Atliktas palyginamasis dviejų kompleksinių sistemų - Cu|Cu(II), glicinas ir Cu|Cu(II), maleino rūgštis - elektrocheminių charakteristikų tyrimas. Nustatytos maleino rūgšties tirpalų pusiausvyrinės charakteristikos. Kiekybiniam titravimo kreivių aprašymui išvestos lygtys, kuriose įvertinti medžiagų bei krūvių balansai bei atsižvelgta į praskiedimo efektus. Jų taikymas pH-metrinių duomenų analizei davė tokias maleato anijonų protonizacijos konstantų reikšmes: log = 6,05, log = 7,48. Nustatyta, kad tirpaluose su 0,3 M K2SO4 priedu protonizuotų ligando formų stabilumas sumažėja (log = 5,75, log = 7,30). Cu(II) maleatinių kompleksų stabilumui nustatyti panaudotas spektrofotometrijos metodas ir pasiūlyta duomenų analizės procedūra. Ji remiasi kiekybiniu absorbcijos spektrų aprašymu, taikant lygtis, išplaukiančias iš valdomo harmoninio osciliatoriaus teorijos. Išanalizavus įvairių sudėčių tirpalų absorbcijos maksimumo dydžius, prieita išvados, kad rūgščiose terpėse vyrauja monoligandinis kompleksas, kurio koncentracinė stabilumo konstanta log b1 = 2,2. Atlikta sistemos Cu|Cu(II), maleino rūgštis pusiausvyrų termodinaminė analizė. Nustatyta, kad esant metalinio vario ir tirpalų sąlyčiui, sistemoje galimi gilūs virsmai, kurių metu iki 90 % Cu(II) transformuojasi į Cu(I). Teorines išvadas patvirtina eksperimentiniai duomenys, gauti spektrofotometrijos ir elektrocheminės kvarco kristalo mikrogravimetrijos metodais. Įvertinti Cu korozijos bei fazinių Cu2O sluoksnių susidarymo... [toliau žr. visą tekstą] / A comparative investigation of electrochemical characteristics of two complex systems, viz. Cu|Cu(II), glycine and Cu|Cu(II), maleic acid, was carried out. The equations were obtained for quantitative description of pH-metric and spectrophotometric data, which were used for determination of equilibrium characteristics in Cu(II)-maleic acid solutions. Thermodynamic analysis shows that deep changes are possible in this system resulting in 90 % transform of Cu(II) into Cu(I). The rates of Cu corrosion and Cu2O formation are estimated to be of the same order (nmol cm-2 s-1). Regularities of formal electrochemical kinetics, which account for the mass transport of chemically interacting particles and for step-wise charge transfer process, are suitable for interpretation of voltammetric data of the Cu|Cu(II), glycine system. Kinetic parameters Cu(II) glycinate complex depend on the nature of the supporting electrolyte: the exchange current density decreases and the cathodic charge transfer coefficient increases in the sequence: Li+ - Na+ - K+ - Cs+. To enhance the Cu(I) generation in maleic acid system, the pre-electrolysis procedure was applied. It was found that its effect depends on solution pH. Applied theoretical model describes satisfactorily the steady-state voltammetric characteristics of Cu|Cu(II), maleic acid system, but some contradictory results were obtained in the case of time-dependent processes. Theoretical and experimental problems to be solved are discussed.

