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Abstract SUMMARY xxviii SUMMARY This thesis is concerned with the analysis of two psychoactive CNS acting drugs; atypical antipsychotic and antidepressant drugs namely Sertindole and Bupropion HCl, respectively. The aim of this thesis was to study the stability of these drugs under various stress conditions to develop validated stability indicating methods that are simple, accurate, rapid, and sensitive for the quantitative determination of the studied drugs in their drug substances and drug products. The thesis comprises five parts and ends with general discussion, references and the arabic summary. Part One: Introduction and literature review This part comprises two sections: Section A: General introduction In this section a brief introduction to CNS acting drugs is presented including: their definition, classification, and mechanism of their pharmacological action. Section B: Literature review This section includes a detailed presentation of Sertindole and Bupropion HCl including their chemical structures, physicochemical properties, stability and pharmacology. It also includes a review on different methods and techniques used for estimation of the studied drugs in their drug substances, drug products and biological fluids. Part Two: Forced degradation Studies of Sertindole and Bupropion HCl In this part, a study of Sertindole and Bupropion HCl degradation under various stress conditions (acid, alkaline and oxidative degradation) is presented .It also includes methods of preparation and characterization of acid, alkaline and oxidative degradates of the studied drugs using UV spectrophotometry, TLC and HPLC techniques. Sertindole acid and oxidative degradates were isolated and subjected to mass spectrophotometry and IR. SUMMARY xxix The structures of acid, alkaline and oxidative degradates of the drugs under study were elucidated using mass spectrophotometry and IR and by using data collected from previously published methods in literature. Suggestion of the different degradation processes pathways of the studied drugs is also presented in this part. Part Three: Stability Indicating Chromatographic Methods for the Determination of Sertindole and Bupropion HCl This part is divided into three sections: Section A: Stability Indicating TLC–densitometric Chromatographic Method for the determination of Sertindole The method was based on TLC separation of Sertindole from its acid and oxidative degradates followed by densitometric measurement of the intact drug spots at 254 nm. The separation was carried out on aluminum TLC plates with 0.2 mm thickness silica gel 60 F254 using acetonitriledichloromethane- 35% ammonia solution, in ratio 5:5:0.3 (v/v/v) as a developing system. Section B: Stability Indicating High Performance Liquid Chromatographic Methods for the Determination of Sertindole and Bupropion HCl These methods were based on the separation of intact Sertindole and Bupropion HCl from their corresponding acid, alkaline and oxidative degradates and the separation of Bupropion HCl from nicotine as a co- administered drug in the presence of Bupropion HCl hydrolytic and oxidative degradates. Mobile phase consisting of 0.065 M ammonium acetate buffer solution – ethanol - acetonitrile in the ratio 45:30:25 (v/v/v), containing 0.25% w/v octane sulphonic acid sodium salt, pH adjusted to 6 with o-phosphoric acid and Waters symmetry C8 column (5μm Particle size, 15 cm x 4.6 mm ) were used for separation of Sertindole. Quantification was achieved with flourimetric detection at λ em 335 nm after excitation at 257 nm. SUMMARY xxx Mobile phase consisted of 0.075 M ammonium acetate buffer solution – methanol – acetonitrile - triethylamine in ratio 44:44:150:0.15(v/v), containing 0.25% w/v octane sulphonic acid sodium salt, pH adjusted to 6 with o-phosphoric acid and Intersil ODS3 column (5μm particle size, 25 cm x 4.6 mm) were used for separation of Bupropion HCl from its hydrolytic, oxidative degradates and nicotine. Quantification was achieved with dual wave length UV detection at 250 nm for Bupropion HCl and nicotine and at 224 nm for Bupropion HCl degradates. The proposed methods were used to investigate the kinetics of the oxidative degradation of Sertindole, and the alkaline and oxidative degradation of Bupropion HCl at different temperatures. Section C: Stability Indicating Rapid Resolution Liquid Chromatographic Methods for the Determination of Sertindole and Bupropion HCl These methods were based on