Le développement de nouvelles formes galéniques nécessite la mise au point de protocoles avec variation d’un ensemble de paramètres jouant sur les caractéristiques du dispositif. Au niveau industriel, cela représente une perte importante de temps et d’argent. Avec le développement d’outils permettant la caractérisation des systèmes et à fortiori des mécanismes impliqués dans la libération du principe actif, l’application des modèles mathématiques se voit être de plus en plus grande permettant de prédire la sortie du principe actif hors de son système. L’un des objectifs de ce travail a été de développer un modèle mathématique mécanique réaliste permettant de quantifier la libération de vitamines à partir de matrice lipidique. Deux techniques différentes de formulation : la compression directe et une suite d’extrusion en phase chauffante/ broyage/ compression directe ont permis la préparation de comprimés à base de Compritol 888 (glyceryl dibehenate NF). L’acide nicotinique a été utilisé comme principe actif modèle hautement soluble dans le milieu environnant. Des études de dissolution ont montrée une libération plus accrue pour des comprimés ayant une charge initiale en vitamine plus importante, cela liée à une augmentation de la porosité de la matrice avec l’épuisement graduel de la vitamine. Concernant la technique de préparation, un taux de sortie beaucoup plus faible dans le cas des comprimés préparés par extrusion en phase chauffante préalable, est mesuré, dû à un emprisonnement de la vitamine par la matrice fondue. A partir de ces observations et des connaissances sur les matrices lipidiques, un modèle basé sur les lois de diffusion de Fick et sur la considération de la coexistence d’une partie du principe actif sous forme dissoute ou non dissoute a été élaboré. Ce modèle permet la prédiction de la quantité de vitamine libérée au cours du temps en fonction de l’impact de la composition, de la technique de préparation et de la taille du système. Ces simulations in-silico sont d’une grande aide pour permettre d’accélérer la production de comprimés à base de Compritol 888. Dans le cas de systèmes multiparticulaires, et encore plus dans le cas de formes enrobées, des modèles mathématiques peuvent également être établis mais montrent une complexité plus grande, notamment due à la membrane polymérique. Dans cette optique, le développement de nouveaux outils pour caractériser les systèmes est primordial. Dernièrement la technologie Terahertz voit son potentiel comme nouvel outil dans la caractérisation de systèmes enrobés croissant. Son emploi dans la détection de différence de taille et d’uniformité de films polymériques d’enrobage pour des systèmes multicouches a été réalisé sur des granules de tailles conventionnelles (1mm de diamètre). Un premier enrobage de metoprolol succinate a été réalisé sur des noyaux de sucre, suivi d’un enrobage permettant le contrôle de la fuite du principe actif à base d’un mélange de Kollicoat SR :Kollicoat IR. Des granules avec différentes tailles d’enrobage ont été étudiées par Terahertz. Une taille homogène de la couche de principe actif pulvérisée a été montré dans tous les types de pellets ; alors qu’une taille croissante de l’enrobage polymérique 46 µm, 71 µm et 114 µm a pu être appréhendée. Ces résultats, mis en corrélation avec les méthodes de dissolution traditionnelles, permettront le développement d’une formule prédisant les cinétiques de libération à partir de la lecture non destructive de l’épaisseur d’enrobage par Térahertz.[...] / Development of new galenic devices needs series experiments with variation of number parameters. For industrial, it’s a lost in time and money. Food and Drug Administration initiated since several years, Process Analytical Technology (PAT) as a tool to analyze and control pharmaceutical process. These tools can be helpful to determine drug release mechanism and allow application of mathematical model to predict drug release kinetics. One objective of this work is to develop a mechanistically realistic mathematical model allowing for the quantification of vitamin release from Compritol 888 (glyceryl dibehenate NF)-based matrix tablets, prepared either by direct compression or via hot-melt extrusion/grinding/compression. Nicotinic acid has been used as highly soluble drug in surrounding medium. Dissolution studies show vitamin release rates increased with increasing initial niacin content, due to the increased matrix porosity upon vitamin depletion. In all cases, niacin release from tablets prepared via hot-melt extrusion was slower than from tablets prepared by direct compression, due to more intense embedding of the vitamin within the lipid. Importantly, a numerical model based