الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 252 |  |  |
| | | from | 252 | | |
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