Yes / Polymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid state characterisation of a polymorphic cocrystal composed of sulfadimidine (SD) and 4- aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared to a physical equimolar mixture and pure SD. / Science Foundation Ireland (SFI) under Grant Number 07/SRC/B1158 and SFI/12/RC/2275.

Thesis (MSc in Medical Science)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Para-aminosalicylic acid (PAS) is one of the first effective anti-tuberculosis agents and has become one of the principal second-line drugs to treat patients with an extended resistance spectrum. Despite being one of the oldest anti-tuberculosis drugs, little data is available regarding its pharmacokinetics, drug interactions, genetic factors and dosing regimens, especially for the relative new granular slow release PAS (GSR-PAS) preparation. Objectives The aim of the study was to investigate the pharmacokinetics, tolerability and safety of a single 8 g once- or 4 g twice-daily GSR-PAS dose in a multidrug- or extensively drug resistant tuberculosis (M/XDR-TB) population, in which some subjects were also co-infected with the human immunodeficiency virus (HIV). An additional objective was to investigate the potential covariates (i.e. genetic factors and drug interactions) that can alter the pharmacokinetics of PAS. Study design and methodology A randomised, two-period, open-label cross-over study was conducted in 32 adults (≥18 years old) with M/XDR-TB admitted at Brooklyn Chest Hospital, Cape Town, South Africa and treated for drug resistant tuberculosis with a multidrug regimen containing GSR-PAS. The subjects were randomised to follow a single 8 g once-daily GSR-PAS regimen or a 4 g twice-daily GSR-PAS regimen for 8 days. On the eighth day blood samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12 and 24 hours. After the 24-hour sample (Day 9) the regimens were crossed-over. The tolerability and safety of the two regimens were determined using Visual Analogue Scales and interviews. PAS plasma concentrations were determined by a developed HPLC-MS/MS method. N-acetyltransferase (NAT1 and NAT2) genotyping was performed. The data of this study together with unpublished data of a previous study in a very similar population were used in a pharmacometric analysis to determine the PK parameters and any subject covariates. Results and Discussion In comparison to the 4 g twice-daily GSR-PAS dose, the single 8 g once-daily GSR-PAS dose generated a pharmacokinetic profile with a significantly higher maximum concentration (Cmax), concentration at 12 hours (C12) and area under the curve 0 to 12 hours (AUC12). The concentrations of all subjects on the twice-daily regimen were maintained above a minimum inhibitory concentration (MIC) throughout a 12-hour interval, while the single 8 g dose was able to sustain the PAS plasma concentrations above the MIC in 18 out of 29 subjects (62.1%) for the entire 24-hour dosing interval. Both regimens were reasonably well tolerated but most subjects preferred the twice-daily dosing. The clearance of PAS was increased by 45% in HIV positive subjects prescribed antiretroviral treatment (ART), possibly due to interaction with efavirenz (EFV). No significant associations were found for any of the individual NAT1 or NAT2 genotypes, but a difference between mean concentrations of the different genotypic groups was reported. Conclusions The 8 g once-daily dose has the potential to be included in future regimens. The higher peak concentrations achieved can be expected to increase the bactericidal effect of GSR-PAS without significant loss of bacteriostatic effect, i.e. time over MIC. The 8 g once-daily dose has a reasonable tolerability and is potentially easier to supervise in an outpatient setting. Since antiretrovirals (ARVs) increase PAS clearance and decrease PAS exposure in HIV co-infected subjects on ART, the 8 g once-daily dose will be less suitable for maintaining bacteriostasis in these patients (inadequate PAS exposure). Therefore, PAS and ARV interactions need to be clarified before the 8 g once-daily dose can be