الفهرس 
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Abstract
This thesis consists of three parts in addition to the references and summary in Arabic. Each part includes an introduction, literature review, descriptive experimental work for the studied drugs, results, discussion and general conclusion.
Part I: Quantitative Determination of Diflunisal, Naproxen and Diflunisal Toxic Impurity
This part consists of four sections.
Section (A): Introduction and Literature Review
This section includes an introduction about the pharmacological actions of Diflunisal (DIF) and Naproxen (NAP), their chemical structures, physical properties and summary of the published methods developed for their analysis in their single forms and in their binary mixtures. Also, it includes a brief account about Diflunisal toxic impurity; Biphenyl-4-ol (BIP) and its harmful effects.
Section (B):Quantitative Determination of Diflunisal and Naproxen in Presence
of Diflunisal Toxic Impurity by Ratio Difference Spectrophotometric Method
In this section, ratio difference (RD) spectrophotometric method was developed for determination of DIF and NAP in presence of BIP.
In this method, the resulted ratio spectra at 250.2 and 260.4 nm (ΔA 250.2 – 260.4nm) and 216.8 and 239.8 nm (ΔA 216.8 – 239.8 nm) were measured and used for calculating DIF and NAP concentrations, respectively. The developed method was successfully applied for quantitation of the studied compounds in laboratory prepared mixtures and in Maxipan® tablets where satisfactory results were obtained. The standard addition technique has been applied to verify their validity and accuracy.
Section (C): Quantitative Determination of Diflunisal, Naproxen and Diflunisal Toxic Impurity by Multivariate Calibration Methods In this section, multivariate calibration methods using PCR and PLS models have been applied using a five level, three -factors calibration design over the wavelength range of 220-350 nm. These developed methods were successfully applied for analysis of DIF, NAP and BIP in their ternary mixtures in the concentration range of 2-6, 0.5-2.5 and 1-5 µg mL-1 for DIF, NAP and BIP, respectively. . These models were successfully applied for determination of DIF and NAP in Maxipan® tablets. The methods compared favorably with the reported method. Section (D): chromatographic Methods for Quantitation of Ternary Mixture of Diflunisal, Naproxen and Diflunisal Toxic Impurity
In this section, simple and specific TLC-densitometric and HPLC methods have been developed for simultaneous determination of DIF, NAP and BIP in their ternary mixture. In the developed TLC- densitometric method, good separation was achieved upon using methylene chloride: methanol: ethyl acetate: acetic acid (9:0.5:0.5:0.05, by volume) as a developing system and 240 nm as a scanning wavelength. Moreover, in the proposed HPLC method, methanol: water (55:45, by volume, adjusted pH= 4 with orthophosphoric acid) was used as a mobile phase at constant flow rate of 1 mL min-1 with UV detection at 215 nm and using a stationary phase of C18 column. The suggested methods were successfully applied for quantitation of DIF and NAP in their pure forms and in their combined pharmaceutical formulation.
Statistical comparison with the reported method showed no significant difference within probability of 95% regarding both accuracy and precision.
Part II: Quantitative Determination of Two Binary Mixtures Containing Pyridoxine Hydrochloride
This part consists of three sections.
Section (A): Introduction and Literature Review
This section includes an introduction about the pharmacological actions of Pyridoxine hydrochloride (PYH), Cyclizine hydrochloride (CYH) and Meclizine hydrochloride (MEH), their chemical structures, physical properties and summary of the published methods developed for their analysis in their single forms and in mixtures.
Section (B): Spectrophotometric Methods for Resolving Two Binary Mixtures
Containing Pyridoxine Hydrochloride
In this section, modified area under the curve (MAUC) and mean centering of ratio spectra spectrophotometric (MCR) methods were used for selective determination of PYH, CYH and MEH.
In the first method, PYH was determined by measuring the amplitude value of the plateau at 283 nm obtained after division on standard spectrum of 20 µg mL-1 of PYH. where the areas under the curve in the ranges of 215-228 nm for CYH and 230-243 nm for MEH in the subtracted ratio spectra were used for CYH and MEH determination.