on Fick’s law of diffusion and considering the co-existence of dissolved and non-dissolved vitamin could successfully be used to quantify vitamin release from both types of tablets, irrespective of the initial niacin loading and tablet size. In-silico simulations can be very helpful to accelerate product optimization of Compritol 888-based matrices, saving development time and costs. For multiparticulates systems, and more again for coated forms, mathematical models are more complexes. In this goal, development of new tools to characterize devices is primordial. Technology Terahertz offers an interesting potential. This technique can be used to detect difference in size and uniformity for polymeric film from multilayer pellets of 1 mm diameter. Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat® SR: Kollicoat® IR polymer blend. Pellets with several coating thickness are studied. No drug layer thickness difference between batches was observed, and the average coating thicknesses were 46 µm, 71 µm and 114 µm, for the different batches. Terahertz results compared with experimental data from dissolution methods, allow predicting coating thickness results correlated with the subsequent drug release behavior. Multiparticulates systems have important interest: they allow avoiding “dose dumping”. Dose dumping is described as an unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form (Meyer, 2005). This phenomenon can be observed in the case of ethylcellulose-based devices in presence with ethanol rich-media. Recently, ethylcellulose:guar gum blend have been reported to provide ethanol-resistant drug release kinetics from coated dosage forms. Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. These granules show no change in drug release profiles upon contact with medium containing 40% of ethanol (v/v). This is because the ethanol insoluble guar gum effectively avoids undesired ethylcellulose dissolution in ethanol-rich bulk fluids. However, so far the importance of crucial formulation parameters, including the minimum amount of guar gum to be incorporated and the minimum required guar gum viscosity, remains unclear. It was found that more than 5% guar gum (referred to the total polymer content) must be incorporated in the film coating and that the apparent viscosity of a 1% aqueous guar gum solution must be greater than 150 cPs to provide ethanol-resistance. [...]

Made available in DSpace on 2014-10-09T12:38:33Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:05:29Z (GMT). No. of bitstreams: 1 06050.pdf: 2669277 bytes, checksum: d5c09b330819048bd8379029a5eabfe4 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Made available in DSpace on 2014-10-09T12:38:33Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:05:29Z (GMT). No. of bitstreams: 1 06050.pdf: 2669277 bytes, checksum: d5c09b330819048bd8379029a5eabfe4 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

O aÃo ABNT 1045 tem aplicaÃÃo em diversos componentes utilizados na indÃstria do petrÃleo. Devido Ãs condiÃÃes severas de serviÃo, a ocorrÃncia de quebras e desgastes nestes equipamentos à freguente. A recuperaÃÃo à feita utilizando-se um processo de soldagem. PorÃm, aÃos com mÃdio teor de carbono exigem cuidados, pois o ciclo tÃrmico de soldagem promove uma microestrutura de elevada dureza e baixa tenacidade. Considerando-se este problema, aplicou-se as TÃcnicas da Dupla e Tripla Camadas, na soldagem do aÃo ABNT 1045, com eletrodos revestidos AWS E 7018-1 e AWS E 307-16. Para viabilizar o procedimento de soldagem multipasses os resultados obtidos foram aplicados na execuÃÃo de juntas do tipo semi-V. Realizou-se o amanteigamento em duas camadas, utilizando-se quatro relaÃÃes de energia (5(5, 5/10, 10/5, 10/10 kJ/cm) para o eletrodo AWS E 307-16 e cinco (5/5, 5/10, 10/5, 10/10, 10/16 kJ/cm) para o eletrodo AWS E 7018-1. Para o eletrodo inoxidÃvel foi realizado tambÃm o amanteigamento com trÃs camadas utilizando-se trÃs relaÃÃes de energia (5/5/5, 5/10/10 e 10/10/10 kJ/cm). Foi feito o levantamento do perfil de microdureza da ZAC da primeira camada do amanteigamento para cada corpo de prova semi-V. Para avaliar a eficiÃncia da tÃcnica quanto à tenacidade foi realizado o ensaio de impacto Charpy-V da ZAC a temperatura ambiente nas condiÃÃes como soldado e com TTPS. O entalhe dos corpos de prova Charpy foi posicionado na ZAC-GG da primeira camada a 1 mm da zona de ligaÃÃo (regiÃo mais critica). Foi realizado, tambÃm, ensaio de impacto Charpy no metal de solda, localizando o entalhe na regiÃo com maior relaÃÃo percentual entre as zonas colunar e recristalizada. Concluiu-se que as TÃcnicas da Dupla e da Tripla Camada mostraram-se eficientes, pois para toda as relaÃÃes de energias