Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This work presents a simple and accessible synthetic route for the preparation of a series, of nineteen new N-substituted 4-trifluormethyl-5- (propan-1-ol-3-yl)-pyridin-2-(1H)-imines, obtained from the reaction between 3- (3,4-dihydro-2H-pyran-5-yl)-4,4,4-trifluorobut-2-enenitrile with the following amines: methylamine, ethylamine, propylamine, iso-propylamine, butylamine, sec-butylamine, benzylamine, phenethylamine, 2-methoxy-phenethylamine, 4- methoxy-phenethylamine, 3,4-methoxy-phenethylamine, 4-fluorophenethylamine, 2-chloro-phenethylamine, 3-chloro-phenethylamine, 4-chlorophenethylamine, 2-(1-cyclohexenyl)-ethylamine, 2-N-morpholyl-ethylamine, N,N-dimethyl-ethyl-1,2-diamine e N,N-diethyl-ethyl-1,2-diamine. The 2-pyridinimines were synthetized through a solvent free methodology and in a short reaction time. The purification step was performed with liquidliquid extractions. After evaporation of the solvent, the product was washed with hot hexane to remove any trace of residual amine. The products were obtained with yield between 29-82%. The 2-pyridinimines obtained in this work were characterized by 1H and 13C NMR, 2D NMR, Mass Spectrometry, and Infrared Spectroscopy and their purity confirmed by Elemental Analysis and/or High Resolution Mass Spectrometry. / Este trabalho apresenta uma rota sintética simples e acessível para a preparação de uma série inédita com dezenove compostos 4-trifluormetil-5- (propan-1-ol-3-il)-1H-piridin-2-iminas N-substituídas, a partir da reação entre o 3-(3,4-diidro-2H-piran-5-il)-4,4,4-trifluorbut-2-enonitrila com as seguintes aminas primárias: metilamina, etilamina, propilamina, iso-propilamina, butilamina, sec-butilamina, benzilamina, fenetilamina, 2-metóxi-fenetilamina, 4- metóxi-fenetilamina, 3,4-metóxi-fenetilamina, 4-fluor-fenetilamina, 2-clorofenetilamina, 3-cloro-fenetilamina, 4-cloro-fenetilamina, 2-(1-cicloexenil)- etilamina, 2-N-morfolil-etilamina, N,N-dimetil-etil-1,2-diamina e N,N-dietil-etil- 1,2-diamina. A síntese destes compostos foi realizada através da utilização de uma metodologia livre do uso de solventes em curtos tempos reacionais. A etapa de purificação foi realizada com extrações líquido-líquido. Posteriormente, o produto proveniente da extração, foi lavado com hexano a quente, a fim de remover algum traço de amina residual. Os rendimentos obtidos dos compostos foram em torno de 29-82%. As 2-piridiniminas obtidas neste trabalho foram caracterizadas por Ressonância Magnética Nuclear de Hidrogênio, Ressonância Magnética Nuclear de Carbono-13, Espectrometria de Massas e Espectroscopia de Infravermelho, seus graus de pureza comprovadas via Análise Elementar e/ou Espectrometria de Massas de Alta Resolução.

Lithium-ion batteries (LIBs) have been widely used as the most popular rechargeable energy storage and power sources in today’s portable electronics, electric vehicles, and plug-in hybrid electric vehicles. LIBs have gained much interest worldwide in the last three decades because of their high energy density, voltage, rate of charge and discharge, reliability, and design flexibility. I am exploring the possibility of developing battery manufacturing technologies that would lower the cost, reduce the environmental impact, and increase cell performance and durability. This dissertation is focused firstly on understanding the effect of mixing sequence (the order of introducing materials) and optimizing the electrode fabrication for the best electrochemical performance, durability, lower cost, and improve the existing manufacturing processes. The electrode system consists of active material, polymer binder, conductive agent, and solvent. I have investigated four different mixing sequences to prepare the slurries for making the positive electrode. The key sequence-related factor appears to be whether the active material and conductive agent are mixed in the presence of or prior to the introduction of the binder solution. The mixing sequences 1, 2, 3, and 4 were optimized, and the rheological behavior of the slurries, morphology, conductivity, and mechanical and electrochemical properties of electrodes were investigated. Slurries from sequences 1 and 4 show different rheological properties from 2 and 3. The amount of NMP required to achieve a comparable final slurry viscosity differed significantly for the sequences under study. The sequence 1 shows better long-term cycling behavior than sequences 2, 3 and 4. This study quantifies the link between electrode slurry mix parameters and electrode quality. Secondly, a new method of making lithium-ion battery electrodes by adapting an immersion precipitation (IP) technology commonly used in membrane manufacturing was developed and demonstrated. The composition, structure, and electrochemical performance of the electrode made by the IP method were compared favorably with that made by the conventional method. The toxic and expensive organic solvent (NMP) was captured in coagulation bath instead of being released to the atmosphere. The IP electrodes show an excellent performance and durability at potentially lower cost and less environmental impact. Thirdly, I have developed and demonstrated a solvent-free dry-powder coating process for making LiNi1/3Mn1/3Co1/3O2 (NMC) positive electrodes in lithium-ion batteries, and compared the performance and durability of electrodes made by the dry-powder coating processes with that by wet-slurry coating processes. The technology that has been used is the electrostatic spray deposition (ESD) process. This process eliminates volatile organic compound emission, reduces thermal curing time from hours to minutes, and offers high deposition rates onto large surfaces. The long-term cycling shows that the dry-powder coated electrodes have similar performance and durability as the conventional wet-slurry made electrodes.