In the developed mean centered of ratio spectra spectrophotometric method (MCR), the amplitudes of the second mean centered ratio spectra at 228.8, 260.2 and 270.8 nm for PYH, CYH and MEH, respectively were measured.
Selectivity of the methods was tested by application to different synthetic mixture where good results were obtained. On the other hand, accuracy was verified by application of standard addition technique on Emetrex® and Dizerest B6® tablets where no interference from additives was found.
Section (C): chromatographic Methods for Resolving Two Binary Mixtures Containing Pyridoxine Hydrochloride
This section is concerned with the development of sensitive, economic and specific TLC-densitometric and HPLC methods for determination of PYH, CYH and MEH in their bulk powder and laboratory prepared mixtures. In the developed TLC-densitometeric method, the studied components were well separated using methylene chloride: acetone: methanol (7:1:0.5, by volume) as a developing system and 220 nm as a scanning wavelength. For HPLC method, the mobile phase used was consisted of methanol: 0.05 M K2HPO4 solution (90:10, v/v, pH 5 with H3PO4 and KOH) at a constant flow rate of 1 mL min-1 with UV detection at 220 nm and using C18 column.
Linear relationships were obtained between the mean integrated peak area and the corresponding concentrations of PYH, CYH and MEH. The developed methods were successfully applied for quantitation of the studied drugs in Emetrex® and Dixerest B6® tablets, the standard addition technique has been applied to verify their accuracy.
Part III: Quantitative Determination of Pyrazinamide and Its Impurity; Pyrazine-2-carboxylic acid
This part consists of three sections.
Section (A): Introduction and Literature Review
This section includes an introduction about the pharmacological actions of Pyrazinamide (PYN), its chemical structure, physical properties and summary of the published methods developed for its analysis in its single form and in mixtures with other components. Also, it gives some information about the studied PYN impurity; Pyrazine-2-carboxylic acid (PYA).
Section (B): Quantitative Determination of Pyrazinamide and Its Impurity; Pyrazine-2-carboxylic Acid by Spectrophotometric Methods
In this section, third derivative (3D), first derivative of ratio spectra (1DD) and mean centering of ratio spectra spectrophotometric (MCR) methods have been developed and optimized for simultaneous analysis of PYN and PYA using methanol as a solvent.
Third derivative spectrophotometric (3D) method was used for determination of PYN and PYA at 276.2 and 274.6 nm, respectively. While First derivative of ratio spectra spectrophotometric (1DD) method was used for determination of PYN and PYA at 225.8 and 245.2 nm, respectively.
In the developed mean centered of ratio spectra spectrophotometric method (MCR), the amplitudes of the mean centered ratio spectra at 268.4 and 268.8 nm for PYN and PYA, respectively were measured
The methods were valid for determination of PYN and PYA in different laboratory prepared mixtures and for determination of PYN in B.T.B® tablets. Also, statistical comparison of the results of the proposed methods with those of the reported one showed no significant difference.
Section (C): Quantitative Determination of Pyrazinamide and Its Impurity; Pyrazine-2-carboxylic Acid by Different chromatographic Methods
In this section, selective and accurate TLC-densitometric and HPLC methods were validated for determination of PYN and PYA in their mixture. In the developed TLC-densitometric method, well defined peaks were completely separated on using methylene chloride: methanol: ammonia solution (7:3:0.1, by volume) as a developing system and 275 nm as a scanning wavelength.
For HPLC method, the mobile phase used was consisted of methanol: 0.05% orthophosphoric acid (60: 40, v/v, adjusted pH to 5) with a flow rate of 1.2 mL min-1 with UV detection at 275 nm and using ZOBRAX SB-CN column.
The utility of the developed methods was successfully verified by application to B.T.B® tablets where no interference from additives was found. No significant difference was observed upon comparing the results of the proposed methods and the reported HPLC one.