recommended for the HIV co-infected patients on ART. / AFRIKAANSE OPSOMMING: Agtergrond Para-aminosalisielsuur (PAS) is een van die eerste effektiewe anti-tuberkulose middels en het een van die hoof tweede-lyn middels geword om pasiënte met 'n uitgebreide weerstand spektrum te behandel. Ondanks die feit dat PAS die oudste anti-tuberkulose middel is, is daar baie min data beskikbaar met betrekking tot die farmakokinetika, middel interaksies, genetiese faktore en dosering, veral in die geval van die relatiewe nuwe granulêre stadige vrystelbare PAS voorbereiding (GSV-PAS). Doel Die doel van die studie was om navorsing te doen oor die farmakokinetika, verdraagsaamheid en veiligheid van ʼn enkele 8 g een keer daaglikse en 4 g twee keer daaglikse GSV-PAS dosering in ʼn multi- of uitgebreide weerstandige tuberkulose (M/XDR-TB) populasie, waar sommige proefpersone ook met die Menslike Immuniteitsgebreksvirus (MIV) geko-infekteer is. ʼn Verdere doel van die studie was om te bepaal of potensiële kovariate soos genetika en medisyne interaksies die farmakokinetika van PAS verander. Metodes ʼn Onwillekeurige, twee-periode, oop-etiket oorkruisingstudie was op 32 M/XDR-TB volwassenes (≥ 18 jaar oud) uitgevoer terwyl hulle vir middel weerstandige tuberkulose in Brooklyn Chest hospitaal (Kaapstad, Suid-Afrika) behandel is. Die deelnemers was onwillekeurig ingedeel om ʼn 8 g eenkeer daaglikse GSV-PAS dosering of ʼn 4 g twee keer daaglikse GSV-PAS dosering vir agt dae te volg. Op die agste dag was bloedmonsters op die volgende ure 0, 1, 2, 3, 4, 6, 8, 12, en 24 geneem. Na die 24-uur monster (Dag 9) was die doserings omgekeer. Die verdraagsaamheid en veiligheid van die twee doserings is bepaal deur gebruik te maak van Visueel Analogiese Skale en onderhoude. PAS plasma konsentrasies is bepaal deur 'n ontwikkelde HPLC-MS/MS metode. N-asetieltransferase (NAT1 en NAT2) genotipering is uitgevoer. Die data van hierdie studie saam met ongepubliseerde data van 'n vorige studie is gebruik in farmakometriese analise om die farmakokinetiese parameters en enige kovariate te bepaal. Resultate en Bespreking In vergelyking met die 4 g GSV-PAS twee keer daaglikse dosis, het die enkele 8 g daaglikse dosis, ‘n pharmakokinetiese profiel met ‘n beduidende hoër maksimum konsentrasie (Cmax), 12-uur konsentrasie (C12) en area onder die kurwe van 0 tot 12 uur (AUC12), gegenereer. Die PAS plasma konsentrasies van alle proefpersone, wat op die twee keer daaglikse dosis was, was tydens die 12-uur interval bo die die minimum inhiberende konsentrasie (MIK) gehou. Terwyl die enkele 8 g dosis die PAS plasma konsentrasies vir die duur van die 24 uur interval bo die MIK in 18 van 29 (62%) proefpersone gehandhaaf het. Die meeste proefpersone het die twee-daaglikse dosering verkies, maar beide doserings was redelik goed verdra. Die verwydering van PAS het met 45% toegeneem in HIV positiewe proefpersone wat antiretrovirale behandeling ontvang het, moontlik weens interaksies met efavirenz. Geen beduidende assosiasies vir enige van die individuele NAT1 of NAT2 genotiepes was gevind nie, maar ‘n verskil tussen die gemiddelde konsentrasies van die verskillende genotiepes is gerapporteer. Gevolgtrekking Die 8 g een keer daaglikse dosis het die potensiaal om in toekomstige doserings ingesluit te word. Die hoër piek konsentrasies van die 8 g daaglikse dosis, kan moontlik die bakterisidiese (kiem-dodende) effek van GSV-PAS verhoog, sonder om die beduidende bakteriostatiese (kiem-inhiberende) effek (o.a. tyd oor MIK), te verloor. Die 8 g een keer daaglikse dosis is redelik verdraagsaam en kan potensieël makliker gekontrolleer word in die geval van buite-pasiënte. Serdert antiretrovirale middels (ARVs) PAS verwydering verhoog en gevolglik die PAS plasma konsentrasies verlaag in die MIV ko-infekteerde proefpersone wat op ARVs is, sal die 8 g een keer daaglikse dosis minder geskik wees vir die handhawing van bakteriostasis in hierdie pasiënte (onvoldoende PAS blootstelling). Dus moet daar klarigheid verkry word oor PAS en ARV interaksies voordat die 8 g een keer daaglikse dosis vir MIV ko-infekteerde pasiënte op ARVs aanbeveel kan word.