Made available in DSpace on 2016-06-23T12:15:52Z (GMT). No. of bitstreams: 2 8.pdf: 3689916 bytes, checksum: a4c61da95d92274fea88f64811279b9b (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2015 / Made available in DSpace on 2016-07-05T22:38:01Z (GMT). No. of bitstreams: 3 8.pdf.txt: 190771 bytes, checksum: 7024cfb0c1d780928508c0218ded115f (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 8.pdf: 3689916 bytes, checksum: a4c61da95d92274fea88f64811279b9b (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / A hipertensão arterial é o principal fator de risco para doenças cerebro vasculares e doenças isquêmicas do coração, sendo uma das causas mais importantes para a morbidade e a mortalidade cardiovascular. O maleato de enalapril, fármaco alvo deste estudo, é um pró-fármaco que, após a administração oral, é rapidamente absorvido e hidrolisado em seu metabólito ativo, o enalaprilato, um potente inibidor da enzima conversora da angiotensina. Ao longo do tempo vem sendo dada maior atenção aos fatores que podem influenciar na variabilidade da biodisponibilidade, como a determinação físico-química do insumo farmacêutico ativo (IFA) e excipientes utilizados na formulação, assim como processo de fabricação. O estudo de pré-formulação é de grande importância para o desenvolvimento do medicamento maleato de enalapril 20mg. O insumo farmacêutico ativo (IFA) possui dois polimorfos, que foram aqui caracterizados por difração de raios X de pó (DRXP), também foram aplicadas técnicas de análise térmica como DSC (differential scanning calorimetry) e TGA (thermogravimetric analysis), porém não demostraram efetividade na caracterização do IFA. Estas técnicas também foram aplicadas para caracterização dos excipientes utilizados nas duas propostas de formulação inicial e de medicamentos já comercializados no mercado nacional. As análises de caracterização dos medicamentos do mercado foram de grande importância para identificar/propor o processo de fabricação dos medicamentos e observar diferenças no uso de excipientes, dando suporte para a definição preliminar das formulações a serem testadas, além do processo de fabricação. O IFA tem grande sensibilidade à temperatura e umidade, degradando-se em duas substâncias dicetopiperazina e enalaprilato. Neste estudo foram ainda realizadas análises físico-químicas de duas formulações de maleato de enalapril 20mg comprimidos simples. Cada formulação foi preparada por um processo diferente granulação via úmida e mistura para compressão direta. Os comprimidos das duas formulações foram acondicionados em dois diferentes materiais de embalagem, por 30 dias, em câmara climática a 30 ºC e 40 ºC com 75% de umidade relativa. Os resultados demonstraram que o processo de granulação via úmida provê maior estabilidade físico-química aos comprimidos, durante o tempo estudado. Os resultados de DRXP e DSC confirmaram a similaridade do medicamento referência com a formulação 1, proposta por granulação via úmida. Foi possível delinear a formulação preliminar e o processo de fabricação adequado para o desenvolvimento da formulação do maleato de enalapril 20mg comprimidos simples. / Hypertension is a major risk factor for cerebrovascular disease and ischemic heart disease, one of the most important causes of morbidity and cardiovascular mortality. There are many classes of antihypertensive agents with many effective representatives in reducing blood pressure. The enalapril maleate, drug aim of this study is a prodrug which, after oral administration, is rapidly absorbed and hydrolyzed to its active metabolite, enalaprilat, a potent inhibitor of angiotensin converting enzyme. By the time it has been given greater attention to the factors that may influence the variability of bioavailability, as the physicochemical determination of active pharmaceutical ingredient (API) and excipients used in the formulation, as well as the manufacturing process. The pre-formulation study is of great importance for drug development of enalapril maleate 20 mg tablets. The active pharmaceutical ingredient (API) has two polymorphs, which are here characterized by powder diffraction X-ray (XRPD) were applied also techniques of thermal analysis such as DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis), but not demonstrated effectiveness in characterizing the API. These techniques have also been applied to characterization of the excipients used in the two proposals for initial formulation and drugs already marketed in the Brazilian market. The analytical characterization of the market drugs were of great importance to identify / propose the drug manufacturing process and observe differences in the use of excipients, providing support for the preliminary setting of the formulations to be tested, besides the manufacturing process. The API has great sensitivity to temperature and humidity, degrade into two substances - diketopiperazine and enalaprilat. In this study, physical and chemical analyzes were performed on two enalapril maleate 20 mg tablets. Each formulation was made by a different process - wet granulation and blend for direct compression. Tablets of the two formulations were placed in two different packaging materials, for 30 days in a climatic chamber at 30 °C and 40 °C with 75 % relative humidity. The results showed that the wet granulation process generates higher physical and chemical stability to the tablets during the studied time. The results of XRPD and DSC confirmed the similarity of the reference medicine with the formulation 1, proposed by the wet granulation. It was possible to delineate the preliminary formulation and manufacturing process suitable for the development of the formulation of enalapril maleate 20 mg tablets.