratio Spectra Were Mean Centered And The Concentrations Of CMZ Were Assessed By Evaluate The Peak Amplitude from 259 To 287 Nm (Peak To Peak). Regarding IMS, Its Absorption Spectra Were Divided By The Absorption Spectra Of 10 µg Ml-1 Of CMZ And Mean Centering Of The Resulted Ratio Spectra. The Peak Amplitude At 259 Nm Were Measured And Used For Determination Of IMS. Peak Amplitude Values Of MCR Spectra Showed Good Linearity For Determination Of CMZ And IMS In The Concentration Ranges Of 0.5–30 µg Ml-1 And 0.5–14 µg Ml-1, Respectively. The Proposed Method Achieved A Successful Assay Of CMZ In Its Pharmaceutical Formulations. Applying The Standard Addition Technique For Analysis Of CMZ Offered Additional Proof Of The Good Results Of Accuracy. The Results Indicated No Interference Due To Additives And Excipients With The Studied Mixture.
Section H: Validation And Eco-Scale Assessment Of Stability Indicating HPTLC Method For Simultaneous Determination Of Carbamazepine And Its Degradation Product, Iminostilbene In Pure Form, Pharmaceutical Formulations And Spiked Human Plasma
An Excellent Green HPTLC Method Was Developed For Determination Of CMZ And IMS, The Main Degradation Product And Official Impurity Of It. Separation Of The Components Was Completed On A Stationary Phase Of Silica Gel F254 HPTLC Sheets Using Mixture Of Petroleum Ether: Acetone (7:3, V/V) As A Developing System Then The Air-Dried Plates Were Scanned At 230 Nm. To Assess The Greenness Profile Of The Developed Method Compared To The Reference HPLC Method, Analytical Semi-Quantitative Eco-Scale Assessment Protocol Was Applied And The Total Score Value Of The Proposed Method Was Calculated And Found To Be 85, So It Was Proved To Be Excellent Green Analytical Method (≥75). Unlike, The Official One Had A Score Of 65, So It Was Considered As Fair Green Analytical Method (≥50). The Suggested Method Was Found To Be Greener Than The Official Method With Regard To Solvent Consumption And Waste Emission. The Green HPTLC Method Was Successfully Applied To Determine CMZ In The Marketed Dosage Form With No Intrusion Of Other Co-Formulated Ingredients. Successful Application Of The Developed Method Was Also Revealed By Simultaneous Determination Of CMS And IMS In Raw Materials And Plasma Samples In Ranges Of 0.1-1.4 µg/Band And 0.1-1.2 µg/Band For CMS And IMS, Respectively. As The Maximum Plasma Concentration Of The Studied Medication Was Within Its Calibration Range, The Proposed HPTLC Method Can Be Employed For Further Pharmacokinetic Studies. For Comprehensive Validation Of The Presented Method, ICH Figures Of Merit Were Evaluated.
This Thesis Contains 213 References, 100 Figures, 79 Tables And Ends With A Summary In Arabic Language.