الفهرس 
Part I: general introductionOnly 14 pages are availabe for public view
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Abstract
The present thesis is focused on the development of new simple, sensitive, and green analytical methods for the analysis of two anticancer drugs (Doxorubicin and Mitoxantrone) in bulk, their pharmaceutical preparations, and spiked human plasma.
The presented thesis falls into eight parts:
Part I:
General Introduction
This part provides a general introduction about the investigated compounds such as chemical structure, chemical properties, pharmacological aspect, and analytical review for the reported analytical techniques used for determination of the studied drugs in pure forms, dosage forms, and biological fluids. At the end of this part, the aim of the suggested work was outlined.
Part II:
Facile one-pot green solvent synergized fluorescence approach for determination of doxorubicin in presence of paclitaxel; co-administered drug, Application to stability study and analysis in bulk, vial, and biological fluids
This part describes a green, fast, simple, economical, ultra-sensitive, and accurate spectrofluorimetric method for the estimation of Doxorubicin hydrochloride (DOX), a type II topoisomerase enzyme inhibitor either alone and in the presence of concurrently administered drug; paclitaxel in bulk, pharmaceutical dosage form and biological fluids. The proposed method was based on studying the fluorescence demeanor of DOX in different organized media and solvents. The intrinsic fluorescence was found to be greatly enhanced in acidic ethanolic solution. The maximum intensity of fluorescence was observed at 590 nm after excitation at 475 nm. Different experimental parameters were examined and adjusted involving various organized media, solvents, and pH. The method was validated according to ICH guidelines. The linearity of the method was accomplished in the range of 0.007–4.0 µg ml-1. The values of LOD and LOQ were 2.0 and 6.0 ng ml-1 respectively. The present method is extremely sensitive enough for the determination of traces of the drug in various biological fluids with excellent % recovery. The proposed method was extended to investigate the stability of DOX following various induced degradation protocols including acidic, alkaline, oxidative, and photolytic. In addition, the kinetics of the degradation of DOX was investigated and the apparent first-order rate constant, half-life times, and quantum yield was calculated.
Part III:
Investigating the interaction of mitoxantrone with anionic surfactants by spectrofluorimetry and its application for the feasible analysis of pharmaceutical preparation and biological fluids
In this part, the behavior of mitoxantrone (MTX), an anthracenedione antineoplastic agent, in different types of the organized medium was explored using molecular spectrofluorimetry. The original fluorescence and quantum yield of MTX was augmented about five folds in the aqueous buffered solution (Britton–Robinson, pH 3.0) by the addition of SDS. Enhancement in the fluorescence intensity did not come from the boost in the ultraviolet (UV) light absorbance of the drug but due to shielding of the lowest excited singlet state of the drug inside the cavity of the micelle from the radiationless process. Accordingly, a versatile, sensitive, and feasible spectrofluorimetric method was constructed and evaluated for MTX determination. Fluorescence measurements were performed at 675 nm (λex 610 nm). A linear relationship was shown between fluorescence intensity and drug concentration within the range of 0.01–2.0 μg ml−1 of MTX with a correlation coefficient of 0.9999 and a detection limit of 2 ng ml−1. The developed method was effectively used for the analysis of MTX in biological samples and dosage forms. In addition, the method was expanded to study the stability of MTX exposed to different drastic degradations and the kinetic parameters of the degradation were calculated.
Part IV:
A β-diketone based derivatized fluorimetric approach for the determination of anthracycline antineoplastic drug; doxorubicin. application to biological fluids and dosage form and evaluation of approach greenness
A new, feasible, and selective fluorimetric strategy for doxorubicin assay has been outlined in this part. The analytical method relies on the development of condensed fluorescent derivatives upon its reaction with ninhydrin reagent. The final product was monitored at λem 482 nm after excitation at λex 391 nm. Under appropriate reaction conditions, the primary amine group in doxorubicin is condensed with ninhydrin (β-diketone), and phenylacetaldehyde (Benzacetaldehyde) in the presence of Teorel buffer as a buffered medium. The method showed linearity when the concentration of doxorubicin was plotted against response in the range (1 – 10 μg mL-1). The layout of the reaction variables was explored and the analysis of the validity parameters was addressed according to ICH directives that have been done exactly. Besides, an interference study was carried out to ensure that there was no inconsistency with the pharmaceutical excipients. Finally, the proposed approach was successfully applied to the DOX assay in the commercially available dosage form with high accuracy (99.10–101.03) and relative error (-0.814–1.03) %.