aplicadas, utilizando-se os dois tipos de eletrodos, alcanÃou-se tenacidade semelhante à obtida nos corpos de prova com Tratamento TÃrmico PÃs Soldagem e muito superior a tenacidade do metal de base / The AISI 1045 has application in various components used in the petroleum industry. Due to the harsh conditions of service, the occurrence of breakage and wear such equipment is freguente. Recovery is performed using a welding process. However, steels having average carbon contents require care, since the thermal cycle of welding promotes a microstructure with high hardness and low tenacity. Considering this problem, we applied the techniques of double and triple layers in welding of AISI 1045 with coated electrodes AWS and AWS E 7018-1 E 307-16. To enable the multipass welding procedure results were applied in the execution of joints in the semi-V. The buttering is carried out in two layers, using four energy ratios (five (5, 5/10 10/5, 10/10 kJ / cm) for the electrode AWS E 307-16 and five (5/5 , 5/10 10/5 10/10 10/16 kJ / cm) to the electrode and AWS 7018-1. For steel electrode was also performed with the buttering three layers using three energy ratios (5 / 5/5, 10/05/10 and 10/10/10 kJ / cm). was made of the profile of the hardness of HAZ of the first layer of the buttering for each specimen semi-V. To evaluate the efficiency of technique and the toughness test was performed Charpy-V impact of HAZ at room temperature under the conditions as welded and PWHT. The notch Charpy the samples was placed in HAZ-GG of the first layer 1 mm of the bonding zone ( most critical region). was carried out, also, Charpy impact test in the weld metal, locating the notch in the region with the highest ratio between columnar and recrystallized zones. It was concluded that the techniques of Double and Triple Layer proved efficient, because for all the relations of energy applied, using both types of electrodes was reached toughness similar to that obtained in specimens with Post Weld Heat Treatment and much higher than the toughness of base metal

The use of coated seed to establish crops is not a novel practice. Seed coatings have been used on small seeded crops to improve the handling ability by making the seed unit larger and heavier. Producers can therefore calibrate their sowing equipment more efficiently and wind will not cause as much drift at sowing. Seed coating can have an added benefit for leguminous crops if the symbiotic inoculant (Rhizobium) is added to the coating. This saves the producer time and allows peace of mind that inoculation was done by trained professionals. Other than the inoculation, there are some other constituents in the seed coating that can have benefits to the plant. It can, however, be theorized that added nutrients or pesticides will be beneficial to the plants only if these nutrients are deficient in the growth medium or when pests are present. This study evaluated the effect of seed coating on the life stages of germination, emergence and survival, seedling growth and ultimate yield of mature lucerne (Medicago sativa L.) plants, comparing the results with non-coated seed. Two cultivars were used in the evaluation, SA Standard and SuperCuf, to determine if the effects would be similar, or would genetic differences between the cultivar play a significant role. These life stages (germination, emergence and seedling growth) were chosen due to the importance of these stages to the success of establishment. Fast and uniform germination will result in a uniform stand with strong competition against weed infestation. The effect of growth medium on the emergence of seedlings and the interaction between the seed coating and the growth medium was important to determine to identify limitations in the use of seed coating. Changes in the growth of seedlings in terms of some physio-morphological characteristics will assist in identifying parameters influenced by the coating. It was, however, essential to not only do these trials under ideal agricultural conditions, but to identify if similar results would be obtained from stressed conditions, such as salinity, which is a growing concern for crop production areas. The question of whether seed coating will influence the ultimate production of the crop could then be answered. It was found that the method in which germination is tested can have a significant outcome for the results obtained. When the Jacobsen apparatus was compared with the use of petri dishes, using specification according to ISTA, it was found that the water movement in the Jacobsen apparatus overcomes concentrated nutrient conditions, especially for SuperCuf. Under saline conditions the coated SA Standard seed had higher germination