Magister Pharmaceuticae - MPharm / Fast dispersible tablets (FDTs) are solid single-unit dosage forms that are placed in the mouth and allowed to disperse or dissolve in the saliva without the need of water. The basic approach to formulating FDTs consists of adding a superdisintegrant to a tablet formulation. These tablets offer both the advantages of conventional tablets and liquid dosage forms along with distinctive properties which include accurate dosing, ease of administration, quick onset of action, enhanced bioavailability, and increased patient adherence. FDTs have been found to be effective in remedying therapeutic in-adherence caused by dysphagia (swallowing difficulties) particularly in paediatric and geriatric subjects. There is a strong correlation between therapeutic success and patient adherence especially with HIV/AIDS treatment regimens, consequently the dosage form should be patient friendly and devoid of unappealing characteristics. This study aimed at developing a cost effective fast dispersible tablet of lamivudine using alternative excipients and conventional techniques. Only conventional tablets and oral liquid dosage forms of lamivudine are available on the South African market. Two natural polymers reported to have superdisintegrating properties were selected to serve as multipurpose excipients in this study. The polymers were identified, characterised and compared using thermal, spectroscopic and micromeritic analytical tools. The polymer that displayed the best characteristics in terms of micromeritic, tableting and disintegrating properties was retained and used for the optimum formulation. The optimum formulation was composed of 150 mg of lamivudine, 23% w/w unripe banana powder and 2% w/w magnesium stearate. FDTs of lamivudine were obtained using the compression technique with and without wet granulation. The tablets were assessed as per the United States Pharmacopoeia (USP) guidelines and other evaluation procedures pertaining to FDTs. The wet granulated tablets were found to be less friable and thus more resilient than the directly compressed tablets. In-vitro disintegration of the wet granulated tablets occurred within 50±3 sec in deionised water (pH 7) and 35±2 sec in a phosphate buffer solution (pH 6.8). Consequently, the innovative tablets fulfilled the core requirement of FDTs i.e. rapid disintegration. Drug release studies were carried out by analysing dissolution aliquots of the innovative tablets using a validated High Performance Liquid Chromatography (HPLC) method, and comparing them to Aspen Lamivudine®, a conventional tablet of lamivudine presently on the South African market. Complete dissolution in deionised water (pH 7) was attained within 10 minutes and 30 minutes for the innovative tablets and Aspen Lamivudine® respectively.

Ces dernières années, l’OMS a émis un signal d’alarme à propos de l’occurrence majeure de résistance bactérienne qui constitue un problème de santé publique global. A ce titre, la recherche de nouvelles cibles enzymatiques et le développement de nouveaux antibactériens ciblant ces dernières de manière sélective constitue alors un enjeu actuel impératif. La mise en évidence d’une nouvelle enzyme de la famille des thymidylates synthases par l’équipe de Myllykallio en 2002 et son étude a permis de faire de cette dernière une cible de choix pour la conception de nouveaux antibactériens par sa présence exclusive chez des bactéries pathogènes pour l’Homme, sa non-similarité structurelle avec l’enzyme thymidylate synthase classique et son mécanisme particulier mettant en jeu un couple de cofacteurs oxydo-réducteurs(NADPH/FAD). Ce manuscrit, divisé en trois grandes parties, s’intéresse dans un premier temps à la synthèse métallo-catalysé de nouveaux analogues nucléotidiques du FAD substitué sur l’azote centrale par une chaîne acyclique de type alkényle phosphonate. Dans un second temps, le manuscrit traite de la translation de cette même chaîne latérale sur l’azote N1 couplée à un large panel de base hétéroaromatiquebicyliques ou tricycliques par deux réactions clés : une alkylation régiosélective en conditions deVorbrüggen et une étape de métathèse croisée. Enfin, la troisième partie porte sur la préparation d’acyclonucléosides comportant un motif d’intérêt de type gem-difluoromethylphosphonate connu comme étant un mime isostérique et isoélectronique du groupement phosphate. L’incorporation de ce motif a permis la synthèse de petite librairie d’ANPs inédits à visée anti-FDTS et anti-virales. / In recent years, WHO has warned against the major occurrence of bacterial resistance as a global public health problem. As such, the search for new enzymatic targets and the development of new antibacterials targeting them selectively is therefore an imperative challenge. The discovery of a new enzyme among the family of thymidylate synthases by Myllykallio’s team in 2002 and its study has made it a prime target for the design of new antibacterials by its sole presence in pathogenic bacteria, its structural dissimilarity with the classical thymidylate synthase enzyme and its singular mechanism involving a pair of oxido-reducingcofactors (NADPH / FAD).This manuscript, divided into three main parts, is initially interested in the metallocatalytic synthesis of new nucleotide analogues of FAD substituted on the central nitrogen by analkenyl phosphonate acyclic chain. In the second part, the manuscript deals with the translation of this same side chain on nitrogen N1 on a large panel of bicylic or tricyclic heteroaromatic base through two keyreactions: a regioselective alkylation under Vorbrüggen conditions and a cross metathesis step. Finally, th ethird part relates to the preparation of acyclonucleosides comprising a gem-difluoromethylphosphonatefunctional group which is known to be an isosteric and isoelectronic mimic of the phosphate group. The incorporation of this moeitie has allowed the synthesis of a small library of novel ANPs for anti-FDTS andanti-viral purposes.