Part V:
An intuitive spectrofluorimetric protocol based on dihydropyridine formation for assay of doxorubicin; a type II topoisomerase enzyme inhibitor in bulk, marketed formulation, and biofluids; evaluation of method greenness
This part was devoted to the development and validation of a selective spectrofluorimetric method for the assay of doxorubicin hydrochloride (DOX). The method relies on the condensation reaction between DOX and acetylacetone/formaldehyde using acetate buffer (pH 4.5). The emission of the formed fluorescent product was measured at 485 nm after excitation at 423 nm. Parameters affecting the reaction were studied and carefully controlled. The constructed calibration graph appeared rectilinear in the range of (0.1 – 2.5 µg mL-1) and the estimated LOD was 22 ng mL-1. A product in the Egyptian market was assayed via the suggested method and the final results were in coincidence with that of the reported method. The selectivity of the proposed approach was evaluated and results were satisfying and confirm the reliability of the approach. Finally, the directives of ICH guidelines were applied to establish the validity of the work.
Part VI:
An isoindole fluorescent derivatizing reaction for sensitive fluorimetric assay of doxorubicin in the marketed formulation and biological fluids; evaluation of approach greenness
This part illustrates the development of a new, sensitive, and economic protocol for assay of cytotoxic topoisomerase II inhibitor drug; doxorubicin (DOX). In the presence of β-mercaptoethanol, the amino moiety of doxorubicin condenses with o-phthalaldehyde to give isoindole fluorescent derivative. The isoindole product was measured at λex 336 nm, (λem 438 nm). The condensation variables were carefully adjusted. The fluorescence intensity of measurements was plotted versus DOX concentration to give a linearity range over 0.1–2.5µg mL—1. The proposed approach was fully validated by the directives of ICH guidelines and applied without any influence of the excipients for doxorubicin vial analysis. Furthermore, the procedure was applied in commercial dosage form and also applied to biofluids (spiked urine and plasma). The analysis was accompanied by an excellent percentage recovery. The greenness of the proposed method was evaluated according to the analytical eco scale.
Part VII:
Utility of Eosin Y dye as a probe for the selective determination of mitoxantrone via Resonance Rayleigh scattering and fluorimetric quenching; Application to bulk, vial, and biofluids; greenness evaluation of the method
In this work, spectrofluorimetric and resonance Rayleigh scattering techniques were applied for the determination of mitoxantrone through its facile association complex formation with eosin reagent in an acidic medium. The spectrofluorimetric determination has relied on the quenching effect of mitoxantrone on the fluorescence intensity of Eosin Y at 544.5 nm (excitation = 301 nm). On the other side, the resonance Rayleigh scattering (RRS) method has relied on the enhancement in the resonance Rayleigh scattering intensity of eosin Y at 367 nm. The linear ranges of the two developed methods were 0.07−2.5 µg mL-1 and 0.06−2.0 µg mL-1 with detection limits of 0.016 µg/mL and 0.009 µg/mL for the spectrofluorimetric method and the RRS methods respectively. All reaction conditions for mitoxantrone-eosin Y complex formation were experimentally optimized. In addition, both methods were validated according to ICH guidelines. Moreover, the developed methods were applied for the estimation of mitoxantrone in its pharmaceutical vial dosage form with excellent recoveries. Furthermore, the suggested spectroscopic methods were successfully applied to biological fluids (plasma and urine).
Part VIII
A facile eco-friendly quantitative analytical approach for doxorubicin assay in presence of concurrently administrated drug; paclitaxel by FT-IR spectroscopy using absorbance mode
Green, cost-effective, non-destructive simple and reliable Fourier-transform infrared (FTIR) spectroscopic method was suggested for the assay of a topoisomerase II inhibitor anticancer drug; DOX singly and in its laboratory synthetically binary combined mixture with concurrently administrated taxol drug; paclitaxel. The assay was carried out in bulk powder and pharmaceutical formulation without interference from common dugs excipients. the cited drug has been directly determined in the solid-state by FTIR spectroscopy without any sample pretreatment step. The method was completely validated according to the International Council on Harmonization (ICH) criteria. The analytical signal is linear with the drug concentration in the range of 1.0–18.0 μg/mg. The limits of detection and quantification were 0.22 and 0.72 μg/mg. The FTIR method has been successfully applied for the determination of the cited drug either alone or in the presence of paclitaxel in raw material and commercial pharmaceutical formulation and the obtained results showed high % recovery. The analytical process has also been designed following green chemistry guidelines and the method is consistent with the environmental safety green level.