than the non-coated seed, therefore overcoming inhibitions imposed by the salinity. It is clear that the coating influences germination of lucerne and the interaction with the seed environment is significant. It is also clear that the genetic differences between cultivars are significant and results should not be applied across all lucerne cultivars. When the emergence percentage had been determined in different growth media, namely a commercial growth media, a sandy loam soil and silica medium, it was found that the emergence was influenced by the media. Even though the emergence of seedlings are mostly determined by the nutrients in the cotyledons, some growing conditions did cause lower emergence for non-coated SA Standard seeds and was overcome by the use of coated seed. When the growing conditions were manipulated with saline irrigation it was found that coated SuperCuf had a higher emergence % than the non-coated treatments when irrigated with the 750 μS.cm-1 water. From the data collected from this trial, it can be concluded that, even though the use of seed coating does not always influence the emergence of lucerne seedlings, seed coating does have an influence on the emergence, but it is dependent on the growth medium quality in terms of nutrient composition and salinity. Similar to the germination trial, the genetic influence of the different cultivars was noticeable. To determine the differences caused by seed coating to the physio-morphological characteristics (stem height, leaf area etc.) of lucerne, a pot trial was conducted using different irrigation treatments, municipal water (180 μS.cm-1), 500 and 750 μS.cm-1 water, created with NaCl. It was found that the physio-morphological characteristics were highly correlated, i.e. the stem height, leaf area, number of leaves and dry matter production changed in relation to each other. There were, however, differences in this correlation coated and non-coated seed treatments, when irrigated with 500 μS.cm-1 water. For the seedlings grown from coated seed, the correlation between shoot dry matter yield and the other parameters were low, while the seedlings growth from non-coated seed, leaf area was not correlated with the other parameters. It was concluded that the tolerance mechanism for salinity for plants irrigated with 500 μS.cm-1 water, caused more differences than the other water treatments. Taking into consideration that coating influences the germination and emergence of lucerne and that the two cultivars react differently to the seed coating, the yields obtained from field trials could then be interpreted if differences were observed. Three field trials were established, namely a trial established in autumn (established in 2009) and second trial established in spring (established in 2010) which were sown at 25 kg.ha-1, while a third trial established spring (established in 2010) was sown at 5 different sowing densities, namely 80%, 90%, 100%, 110% and 120% of recommended sowing density (25 kg.ha-1). It was found that the pasture stands established with SA Standard, did not show many differences between the coated and non-coated seed treatments and were mostly restricted to the second growing season, where the non-coated seed treatments had significantly higher dry matter yield than the coated seed treatments. Stands established with SuperCuf, displayed more variation between the seed treatments and the non-coated seed treatments had higher yields in the first season. It was, however, found that the stands established with coated SuperCuf seed had lower stem: leaf ratio’s, indicating that a better quality fodder can be produced from coated seed. The data from the sowing density trial showed very little difference between the yields of the stands established with coated and non-coated SA Standard seed. Differences were, however, observed between seed treatments at 90% and 120% of the recommended sowing density, where the stands established with non-coated seed had higher yields than the stands established with coated seed. It can be concluded that under these trial conditions, the use of coated seed had very little influence on the yield of the lucerne stands. The observed differences suggest that the lucerne growth under these few conditions, the stands established from non-coated seed had better yield, but the stands established from coated seed had better quality. It is, however, more likely that there will be no differences between the seed treatments. Data from the sowing density trial also led to the conclusion that stands established at 20% less seed will not result in lower yields if the stand establishment is successful. The similarity between the seed treatments and the sowing densities suggests that the number of plants per area were the same, caused by seedling mortality during the high growth rate in the early growing stage, or the morphological characteristics, such as number of stems per plant and number of leaves per stem, adapted to result in similar yields and quality. / Dissertation (MSc Agric)--University of Pretoria, 2013. / gm2014 / Plant Production and Soil Science / unrestricted

