الفهرس 
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Abstract
This thesis consists of three parts in addition to references , arabic and english summaries. Each part includes an introduction, literature review, descriptive experimental work for the studied drugs, results, discussion and ends with a conclusion.
Part I: QUANTITATIVE DETERMINATION OF NIFUROXAZIDE AND ITS GENOTOXIC IMPURITIES
This part includes four sections.
Section (A): Introduction and Literature Review
This section includes an introduction about Nifuroxazide (NIF) and four genotoxic impurities (A-D) and summary of the published methods developed for NIF analysis in raw materials, pharmaceutical formulations, and biological fluids.
Section (B): Synthesis and Structural Elucidation of Nifuroxazide Impurities
Synthesis of Imps A, C, and D were carried out and the structures of the prepared compounds were confirmed by IR, NMR, and mass spectroscopy. Firstly, Imp A was prepared from methylhydroxybenzoate (Imp B) and hydrazine hydrate. While, Imp C was synthesized from the reaction of acetic anhydride and of furfural in presence of nitric and sulfuric acids. On the other hand, Imp D was prepared from Imp C and semicarbazide. Purification of the prepared impurities was carried out then their structures were confirmed by IR, Ms, and NMR analysis.
Section (C) : Determination of Nifuroxazide and Its Genotoxic Impurities by Different Multivariate Calibration Methods
Multivariate calibration models, such as SRACLS, CRACLS, and PLS have been successfully applied as selective stability indicating methods for determination of the quinary mixture of NIF and Imps (A-D).
To validate the predictive ability of the developed models, they were applied to predict the concentrations of NIF and Imps (A-D) in an external validation set. Statistical analysis with the reported method showed no significant difference.
Section (D): Determination of Nifuroxazide and Its Genotoxic Impurities by Different chromatographic Methods
This section was concerned with the development of specific stability indicating TLC-Densitometric and RP-HPLC methods for determination of NIF and Imps (A-D) in their bulk powder and pharmaceutical formulations. The five proposed components were well separated using ethylacetate: acetone: methanol: 33% ammonia solution (85: 25: 5: 0.5, by volume) as a developing system and the separated bands were scanned at 230 nm. While, RP-HPLC using gradient elution has been investigated and validated for quantitative analysis of NIF and its four toxic impurities (A-D). The chromatographic separation was achieved by using 0.1% (w/v) sodium lauryl sulfate solution : acetonitrile as mobile phase, then scanning the eluted components at 220 nm. The suggested methods have been applied for determination of the proposed drug in different laboratory prepared mixtures and in pharmaceutical formulation. No significant difference was found between the proposed methods and the reported one when they were compared using student’s t-test and F-test.
Part II: IN VIVO DETERMINATION OF THALIDOMIDE AND ITS CO-ADMINISTERED DRUG (DEXAMETHASONE): STUDYING OF THEIR PHARMACOKINETIC BEHAVIOR
This part includes two sections.
Section (A): Introduction and Literature Review
This section includes an introduction about the pharmacological action of Thalidomide (THD) and dexamethasone (DEX), their chemical structure, physical properties and summary of the methods developed for their analysis in raw material, pharmaceutical formulations, or in biological fluids.
Section (B): Determination of Thalidomide and Dexamethasone by Different chromatographic Methods and Investigation of Their Pharmacokinetic Parameters
In this section, selective, accurate, sensitive, and reproducible methods for studying the pharmacokinetics behaviors of THD and DEX in rat plasma. The applied methods were HPTLC and RP-HPLC methods. These methods have been developed with a particular focus on achieving sensitivity and specificity after intraperitoneal administration of the cited drugs to the rats using paracetamol (PAR) as internal standard. The proposed HPTLC was carried out using methylene chloride: acetone: ethyl acetate (70:40:10, by volume) as a mobile phase and scanning wavelength of 235 nm. While the separation was performed on RP-HPLC using C18 column and a mobile phase consisting of ethanol: 0.1% acetic acid in water (70:30, v/v) maintaining the flow rate at 0.6 mL min-1and scanning at 235 nm. The validation was performed to evaluate the performance of the proposed methods depending on the recommendations published by FDA. Pharmacokinetic parameters have been calculated by the proposed methods and the mutual effect of each drug was observed from the changes in the values of Cmax, half life (t1/2) , clearance , and volume of distribution (Vd).
Part III: QUANTITATIVE DETERMINATION OF BISOPROLOL FUMARATE AND ROSUVASTATINE CALCIUM IN THEIR BINARY MIXTURE
This part includes four sections.
Section (A): Introduction and Literature Review
This section includes an introduction about the pharmacological action of Bisoprolol Fumarate (BIS) and Rosuvastatin Calcium (ROS), their chemical structure, physical properties and summary of the methods reported for their analysis either together or with other components.
Section B: Determination of Bisoprolol Fumarate and Rosuvastatin Calcium by Different Spectrophotometric Methods
In this section, dual wavelength (DW) and area under curve corrected method (AUCCM) methods were described for determination of BIS and ROS in their binary mixture without preliminary separation. In this work, ROS was directly determined at its λ max = 300 nm. Dual wavelength method has been applied for determination of BIS and ROS in their binary mixture where, BIS concentrations were determined by measuring the absorbance difference at 222 nm and 249 nm, while for ROS absorbance difference at 240 nm and 282 nm was used. On the other hand, in AUCCM, BIS was analyzed by using the area in the range of 211-231 nm while, AUC in the ranges of 211-231 nm and 305-325 nm were recorded and used for calculation of a constant factor representing the ratio (AUCROS 211-231 / AUC ROS 305-325) for pure ROS. After simple mathematical calculations ROS could be selectively determined using AUC in the range of 305-325 nm.
The developed methods have been applied for determination of the studied components in different laboratory prepared mixtures; also they were applied for the novel formulated tablets preparation and there was no need for preliminary separation steps. The results obtained by applying the proposed methods for determination of BIS and ROS were statistically compared to those obtained by applying the reported methods with no significant difference between the compared methods
Section (C): Determination of Bisoprolol Fumarate and Rosuvastatin Calcium by Spectrofluorimetric Method
In this section, sensitive, specific and economic spectrofluorimetric method was developed for determination of BIS and ROS, with successful application to spiked human plasma. The emission intensity was measured at 297 and 485 nm using excitation wavelengths of 227 and 242 nm for BIS and ROS, respectively. The proposed method was applied for the laboratory prepared mixture and to the novel formulation with no interference from the added excipients. Method validation was performed according to ICH guidelines. All the calculated parameters were within the accepted limits.
Section (D): Determination of Bisoprolol Fumarate and Rosuvastatin Calcium by TLC-Densitometric Method
The developed TLC-Densitometric method depended on chromatographic separation of BIS and ROS using ethyl acetate: methanol: 33% ammonia solution (7: 3: 0.1, by volume) as developing system. The separated bands were scanned at 230 nm. The Proposed TLC-Densitometric method was applied for determination of BIS and ROS in their laboratory prepared mixture and to the novel formulation where good results were observed indicating no interference from the added excipients.
This thesis contais 261 references, contains 56 figures and 51 tables, ends with an Arabic summary.