Analytical Study Of Certain Drugs Used For Treatment Of Central Nervous System Disorders Of Forensic Medicine Interest.

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1 Dept. of Analytical Chemistry Analytical Study Of Certain Drugs Used For Treatment Of Central Nervous System Disorders Of Forensic Medicine Interest. Thesis Presented By Mira Mansour Mahmoud Ibrahim Wagih B. Pharm. Sci., Alexandria University, 2002 M. Pharm. Sci., Alexandria University, 2014 For the Degree of Philosophy Doctor in Pharmaceutical Sciences (Analytical Chemistry) Under Supervision of Fawzia A. Ibrahim Magda A. Barary Prof. of Pharmaceutical Analytical Chemistry Dr. Amira F. El-Yazbi Lecturer of Pharmaceutical Analytical Chemistry 2017

2 SUPERVISORS TITLE: Analytical study of certain drugs used for treatment of Central nervous system disorders of forensic medicine interest. NAME: Mira Mansour Mahmoud Ibrahim Wagih. Supervisors: Name Position Signature Fawzia A. Ibrahim Magda A. Barary Prof. of Pharmaceutical Analytical Chemistry Dr. Amira F. El-Yazbi Lecturer of Pharmaceutical Analytical Chemistry Head of the Department of Analytical Chemistry Vice Dean for Research and Graduate Studies Dean of Fatma El Zahraa A. Ali Manal I. Eid Nahed M. El-Enany

3 APPROVAL SHEET TITLE: Analytical study of certain drugs used for treatment of Central nervous system disorders of forensic medicine interest. NAME: Mira Mansour Mahmoud Ibrahim Wagih. Supervisors: Name Position Signature Fawzia A. Ibrahim Magda A. Barary Dr. Amira F. El-Yazbi Thesis has been approved by: Prof. of Pharmaceutical Analytical Chemistry Lecturer of Pharmaceutical Analytical Chemistry Name Position Signature Mohie M. Sharf El Dine Fathy M. Salama Fawzia A. Ibrahim For Boys Al Azhar University Head of the Department of Analytical Chemistry Fatma El Zahraa A. Ali Vice Dean for Research and Graduate Studies Manal I. Eid Dean of Nahed M. El-Enany

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6 Acknowledgement Acknowledgement First of all, I thank Allah for giving me the strength and the ability to complete this thesis and for holding me in difficult times I met in this work and in life. Often, there comes a time in life when no words can do justice to one s thoughts and feelings. I must personally thank many persons for this accomplishment of mine, but I am concerned I will miss some. I would like to express my sincere thanks and deep gratitude to Professor Dr. Fawzia A. Ibrahim, Professor of Analytical Chemistry, for suggesting the point and plan of the study, providing brilliant support, continuous encouragement, helpful instructions and assistance through the whole work. My deep thanks go to Professor Dr. Magda A.Barary, Professor of Pharmaceutical Analytical Chemistry, for her active supervision and laborious effort for systemic planning and directing the course of preparing this thesis. Her continuous guidance throughout this research is greatly appreciated. I also wish to express my sincere faithful gratitude to Dr. Amira F. El-Yazbi, Lecturer of Pharmaceutical Analytical Chemistry, for her valuable technical advice, for being a steady influence throughout this thesis, orienting and supporting me with promptness and care. She was always close in the most difficult moments and her support was essential to me to overcome difficult times I passed throughout the development of this work. Finally, my deep gratitude and warm thanks to my family for making me understand the importance of education and providing support and encouragement throughout my studies. They gave me every opportunity to pursue a higher education to the best of my ability. They have been a great inspiration to my life. Thanks for being by my side all the time and making me able to maintain hope in the future. Mira Mansour Mahmoud Ibrahim Wagih