This licentiate thesis comprises two complementary studiesdealing with the sheet-fed offset printing of paper. The firststudy addresses the further development of a practical methodto acoustically monitor and analyse the film splitting ofoffset inks. This method was tested on laboratory printingequipment, specifically monitoring the continuous ink splittingin the nip of an IGT ink distribution unit and the short-timeink splitting in the inked print disc-paper nip of the printingunit of an ISIT instrument. The study verified that the inksplitting component of the acoustic signal contributes to thehigher frequency range (10-20 kHz) of the audible spectrum, andcan thus be separated from the lower frequency machine noise.Furthermore, the film splitting component is sensitive tochanges in the ink and printing conditions, thus enabling itsuse in probing the fundamental mechanisms occurring during inktransfer and also suggesting its applicability fornon-intrusive monitoring of industrial printing presses. Anincrease in film thickness during ink distribution correspondsto an increased acoustic power, with the exception of very lowink amounts, which give reduced acoustic emission due to alubricating effect. The effect of the presence of fountainsolution was simulated by adding emulsion-forming, butnon-evaporative, ethylene glycol. This produces an increase inacoustic power at low amounts, due to resistance to glycol dropdeformation, followed by a decrease at higher amounts owing toexcess glycol lining the rolls. During test printing on paper,increasing ink amounts also display an increased acousticresponse. The second study further developed a theoretical model toexplain and predict the evolution of ink tack in terms of inksetting directly after offset printing on coated paper. Asmeasured by the ISIT, the tack of the printed ink rises duringshorter time periods, attains a maximum, and then falls atlonger times. The proposed model described how the ink tack,characterised by the impulse during disc pull-off, dependsdynamically on the viscoelastic properties of the ink, thecontact with paper and disc, and the flow geometry. The inksetting was modelled as a diffusion-limited transport of theoil vehicle through the ink film and into the pores of thecoated paper. The coupling of the tack and setting models,compared to the ISIT experimental measurements, then provided adiffusion coeffcient for ink setting during the tack riseperiod. This coeffcient decreases with time, and increasinglyrapidly with decreasing ink amounts due to theconcentration-dependent diffusion. For an accurate descriptionthe elasticity and adhesion effects also have to be considered,at least for explaining the tack fall period.

Antibody-coated microprobes have been demonstrated to be useful for detecting the release of neuropeptide transmitters from discrete sites in the central nervous system (CNS). This technique uses glass micropipettes taken through a series of chemical coatings, starting with a γ- aminopropyltriethoxysilane solution and ending with the antibody specific to the peptide transmitter of interest. The key to the reliability and repeatability of the technique is a uniform, even coating of the siloxane polymer to the glass micropipette. The microprobes, as they are called following the completion of the coating process, are inserted stereotaxically into a specific area of the CNS and the physiological intervention is performed. Tip diameters are around 5-10 μm and, depending on the length of the pipette inserted into the CNS, diameters of the pipette shaft will approach 40-50 μm. Once removed, the microprobe is then incubated with the radiolabeled peptide. Binding of the radiolabeled peptide will occur to the antibody sites not occupied by the endogenously released peptide. The images of the microprobes on sensitive autoradiographic film are analyzed for differences in the optical density along a specified length of probe. Areas of lighter density signify sites along the microprobe where endogenous peptide was biologically released during the physiological intervention. Knowing the exact location of the probe tip in vivo in the CNS permits identification of neurophysiological sites corresponding along the length of the microprobe where the peptide was released.