the separation of intact Sertindole and Bupropion HCl from their corresponding acid, alkaline and oxidative degradates. The mobile phase used for separation of Sertindole consisted of, 0.065 M ammonium acetate buffer solution – ethanol – acetonitrile in the ratio, 45:30:25(v/v/v), containing 0.25% w/v octane sulphonic acid sodium salt, and the pH was adjusted to 8 with 25 % ammonia solution, using SB-CN Zorbax column (1.8 μ Particle size, 5 cm x 4.6 mm).Quantification was achieved with UV detection at 226 nm. The mobile phase used for separation of Bupropion HCl from its degradates consisted of, 0.075 M ammonium acetate buffer solution – methanol – acetonitrile – triethylamine in the ratio, 44:44:100:0.15 (v/v), containing 0.25 % (w/v) heptane sulphonic acid and the pH was adjusted to 5 with o-phosphoric acid, using XDB C18 column (1.8 μ particle size, 5 cm x 4.6 mm). Quantification was achieved with dual wave length UV detection at 250 nm for Bupropion HCl and at 224 nm for its degradates. SUMMARY xxxi Part Four: Spectrophotometric Methods for the Determination of Sertindole and Bupropion HCl This part comprises two sections: Section A: Stability Indicating Second Derivative (D2) and Second Derivative Ratio (DR2) Spectrophotometric Methods for the Determination of Sertindole and Bupropion HCl In this section two spectrophotometric techniques were applied for the determination of Sertindole and Bupropion HCl. The first was the second derivative (D2) spectrophotometric technique to develop a method for quantitative determination of both Sertindole in presence of its acid degradate at 261 nm and Bupropion HCl in presence of its alkaline and oxidative degradates by measuring amplitudes at 224 nm and 269 nm. Bupropion HCl was also determined in presence of a mixture of its degradates and the co- administered drug; nicotine at 269 nm. The second technique used was the second derivative of ratio spectra (DR2) to develop stability indicating method for the determination of Sertindole in presence of its acid and oxidative degradates at amplitudes of 260 nm using 10 μg/mL of acid degradate as divisor and amplitudes at 258 nm using 10 μg/ mL of oxidative degradates as divisor, respectively. It was also used for the determination of Bupropion HCl in presence of its alkaline and oxidative degradates by measuring the amplitudes at 224 nm and 270 nm. Bupropion HCl was also determined in presence of a mixture of its degradates and nicotine at 270 nm. Section B: Spectrophotometric Method for the Determination of Sertindole using charge Transfer Complex with p- chloroanilic acid (p- CA) This section includes brief introduction about p- CA and its uses in determination of various therapeutic agents. The spectrophotometric method was based on the reaction of Sertindole as an electron donor with the π acceptor p- CA. The formed anion was measured at 520 nm using acetonitrile as solvent. SUMMARY xxxii The mechanism of the reaction was explained and the optimum conditions for the reaction were determined .Moreover the molar absorbtivity , association constant as well as the standard free energy change using Benesi-Hildebrand plot together with the complex stochiometry by continuous variation method (Job’s method) were all determined . Part Five: Stability Indicating Spectrofluorimetric Methods for the Determination of Sertindole In this part Sertindole was determined spectroflourimetrically using two methods. Method A was based on measuring the native florescence of Sertindole at λ em 335 nm after excitation at λ ex 257 nm, using isopropanol as solvent in presence of its acid and oxidative degradates. Method B was based on measuring the enhanced native flouresence of Sertindole in micellar microenvironment using sodium dodecyl sulfate as sensitizing agent and Britton Robinson buffer pH 3.29 as solvent. The optimum conditions for measurement were carefully studied. All of the proposed methods were statistically compared with the manufacturer methods in case of Sertindole and the official USP methods in case of Bupropion HCl to emphasize their validity in terms of accuracy and precision; for use in the determination of the investigated drugs in their drug substances and drug products. Moreover, the accuracy of the proposed methods was evaluated using one way ANNOVA test. This thesis ends with a general discussion where a comparative study between the suggested methods was presented. The thesis refers to 169 references, contains 54 tables, 93 figures, and 3 Schemes. Part I |