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<p>The production of latex in a solvent-free process within a twin screw extruder is of great industrial interest given the associated reduction in environmental impact when compared to conventional solvent-based emulsification techniques. The ability to produce latex continuously is also advantageous, compared to batch-wise solvent-based processes.</p> <p>The process of solvent-free emulsification in a twin screw extruder is studied. An inline fiber optic spectroscopic system was installed in the extruder to study the residence time distribution profile of resin through the emulsification process. A design of experiment study was performed analyzing the response of latex particle size from screw speed and feed rate factors. Finally, scanning electron microscopy was used to determine the morphology of the poorly- emulsified and pre-emulsified resin.</p> <p>Experimental results demonstrate that the residence time distribution of the polymer within the extruder is largely invariant of screw speed; the system also demonstrated a very low degree of axial mixing – which was not expected but can be attributed to high degree-of-fill within the screw. The results of the design of experiments study show that the final latex particle size is more influenced by the feed rate of the polymer than the screw speed of the extruder. These results were found to be consistent with the literature based on both batch- phase inversion emulsification as well as continuous polymer blending of immiscible phases. Finally, results from a study on morphology provided evidence of water domains within the pre-inverted polymer domains, analogous to a ‘water-in-oil-in water’ dispersion. Evidence of a bicontinuous network of polymer and water was also found to exist. The summation of these experimental results leads to the hypothesis that the solvent-free emulsification process is a phase inversion-type emulsification mechanism as opposed to a direct emulsification mechanism.</p> / Master of Applied Science (MASc)

Current research focuses on the effect of different continuous solid state shear based processing for the production of pharmaceutical amorphous system and cocrystals for poorly water soluble APIs. The S3M technology is getting first time reported for its application in pharmaceutical field and it is considered as technology with good potential for development of pharmaceutical dosage forms. The main objectives of this study include the effect of two solid state shear processes on the product properties in case of solid dispersions and cocrystals. Hot melt extrusion technology has been widely explored for the production of pharmaceutical solid dispersions and cocrystals, it would be helpful to compare how the new invented S3M technology will differ from the existing solid state shear process. The S3M has been also explored for the advantages over HME process in terms of residence time, plasticiser free dispersions, effect of process on degradation of drugs during processing. For this purpose, the process and material modifications during operation of these two technologies was important aspects of this study. The pharmaceutical drugs chosen for the solid dispersion purpose were carbamazepine, ibuprofen, glibenclamide which are BCS class II drugs and paracetamol from BCS class III drug was selected as model drug for solid dispersion manufacturing with PVP. VA64, HPMCP HP55, HPMCAS, Ethyl cellulose as polymers. In case of cocrystals selected drugs were carabamazepine, caffeine, paracetamol and ibuprofen with co-formers nicotinamide, saccharin, salicylic acid, glutaric acid, oxalic acid, maleic acid. The selections of co-formers were done on the basis of functional group complementarity between drug and co-former. All the details about the pairs for cocrystals and for solid dispersions are given in experimental section. Carbamazepine has been explored in depth for solid dispersions with different polymers and with different co-formers in case of cocrystals. The effect of process variables and amount of shear applied during processing was deciding factor in product output and quality. The end product in case of both the solid dispersions and cocrystals varied in their physicochemical, morphological and drug release properties HME process needed addition of plasticisers during preparation of solid dispersions whereas S3M was plasticiser free process which gave good insight on how this will affect the product performance during evaluation studies. The solid dispersions in case of HME were had smooth surfaces and which are non-porous in nature whereas in case of S3M the solid dispersions were highly porous in nature. The differences in the structural and morphological features of solid dispersions somehow did not affect the drug release of drug during in-vitro dissolution studies and both the solid dispersions did not show much difference in drug release. In case of cocrystals processing on S3M it was observed that the S3M process is dependent on the use of polymer as process aid. For this purpose PEO, PVP VA64 and HPMCP HP55 were selected as model polymer as process aid during processing of cocrystals, out of which PEO has been explored widely as processing aid due to its process suitability, low melting and ability to withstand high shear during processing. PVP VA64 was used only in case of carbamazepine cocrystals with salicylic acid and HPMCP HP55 in case of caffeine cocrystals with maleic acid. The effect of concentration of PEO in case of carbamazepine cocrystals as processing aid was studied (concentration range 5%, 10%, 15%, 25% w/w). The concentration of PEO in case of HME cocrystals had direct effect on the drug release of drug dissolution studies which was reduced in case of higher concentration of PEO (25% w/w), which was not observed in case of S3M processes carbamazepine cocrystals. The product in case of cocrystals by S3M was thread like structures whereas in case of HME cocrystals were in form of screw shaped compact mass. The difference in morphological and structural properties of cocrystals did not had major effect on drug release in case of S3M process but in case of HME processed cocrystals the higher amount of polymer slowed the drug release. The degradation studies in case of drugs carbamazepine, paracetamol were carried out whereas in case of polymer for HPMCP HP55 were carried out. It was found that HME processed samples showed higher degradation as compared to S3M processed one in both the cases solid dispersions and cocrystals. This can be attributed to high residence time in case of HME as compared to S3M process. The effect of two high shear processes HME and S3M had significant effect on the morphological and structural properties of the solid dispersions and cocrystals. The variation in the structural and morphological properties did not have direct effect on the drug release of drug during dissolution studies. HME and S3M both the processes had some positive and some negative aspects within them for processing of pharmaceutical dispersions and cocrystals. In case of HME the use of plasticiser is mandatory to maintain low torque levels during processing and to avoid blockage of extruder barrel, whereas in case of S3M the process is plasticiser independent and processing of solid dispersion is very easy as compared to HME with low residence time. Processing of plain drug or co-former was easy in case of HME whereas in case of S3M processing it was mandatory to use polymer as processing aid specially during processing of cocrystals. In case of process controls HME has excellent control over the process parameters which can be controlled and manipulated as per requirement, whereas S3M technology needs to have technical modifications to have better control over its processing parameters. The S3M can be a revolutionary technology for pharmaceutical industry once it is upgraded with better control and optimised process parameters.