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-19T12:55:25Z No. of bitstreams: 1 marciacristinadesouza.pdf: 5105854 bytes, checksum: c8581c343320796810b90eea2875a21d (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T17:57:22Z (GMT) No. of bitstreams: 1 marciacristinadesouza.pdf: 5105854 bytes, checksum: c8581c343320796810b90eea2875a21d (MD5) / Made available in DSpace on 2016-01-25T17:57:22Z (GMT). No. of bitstreams: 1 marciacristinadesouza.pdf: 5105854 bytes, checksum: c8581c343320796810b90eea2875a21d (MD5) Previous issue date: 2015-07-31 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O mecanismo de ação dos fármacos anti-hipertensivos inibidores da enzima conversora da angiotensina (ECA) captopril, lisinopril e enalapril está relacionado à formação de um complexo in vivo com o íon Zn2+ presente no sítio ativo da ECA. Dessa forma, este trabalho consistiu na síntese e caracterização estrutural de três complexos de Zn2+ com os fármacos captopril e lisinopril para comparar se in vitro os sítios de coordenação desses fármacos é parecido com o sugerido in vivo. Além disso, foi sintetizado o dímero dissulfeto de captopril e avaliado a estabilidade do fármaco captopril em relação à formação de seu dímero. Um sal formado pelo princípio ativo íon enaprilato e o íon potássio e a forma polimórfica II do maleato de enalapril foram obtidos. Todos os compostos formados (com exceção de MEFormaII) foram caracterizados pelas técnicas de espectroscopia vibracional (IV e Raman) e análise elementar de CHN, sendo que os complexos LISZn1 e LISZn2 também foram caracterizados por análise térmica. Alguns compostos foram analisados por difração de raios X por mono e policristais. Na estrutura cristalina do complexo CAPZn o íon Zn2+ adotou uma geometria tetraédrica, coordenando-se a quatro ligantes diferentes por dois átomos de oxigênio do grupo carboxilato e dois átomos de enxofre do grupo sulfidrila. Desta forma, a interação in vitro entre o fármaco captopril e o íon Zn2+ foi semelhante àquela sugerida in vivo, uma vez que a coordenação do captopril ocorreu pelo átomo de enxofre. Este complexo apresentou grupo espacial P41 e um polímero de coordenação tridimensional foi formado. O estudo da interação enzima ECA com o fármaco captopril também foi mimetizado pela análise da distribuição da densidade eletrônica do complexo CAPZn, que analisou o caráter das ligações do íon Zn2+ e a ocupação dos orbitais d. Dois complexos inéditos de Zn2+ com o fármaco lisinopril di-hidratado foram obtidos através de diferentes sínteses. As diferenças sintéticas levaram a formação de compostos com diferenças estruturais significativas, uma vez que LISZn1 é amorfo enquanto que LISZn2 é cristalino. A estrutura cristalina do complexo LISZn2 foi determinada por difração de raios X por monocristais. O complexo exibiu o fármaco lisinopril coordenado ao íon Zn2+ pelos átomos de oxigênio dos grupos carboxilato e carbonil bem como pelos átomos de nitrogênio das aminas primária e secundária. A interação in vitro entre o fármaco lisinopril e o íon Zn2+ em LISZn2 foi semelhante em alguns aspectos àquela sugerida in vivo, uma vez que a coordenação do fármaco lisinopril ocorreu pelo átomo de oxigênio do grupo carboxilato central. Este complexo cristalizou-se em um grupo espacial não-centrossimétrico trigonal (P32) e um polímero de coordenação unidimensional foi formado. Esta estrutura cristalina obtida é um exemplo de geminação meroédrica por inversão, o que exigiu métodos de refinamento não usuais. DISCAP foi obtido através de condições hidrotérmicas e cristalizou-se em um sistema cristalino monoclínico e grupo espacial P21. O empacotamento cristalino é estabilizado por ligações de hidrogênio intra e intermoleculares. O estudo da estabilidade do fármaco captopril em relação à formação de seu dímero dissulfeto de captopril foi efetuado através da obtenção de difratogramas e espectros vibracionais Raman do fármaco ao longo do tempo com exposição ao ar. A quantificação das fases presentes na amostra do fármaco captopril exposta por 52 semanas ao ar através do método de Rietveld mostrou que as quantidades de captopril e dissulfeto de captopril presentes na amostra são de 95 e 5%, respectivamente. Cálculos DFT no estado sólido foram realizados para captopril e DISCAP. Os resultados indicaram que DISCAP é aproximadamente 30 Kcal mol-1 mais estável que o captopril. A forma polimórfica II do maleato de enalapril (MEFormaII) foi obtida e comparada à forma I. A principal diferença entre as formas polimórficas se refere à conformação da molécula de enalapril, observada principalmente no ângulo de torção C10-O1-C11-C12, referente ao grupo éster. Os espectros vibracionais do sal formado pelo princípio ativo íon enaprilato