7 Publications Published Papers 1- Spectrofluorimetric Determination of Topiramate and Levetiracetam as Single Components in Tablet Formulations and in Human Plasma and Simultaneous Fourth Derivative Synchronous Fluorescence Determination of their Co-Adminstered Mixture in Human Plasma. Published in Journal of Fluorescence, 2016, 26, (Impact factor = 1.667) 2- Sensitive Inexpensive HPLC Determination of Four Antiepileptics in Human Plasma: Application to Pharmacokinetic Studies. Published in Bioanalysis Journal, 2016, 8, (Impact factor = 2.813) Submitted Papers 1- Simultaneous Determination of Zonisamide, Topiramate, and Sulpiride in Human Plasma by a Specific Fluorescent Turn-on Chemosensor based on 4-Chloro-7- Nitrobenzofurazan Followed by Simple Chromatographic Separation. Submitted in Journal of Chromatography B. 2- Sensitive Inexpensive Spectrophotometric and Spectrofluorimetric Analysis of Ezogabine, Levetiracetam and Topiramate in Tablet Formulations using Hantzsch Condensation Reaction Submitted in Journal of Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy.

8 English Summary English Summary. Most of the drugs used in the treatment of central nervous system disorders have narrow therapeutic drug index. So, the dose of these drugs should be carefully adjusted according to each pathological condition to avoid any toxic manifestations, especially for patients receiving a polytherapy treatment where the risk of toxic side effects is highly increased. Risk of sudden heart failure and also the incidence of suicidal attempts may present an explanation for the high prevalence of many of these drugs category in forensic cases. So, the interpretation of their concentrations in biological specimens is highly needed. Accordingly, it is deemed necessary to propose suitable methods to assay these drugs in their pharmaceutical preparations and in biological fluids. Drugs selected for the present study are: topiramate, levetiracetam, lamotrigine, carbamazepine, oxcarbazepine, zonisamide, sulpiride and ezogabine. The thesis consists of six main parts. A validated spectrofluorimetric method is proposed for the analysis of topiramate and levetiracetam, separately in pharmaceutical tablets and in human plasma. The method was successfully applied for the determination of the two drugs in their tablet formulations and in real human plasma samples for therapeutic drug monitoring of each of them for epileptic patients on either topiramate or levetiracetam monotherapy treatment. Topiramate and levetiracetam were simultaneously determined in human plasma using fourth derivative synchronous spectrofluorimetric technique. The simultaneous determination of both drugs in plasma of epileptic patients on polytherapeutic treatment regimens after oral administration of the two drugs was studied. On the other hand, a simple and reliable HPLC method with UV detection for the simultaneous determination of carbamazepine, levetiracetam, lamotrigine and oxcarbazepine 1

9 English Summary in human plasma samples was proposed. The developed method was successfully applied for pharmacokinetic study of each of the four antiepileptic drugs (AEDs). Also, the therapeutic drug monitoring of these drugs in patient s plasma receiving different binary combinations of the four AEDs has been carried out. Also, a validated, rapid, sensitive and accurate HPLC-fluorescence detection method after pre-column derivatization with NBD-Cl was presented for the simultaneous determination of the two AEDs (zonisamide and topiramate) with the antidepressant drug; sulpiride in volunteers plasma at their therapeutic level with no interference from plasma matrix and any metabolites. The method has successfully been applied to pharmacokinetics study of zonisamide and topiramate. The proposed analytical method was also used for the quantitation of zonisamide and topiramate in human plasma samples of epileptic patients treated with zonisamide or topiramate in combination with antidepressant; sulpiride and of patients on multitherapy combination of both AEDs drugs for synergistic antiepileptic drug combinations. Finally, two sensitive, simple and selective spectrophotometric and spectrofluorimetric methods have been developed for determination of ezogabine, levetiracetam and topiramate in their pure and in tablet dosage forms. The proposed methods are based on the condensation of the primary amino group of the three drugs with acetylacetone and formaldehyde according to Hantzsch reaction yielding highly fluorescent yellow colored dihydropyridine derivatives. For all the previously mentioned methods, statistical analysis of the results has been carried out including derivation of the regression equations for the different calibration graphs, accuracy, precision, limit of detection and quantitation and specificity have been investigated. The thesis consists of 205 pages and compromises six main parts including; 36 tables, 28 figures and 151 references and ends with an arabic summary 2