COMPOUNDS COMBINING PYRAZINAMIDE AND P-AMINOSALICYLIC ACID FRAGMENTS AS POTENTIAL ANTITUBERCULARS II ŽÁK ONDŘEJ Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic A series of new compounds combining pyrazinamide and p-aminobenzoic acid was prepared and in vitro tested for antimycobacterial activity against M. tuberculosis, M. avium, M. kansasii, M. aurum and M. smegmatis. Previously prepared 4-(5-chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (R1 = OH) exerted micromolar activity against M.tuberculosis and low in vitro cytotoxicity in HepG2 cells. Para-Aminosalicylic acid (PAS) has significant antitubercular properties based on its resemblance to p-aminobenzoic acid and interference with the folate pathway in mycobacteria. To assess the role of the PAS fragment, we designed and prepared derivatives with modified substitution on the phenyl ring (R1 ). Further modification was the exchange of 5-Cl on the pyrazine core for (alkyl)amino substituent (JZ-OZ), which was a successful modification in previous series. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Changing the PAS fragment, when we removed or replaced the OH-group at position 2, the antimycobacterial...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Petr Šlechta Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: MSc. Ghada Basem Bouz, Ph.D. Title of diploma thesis: Derivatives combining the fragment of pyrazinamide and 4-aminosalicylic acid as antimycobacterial compounds According to WHO, tuberculosis (TB) is the leading cause of death from a single infectious organism worldwide and the number of cases with drug resistant TB is still increasing, creating the need for new antituberculotics. Therefore, we report design, synthesis and antimicrobial evaluation of a series of hybrid compounds combining different pyrazinamide derivates and p- aminosalicylic acid as potential antituberculotic agents. The compounds were prepared by mixing different pyrazinecarboxylic acids, after activation by 1,1'-carbonyldiimidazole, with p- aminosalicylic acid in dimethylsulfoxide as a solvent. Obtained compounds were in vitro tested for their antimycobacterial activity against M. tuberculosis H37Rv, M. tuberculosis H37Ra and four other mycobacterial strains. Prepared compounds were also in vitro screened for antibacterial, antifungal, and cytotoxic (HepG2) activity. Most compounds showed antimycobacterial activity in range of...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Petr Šlechta Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: MSc. Ghada Basem Bouz, Ph.D. Title of diploma thesis: Derivatives combining the fragment of pyrazinamide and 4-aminosalicylic acid as antimycobacterial compounds According to WHO, tuberculosis (TB) is the leading cause of death from a single infectious organism worldwide and the number of cases with drug resistant TB is still increasing, creating the need for new antituberculotics. Therefore, we report design, synthesis and antimicrobial evaluation of a series of hybrid compounds combining different pyrazinamide derivates and p- aminosalicylic acid as potential antituberculotic agents. The compounds were prepared by mixing different pyrazinecarboxylic acids, after activation by 1,1'-carbonyldiimidazole, with p- aminosalicylic acid in dimethylsulfoxide as a solvent. Obtained compounds were in vitro tested for their antimycobacterial activity against M. tuberculosis H37Rv, M. tuberculosis H37Ra and four other mycobacterial strains. Prepared compounds were also in vitro screened for antibacterial, antifungal, and cytotoxic (HepG2) activity. Most compounds showed antimycobacterial activity in range of...

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 123-135.

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-05-08T13:19:35Z No. of bitstreams: 1 humbertocostagarcia.pdf: 7732602 bytes, checksum: e034ff9506a2c6b4e666fd0b184c56bc (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-17T13:43:22Z (GMT) No. of bitstreams: 1 humbertocostagarcia.pdf: 7732602 bytes, checksum: e034ff9506a2c6b4e666fd0b184c56bc (MD5) / Made available in DSpace on 2017-05-17T13:43:22Z (GMT). No. of bitstreams: 1 humbertocostagarcia.pdf: 7732602 bytes, checksum: e034ff9506a2c6b4e666fd0b184c56bc (MD5) Previous issue date: 2012-11-30 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Esta tese apresenta a síntese, caracterização espectroscópica e estrutural de 24 sistemas supramoleculares, obtidos a partir de reações envolvendo ácidos orgânicos, ligantes