e o íon potássio (HIDROME) mostraram a ausência de bandas referentes ao íon maleato (()) e ao grupo éster do composto enalapril ((), () e ()). Isso é um indício de que o íon maleato não esteja presente no composto formado e que o grupo éster do composto enalapril possa ter sido hidrolisado. A investigação das estruturas cristalinas obtidas forneceu os modos de coordenação desses ligantes ao íon Zn2+, além da proporção metal-ligante nos complexos formados e as interações intermoleculares responsáveis pela estabilização do sólido cristalino. Esta investigação contribuiu para um melhor entendimento de como ocorre a interação ECA-fármaco no organismo humano. / The mechanism of action of the angiotensin-converting enzyme (ACE) inhibitors antihypertensive drugs captopril, lisinopril and enalapril is related to the formation of a (in vivo) complex with the catalytic Zn2+ ion present at the active site of ACE. Thus, this work consisted in synthesis and structural characterization of three complexes of Zn2+ with the drugs captopril and lisinopril to observe whether in vitro the coordination sites of these drugs is similar to that suggested in vivo. Furthermore, it was synthesized the captopril disulfide dimer and evaluated the stability of drug captopril in relation the formation of its dimer. A salt formed by active principle enalaprilat ion and potassium ion and the form II of enalapril maleate were obtained. All compounds formed (with exception of MEFormaII) were characterized by vibrational spectroscopy techniques (IR and Raman) and elemental analyses for C, H and N, and the LISZn1 and LISZn2 complexes were also characterized by thermal analysis. Some compounds were analyzed by single crystal and powder X-ray diffraction. In the crystal structure of the CAPZn complex, the coordination sphere of Zn2+ ion showed a tetrahedral geometry. Each Zn2+ center is coordinated to four captopril ligands by two oxygen atoms of the carboxylate group and two sulfur atoms of the sulfhydryl group. Therefore, the interaction in vitro between the captopril drug and Zn2+ ion was similar to which is suggested in vivo, since the coordination of captopril drug occurred by the sulfur atom. CAPZn crystallized in a non-centrosymmetric space group, P41 and a three-dimensional coordination polymer was formed. The study of ACE enzyme interaction with the drug captopril was also mimicked by analyzing distribution of the electron density of CAPZn complex, which analyzed the character of the bond of metal ion and the occupation of d orbitals. Two new zinc complexes with the lisinopril drug were obtained from different synthesis. The synthetic differences led to the formation of compounds with significant structural differences since LISZn1 is amorphous while LISZn2 is crystalline. The crystal structure of LISZn2 complex was determined by X-ray diffraction technique. The complex exhibited the lisinopril drug coordinated to a Zn2+ ion by the oxygen atoms of the carboxylate and carbonyl groups as well as the primary and secondary amine nitrogen atoms. The interaction in vitro between the lisinopril drug and Zn2+ ion in LISZn2 was similar in some aspects to which is suggested in vivo, since the coordination of lisinopril drug occurred by the oxygen atom of central carboxylate group. This complex crystallized in a trigonal noncentrosymmetric space group (P32), and a one-dimensional coordination polymer was formed. This structure obtained is an example of twinning by inversion merohedry. It could not be solved by routine methods. DISCAP was obtained under hydrothermal conditions and crystallized in acentric space group P21. The crystal packing is stabilized by intramolecular and intermolecular hydrogen bonds. The study of the stability of the captopril compound was conducted by obtaining Raman spectra and diffractograms of drug over time with air exposure. The quantification of crystalline phases present in the sample captopril drug exposed for 52 weeks to the air through the Rietveld method demonstrated that the quantity captopril and captopril disulfide in the sample are 95 and 5%, respectively. DFT calculations in the solid state were performed for captopril and DISCAP. The results indicated that the DISCAP is approximately 30 kcal mol-1 more stable than captopril. The polymorphic form II of enalapril maleate (MEFormaII) was obtained and compared to the form I. The main difference between the polymorphic forms refers to the conformation of enalapril molecule, observed mainly in torsion angle C10-O1-C11-C12, relative to the ester group. The vibrational spectra of the salt formed by active principle enalaprilat ion and potassium ion (HIDROME) showed the absence of bands related to (), (), () and (). This is an indication that the maleate ion is not present in compound formed and that the ester group may have been hydrolyzed. The investigation of the crystal structures obtained provided the coordination modes these ligands to the Zn2+ ion, in addition to the metal-ligand ratio in complexes formed and molecular interactions responsible for the stabilization of the crystalline solid. This investigation contributed to a better understanding of how occurs the interaction ACE-drug in human organism.