During myocardial ischemia, the cranial cervical spinal cord (C1-C2) modulates the central processing of the cardiac nociceptive signal. This study was done to determine 1) whether C2 SCS-induced release of an analgesic neuropeptide in the dorsal horn of the thoracic (T4) spinal cord; 2) if one of the sources of this analgesic peptide was cervical propriospinal neurons, and 3) if chemical inactivation of C2 neurons altered local T4 substance P (SP) release during concurrent C2 SCS and cardiac ischemia. Ischemia was induced by intermittent occlusion of the left anterior descending coronary artery (CoAO) in urethane-anesthetized Sprague-Dawley rats. Release of dynorphin A (1-13), (DYN) and SP was determined using antibody-coated microprobes inserted into T4. SCS alone induced DYN release from laminae I-V in T4, and this release was maintained during CoAO. C2 injection of the excitotoxin, ibotenic acid, prior to SCS, inhibited T4 DYN release during SCS and ischemia; it also reversed the inhibition of SP release from T4 dorsal laminae during C2 SCS and CoAO. Injection of the κ-opioid antagonist, nor-binaltorphimine, into T4 also allowed an increased SP release during SCS and CoAO. CoAO increased the number of Fos-positive neurons in T4 dorsal horns but not in the intermediolateral columns (IML), while SCS (either alone or during CoAO) minimized this dorsal horn response to CoAO alone, while inducing T4 IML neuronal recruitment. These results suggest that activation of cervical propriospinal pathways induces DYN release in the thoracic spinal cord, thereby modulating nociceptive signals from the ischemic heart.

Antibody coated microprobes, inserted into the spinal cord at the L4-5 level, were used to detect whether endomorphin-2 (Endo2) was released from spinal dorsal horns in anesthetized rats in response to formalin injected into the hindpaw footpads. Saline injections were used as a control and substance P (SP) was measured to verify activation of nociceptive afferent fibers. SP but not Endo2 was released during pre-stimulation periods. Saline injections did not cause the release of either Endo2 or SP from the spinal cord. Formalin injections caused an increase in Fos expression as well as a release of SP, but not Endo2 from the ipsilateral side dorsal horn in L4-5. We conclude that Endo2 does not play a role in mediating the in vivo responses to acute inflammatory nociceptive signals at the spinal level in the anesthetized rat model.

<p> Swellable microspheres prepared by the precipitation polymerisation of divinylbenzene-80 (DVB-80) and 2-hydroxyethyl methacrylate (HEMA), in a solvent mixture of methyl ethyl ketone (MEK) and heptane, were functionalised with 2bromopropionyl bromide, and 2-bromoisobutyryl bromide to prepare Atom Transfer Radical Polymerisation (ATRP) initiators. </p> <p> Methyl acrylate (MA) and methyl methacrylate (MMA) were grafted from the microspheres using CuBr and either 4,4'-dinonyl-2,2'-dipyridyl (dNbipy), or N,N,N',N",N"-pentamethyldiethylenetriamine (PMDET A) ligands. The morphology of the grafted microspheres was studied using electron microscopy (ESEM and TEM) and x-ray microspectroscopy. Adding equimolar sacrificial initiator resulted in improved control over the grafting and gave grafted and soluble polymer, with narrow polydispersity (PDI) and number average molecular weight (Mn) close to expected values. </p> <p> Base catalysed transesterification was used to cleave the grafted polymer. It was found that adding free initiator permits grafting from within lightly cross-linked gels to be carried out with good control over Mn and PDI. </p> / Thesis / Master of Science (MSc)