Yes / Reproducible control of stoichiometry and difficulties in large scale production have been identified as two of the major challenges to commercial uptake of pharmaceutical co-crystals. The aim of this research was to extend the application of SFCC to control stoichiometry in caffeine: maleic acid co-crystals. Both 1:1 and 2:1 caffeine: maleic acid co-crystals were produced by control of the feedstock composition and process conditions. It was also observed that formation of 2:1 stoichiometry co-crystals involved formation of a 1:1 co-crystal which was subsequently transformed to 2:1 co-crystals. The investigation of stoichiometric transformation revealed that although 1:1 co-crystals could be converted into 2:1 form with addition of excess caffeine, the reverse was not possible in the presence of excess maleic acid. However, conversion from 2:1 into 1:1 was only achieved by melt seeding with the phase pure 1:1 co-crystals. This investigation demonstrates that stoichiometric control can be achieved by SFCC by control of parameters such as extrusion temperature.

For the first time, octahydroxyl methylresorcinarene with four hexyl groups on the lower rim was utilized in the in-situ preparation of a silica-based sol-gel organic-inorganic hybrid coating for sample preconcentration by capillary microextraction (CME). Tetraethoxysilane (TEOS) was chosen as a sol gel precursor to create a cross-linked sol-gel network via acid-catalyzed hydrolytic polycondensation reactions. Sol-gel chemistry helped in the in situ preparation of resorcinarene-containing extraction phase in the form of a surface coating. It also provided an effective means to chemically bind the coating to the inner surface of fused silica capillary via condensation of the hydroxyl groups in the sol-gel network with the silanol groups on the fused silica capillary inner surface. These chemically bonded sol-gel coatings demonstrated excellent thermal stability (up to 350 oC). The sol-gel resorcinarene coatings successfully extracted traces of polycyclic aromatic hydrocarbons (PAHs), ketones, phenols, amines, and alcohols from aqueous samples providing parts per trillion level detection limits (0.828 - 46.01 ng/L) in GC using a Flame Ionization Detector (FID). CME was performed by passing the aqueous samples through the resorcinarene coated microextraction capillary (10 cm). The extracted analytes where then thermally desorbed into the GC column connected to the exit end of the sol-gel microextraction capillary via a press-fit quartz connector. Peak area relative standard deviation (RSD %), a measure of the extraction performance reproducibility for the coated capillary, was found in the range of (1.1 % - 8.3 %). The sol-gel resorcinarene sorbent was characterized by FTIR spectrum which indicated the presence of hydroxyl groups in the coating even after the sol-gel reactions were completed which explains the affinity of the resorcinarene sol-gel coating toward polar analytes. Scanning Electron Microscopy (SEM) images of the coating reveraled the porous morphology and thickness of 3.5 - 4.0 µm for the coating. The sol-gel resorcinarene coated capillary provided excellent extraction performance for wide range of analytes.