nitrogenados e alguns íons metálicos da primeira série de transição. Os compostos foram denominados [Mn(bpa)(H2O)4]B2.4H2O (1), [Fe(bpa)(H2O)4]B2.4H2O (2), [Co(bpa)(H2O)4]B2.4H2O (3), [Zn(bpa)(H2O)4]B2.4H2O (4), [Co2(mal)2(bpa)(H2O)2] (5), (bipi)(Hbipi+)AS-.H2O (6), [Co(bipi)2(H2O)4]ASCl.3H2O (7), (H2bpe)B2.2H2O (8), [Fe(bpe)(H2O)4]B2.4H2O (9), [Co(bpe)(H2O)4]AS2.4H2O (10), [Ni(bpe)(H2O)4]AS2.4H2O (11), [Zn(bpe)(H2O)4]AS2.4H2O (12), HASbpa (13), [Co(bpa)(H2O)4]AS2.4H2O (14), [Mn2(bpp)4(H2O)4]AS4.H2O (15), [Co2(bpp)4(H2O)4] AS4.H2O (16), [Zn(bpp)(AS)2] (17), [Mn(Hbpa)2(H2O)2(4-sb)2].2H2O (18), [Co(Hbpa)2(H2O)4](4-sb)2 (19), [Ni(Hbpa)2(H2O)4](4-sb)2 (20), [Zn(Hbpa)2(H2O)4](4-sb)2 (21), [Mn(bipi)2(H2O)4](H2Vi)2 (22), Mn(bpa)2(H2O)4](H2Vi)2 (23) e [Mn(bpp)2(HVi)]H2O (24). Para os compostos obtidos, a técnica de difração de raios X por monocristal foi utilizada para descrever o modo de coordenação, distância, ângulo de ligação e a presença de interações supramoleculares, tais como empacotamento π, ligação de hidrogênio, C–H...π, N–H...π e eletrostáticas. Tais interações foram importantes, para a estabilidade das estruturas e na formação de arranjos denominados não covalentes, que foram classificadas segundo a nomenclatura da literatura, e nomeadas neste trabalho, para alguns compostos como pseudo favo de mel, cadeia, retângulo, dentre outros. O estudo vibracional de todos os compostos sintetizados, envolvendo a espectroscopia Raman e infravermelho forneceu informações importantes, sobre a geometria de coordenação e a presença dos blocos construtores utilizados em cada síntese. O uso de bandas marcadoras, utilizadas para monitorar os ligantes presentes nos produtos obtidos, demonstrou sua importância na posição do número de onda de cada uma das bandas, quando comparadas com os ligantes livres, a fim de identificar a presença de cada um dos blocos construtores utilizados. Por fim, todas as informações estruturais e espectroscópicas foram discutidas, a fim de compreender as forças não covalentes responsáveis pela existência da estrutura no estado sólido, consideradas muito importante no contexto da química supramolecular. / This thesis presents the synthesis, spectroscopic and structural characterization of twenty-four supramolecular compounds, obtained from the reaction involving organic acids, nitrogenous ligands and several transition metal ions. The obtained compounds were named [Mn(bpa)(H2O)4]B2.4H2O (1),[Fe(bpa)(H2O)4]B2.4H2O (2), [Co(bpa)(H2O)4]B2.4H2O (3), [Zn(bpa)(H2O)4]B2.4H2O (4), [Co2(mal)2(bpa)(H2O)2] (5), (bipi)(Hbipi+)AS-.H2O (6), [Co(bipi)2(H2O)4]ASCl.3H2O (7), (H2bpe)B2.2H2O (8), [Fe(bpe)(H2O)4]B2.4H2O (9), [Co(bpe)(H2O)4]AS2.4H2O (10), [Ni(bpe)(H2O)4]AS2.4H2O (11), [Zn(bpe)(H2O)4]AS2.4H2O (12), HASbpa (13), [Co(bpa)(H2O)4]AS2.4H2O (14), [Mn2(bpp)4(H2O)4]AS4.H2O (15), [Co2(bpp)4(H2O)4]AS4.H2O (16), [Zn(bpp)(AS)2] (17), [Mn(Hbpa)2(H2O)2(4-sb)2].2H2O (18), [Co(Hbpa)2(H2O)4](4-sb)2 (19), [Ni(Hbpa)2(H2O)4](4-sb)2 (20), [Zn(Hbpa)2(H2O)4](4-sb)2 (21), [Mn(bipi)2(H2O)4](H2Vi)2 (22), Mn(bpa)2(H2O)4](H2Vi)2 (23) and [Mn(bpp)2(HVi)]H2O (24). For most of the obtained compounds, the X-ray single crystal diffraction technique has been used to describe the coordination mode, distances, bond angles as well as the presence of supramolecular interactions, such as π-stacking, hydrogen bonding, C–H…π, N–H…π and electrostatic interactions. Such interactions were considered very important for the stability of the structures and for the generation of the so-called non-covalent arrangements, which are classified according to the literature nomenclature, being mentioned in this work for some of the compounds, such as pseudo honeycomb, chain or rectangle, among others. The vibrational study of all the synthesized compounds, involving infrared and Raman spectroscopic techniques, has also provided important information about the coordination geometry and the presence of the building blocks used in each synthesis. The use of specific vibrational bands, used as markers to monitoring the ligands present in the obtained products, has shown the importance of the wavenumber position of each one of the bands, when compared to the free ligands, in order to identify the presence of each one of the building blocks used. At last, all the structural and spectroscopic information have been discussed in order to understand the non covalent forces responsible for the existence of the solid state structures, considered very important in the context of supramolecular chemistry.