The twin screw extrusion technique has been explored to produce lyotropic liquid crystal coated powder precursor by exploiting Pluronic F127 thermoreversible gelation property to get powder precursor without granular aggregates or with less compacted granular aggregates. The highly soluble chlorpheniramine maleate loaded in Pluronic F127 solution coated MCC particles prepared through twin screw extrusion was examined to produce the cubic phase (gel) for the development of controlled release formulation and for coating of very fine particles which cannot be achieved by traditional bead coaters. Controlled release formulations are beneficial in reducing the frequency of administration of highly soluble drugs having short half life and also to address the problem of polypharmacy in old age patients by reduction of dosage frequency. An unusual refrigerated temperature (5 C) profile for twin screw extrusion was selected based on the complex viscoelastic flow behaviour of Pluronic F127 solution which was found to be highly temperature sensitive. The Pluronic F127 solution was found to be Newtonian in flow and less viscoelastic at low temperature, such that low temperature (5 C) conditions were found to be suitable for mixing and coating the MCC particles to avoid compacted aggregates. At higher temperatures (35-40 C) Pluronic F127 solution exhibited shear thinning and prominent viscoelasticity, properties which were exploited to force CPM containing Pluronic F127 solution to stick over the MCC surface. This was achieved by elevating the temperature of the last zone of the extrusion barrel. It was found that to avoid compacted aggregates the MCC must be five times the weight of the Pluronic F127 solution and processed at a screw speed of 400 RPM or above at refrigerated temperature. Processing was not found to be smooth at ambient temperature with frictional heat and high torque generation due to significant compaction of coated particles which can be attributed to the elastic behaviour of Pluronic F127 solution at temperatures between ambient to typical body temperature. PLM images confirmed the cubic phase formation (gel) by Pluronic F127 coating which was found to be thick with maximum Pluronic F127 concentration (25%). SEM images showed smoothing of surface topography, and stretching and elongation of MCC fibres after extrusion which is indicative of coating through extrusion processing. Plastic deformation was observed for the lower Pluronic F127 concentration and higher MCC proportions. There was a significant decrease in work done for cohesion by the powder flow analyser observed in the batches with more aggregates compared with batches with least aggregates. A regression analysis study on factorial design batches was conducted to investigate the significant independent variables and their impact on dependent variables for example % torque, geometric mean diameter and work done for cohesion, and to quantitatively evaluate them. From the regression analysis data it was found that the coefficient of determination for all three dependent variables was in the range of 55-62%. The pharmaceutical performance of the prepared coated LLC precursor through twin screw extrusion in terms of controlled release was found to be very disappointing. Almost 100% chlorpheniramine maleate was released within 10-15mins, defined as providing burst release. The MDSC method was developed within this work to detect Pluronic F127 solution cubic phase formation. The MDSC method was developed to consider sample size, effect of heating and cooling, sample heat capacity, and the parameters for highest sensitivity which can be followed by sample accurately without the phase lag to produce accurate repeatable results.

Der wichtigste exzitatorische Neurotransmitter Glutamat spielt eine grosse Rolle in der Gehirnentwicklung, wie neuronale Migration und Synaptogenese. Ob glutamaterge Stimulation für das Überleben entwickelnder Neuronen notwendig ist, war bislang jedoch unbekannt. Um zu untersuchen, ob eine Hemmung von Glutamatrezeptoren im unreifen Gehirn zu Neurodegeneration führt, wurden Ratten im Alter von 1 bis 31 Tagen für 24 Stunden mit dem N-Methyl-D-Aspartat-(NMDA) Glutamatrezeptorantagonisten Dizocilpin (MK801) behandelt. Die Dichte neuronaler Degeneration wurde mikroskopisch in Kupfer-Silber- und TUNEL- gefärbten Hirnschnittpräparaten ermittelt und Unterschiede mittels ANOVA analysiert (Signifikanzniveau p / The predominant excitatory neurotransmitter glutamate plays a major role in certain aspects of neural development. However, whether developing neurons depend on glutamate for survival remains unknown. To investigate if deprivation of glutamate stimulation in the immature mammalian brain causes neuronal cell death (apoptosis), rat pups aged 0 to 30 days were treated for 24 hours with dizocilpine maleate (MK801), an N-methyl-D-aspartate-(NMDA) glutamate receptor antagonist. Density of neural degeneration was evaluated by a stereological dissector method in cupric-silver and TUNEL-stained brain slices. Groups were compared by ANOVA and significance considered at p