Cette thèse a été consacrée à la mise au point de deux systèmes d'administration destinés à la voie orale, pour deux molécules différentes.Dans la première partie, des microparticules (MPs) à base de xylane et d'Eudragit® S-100 ont été produites pour encapsuler l’acide 5-aminosalicylique et permettre son absorption au niveau du colon. Le xylane a été extrait à partir de rafles de maïs et caractérisé selon ses propriétés physico-chimiques, rhéologiques et toxicologiques. Par la suite, les MPs ont été préparées soit par réticulation interfaciale, soit par séchage par atomisation et caracterisés quant à leur morphologie, leur taille moyenne et leur distribution, leur stabilité thermique, leur cristallinité, leur efficacité et leur profil de libération du médicament in vitro. Des MPs de caractéristiques physiques appropriées avec des rendements satisfaisants ont été préparées par ces deux méthodes, bien que les systèmes séchés par pulvérisation aient montré une plus grande stabilité thermique. En général, ces derniers systèmes étaient plus prometteurs en raison de leur stabilité thermique et de l'absence d'agents réticulants toxiques. Toutefois, la méthodologie doit être optimiser afin d’améliorer le chargement de principe actif ainsi que sa libération.Dans la deuxième partie de cette thèse, des microémulsions huile-dans-l’eau (ME H/E) à base de triglycérides à chaîne moyenne ont été preparées afin de vectoriser et d’augmenter la solubilité de l'amphotéricine B (AmB). Des diagrammes de phases ont été construits en utilisant des mélanges de tensioactifs dont les valeurs de la balance hydrophile-lipophile variaient entre 9,7 et 14,4. Les MEs H/E sans et avec AmB étaient composées de gouttelettes sphériques non agrégées de diamètre moyen autour de 80 et 120 nm, respectivement, et avec une faible polydispersité. L'incorporation de l'AmB était élevée et dépendait de la fraction volumique de la phase dispersée. La viabilité des cellules J774.A1 n’était pas diminuée par l’exposition aux concentrations d’AmB encapsulée allant jusqu’à 25μg/mL. Par conséquent, les MEs H/E à base d’esters de propylèneglycol et d'acide caprylique peuvent être considéré comme des vecteurs adaptés pour l’AmB. / This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S-100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spray-dried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on medium-chain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophilic-lipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 µg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB.

This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S-100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spray-dried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on medium-chain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophilic-lipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 µg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB.

Disponibiliza??o do trabalho em conte?do parcial, conforme Termo de Autoriza??o. / Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2017-03-27T19:34:05Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) fernanda_souza_paula_parcial.pdf: 515579 bytes, checksum: f72e2289acf5068c063e2bd00f0fefc3 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2017-04-24T16:35:34Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) fernanda_souza_paula_parcial.pdf: 515579 bytes, checksum: f72e2289acf5068c063e2bd00f0fefc3 (MD5) / Made available in DSpace on 2017-04-24T16:35:34Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) fernanda_souza_paula_parcial.pdf: 515579 bytes, checksum: f72e2289acf5068c063e2bd00f0fefc3 (MD5) Previous issue date: 2017 / O trabalho investiga a utiliza??o de plataformas eletroqu?micas contendo filmes polim?ricos derivados do ?cido 4-aminosalicico (4-AMS) para imobiliza??o da enzima Urato oxidase (UOx) visando aplica??o na quantifica??o de ?cido ?rico (AU) em amostras de urina. Investigou-se a eletrodeposi??o do 4-AMS pelas t?cnicas de voltametria c?clica (VC) e cronoamperometria (CA) sobre eletrodos de grafite (EG). Por VC foram realizados 100 ciclos de potencial na faixa de -0,25 a 1,25 V ? 50 mV/s em solu??o 2,50 mM do mon?mero preparado em H2SO4 0,50 M. Utilizando a CA, a eletropolimeriza??o foi realizada a potencial constante de +0,928 V durante 5600s no mesmo meio reacional utilizado na VC. O poli(4-AMS) obtido por VC e CA mostrou dois pares redox, os quais est?o relacionados a eletroatividade do filme polim?rico, na regi?o de potencial de +0,50/+0,40 V. Contudo, maiores valores de Ipa e Ipc foram obtidos para os eletrodos modificados por VC, sugerindo que estes filmes s?o mais eletroativos. A deposi??o do azul da Pr?ssia (AP), mediador da rea??o de per?xido, foi investigada sobre os EG, com posterior modifica??o com poli(4-AMS). Notou-se que a presen?a do AP n?o altera o perfil voltam?trico da eletropolimeriza??o do 4-AMS. Contudo, quando comparada com a eletropolimeriza??o somente nos EG, obteve-se filmes mais resistivos e com menor eletroatividade. Analisando as propriedades eletroqu?micas e morfol?gicas, por VC conseguiuse filmes mais uniformes, com maior quantidade de material depositado e maior eletroatividade. A eletropolimeriza??o foi realizada tamb?m sobre eletrodos impressos de grafite contendo azul da Pr?ssia (EI/AP), onde posteriormente imobilizou-se 5 U da UOx, e o biossensor foi acoplado a uma c?lula de fluxo num sistema de an?lise por inje??o em fluxo (FIA) de linha ?nica. A vaz?o e o volume da al?a de amostragem foram otimizados em 2,10 mL/min e 200 ?L, repectivamente. O valor de pH da solu??o do analito foi otimizado em 8,27. Medidas de reprodutibilidade mostraram desvio padr?o de 2,15% (n=10). O biossensor respondeu linearmente para AU na faixa de 1,0 x 10-5 a 2,0 x 10-4 M, com limite de detec??o de 3,0 ?M. Amostras de urina foram dilu?das (1:10) e injetadas diretamente no biossensor. A reposta foi reprodut?vel mostrando baixo desvio padr?o para as medidas, e valores encontrados dentro da faixa esperada para o analito em amostras de urina. Testes de adi??o e recupera??o mostraram valores de 97,35% (?2,43). O biossensor mostrou-se bastante promissor para a proposta do trabalho, apresentando resultados muito satisfat?rios para as an?lises e par?metros investigados. / Disserta??o (Mestrado) ? Programa de P?s-Gradua??o em Qu?mica, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2017. / This work investigates the use of electrochemical platforms containing polymeric films derived from 4-aminosalicylic acid (4-ASA) modified with the enzyme Urate oxidase (UOx) for quantification of uric acid (UA) in urine samples. The electrodeposition of 4-ASA was investigated through Cyclic Voltammetry (CV) and Chronoamperometry (CA) on graphite electrodes (GE). 100 cycles were performed in the range of -0.25 to 1.25 V at 50 mV/s in 2.50 mM monomer solution prepared in 0.50 M H2SO4. Using CA, the deposition was performed at a potential of +0.928 V for 5600 s in the same CV reaction medium. The poly(4-ASA) showed two redox pairs related to the electroactivity of the polymeric film in the potential range of + 0.50 /+ 0.40 V. However, higher values of Ipa and Ipc were obtained for the electrodes modified through CV, suggesting that these films are more electroactive. The deposition of Prussian blue (PB), mediator of the peroxide reaction, was investigated on the GE with subsequent modification with poly (4-ASA). It was observed that the presence of PB does not alter the voltammetric profile of 4-ASA electropolymerization. However, when compared with the electropolymerization in bare GE, more resistive films were obtained with lower electroactivity. Analyzing the electrochemical and morphological properties through CV, more uniform films were obtained, with more material deposited and greater electroactivity. The electropolymerization of poly(4-ASA) was also conducted on screen printed electrodes containing Prussian Blue (SPE/PB), with subsequent immobilization of 5U of Uox. This biosensor was coupled to a flow cell in a Flow Injection Analysis (FIA) system of single line. The flow rate and the sampling loop volume were optimized at 2.10 mL/min and 200 ?L, respectively. The pH value of the analyte solution was optimized at 8.27. Reproducibility measures showed a standard deviation of 2.15% (n = 10). The biosensor responded linearly to UA in the range of 1.0 x 10-5 to 2.0 x 10-4 M, with a detection limit of 3.0 ?M. Urine samples were diluted (1:10) and directly injected over the biosensor. The response was reproducible with low standard deviation and values found within the range expected for the analyte in urine samples. Addition and recovery tests showed values of 97.35% (?2.43). The biosensor is very promising for the work proposal, presenting very satisfactory results for the analyzes and investigated parameters.