In recent years, stringent world-wide regulation of copper in drinking water, wastewater discharge and sludge has prompted utilities to carefully evaluate copper sources and sinks, benefits and detriments, and mitigation. This work compiled the individual efforts of researchers and utilities to provide a basis for holistic decision-making. Mass balances suggest that between 14-61% of copper in wastewater originates from home plumbing. Dosing of pure copper sulfate "root killer" by consumers, which is of unlikely value, accounted for up to 27% of copper inputs. Removal of copper in wastewater treatment ranged from 24-90%, suggesting a potential for optimization of these processes if desired. Finally, though utilities are pressured to reduce copper inputs at all stages of the urban water cycle, substantial benefits including human and wastewater bacteria micro-nutrition, water disinfection and algae control should not be overshadowed. To better understand copper inputs from corrosion in soft waters, a 12 month study was executed. Free chlorine (0.7 mg/L) was determined to have minimally adverse effects on copper release at pH 9.5 but no significant effect at pH 7.0, and higher temperatures usually increased copper release. Organic matter including soluble and particulate NOM, sodium alginate, and gum xanthan, tended to worsen copper release. Their direct effects included complexation and mobilization of pre-existing copper scale as particulates. Indirect effects were also discovered, including a propensity of gum xanthan and alginate to decrease pH, increasing copper release, and also to produce a microbiologically unstable water, decreasing the dissolved oxygen necessary for fueling corrosion reactions. The range of organic matter effects could be placed within a unified conceptual framework. / Master of Science

This is a visual story of my attempt at understanding impression. / Master of Architecture

Recent efforts to restore depressed or extirpated populations of freshwater mussels have focused on artificial propagation as an effective and practical conservation strategy. Although artificially cultured juveniles have been produced and released to the wild, no study has investigated the best time of year or the best developmental stage to release these juveniles. Several experiments were conducted to gain knowledge of appropriate culture and release techniques. Juvenile wavyrayed lampmussels (<I>Lampsilis fasciola</I>) were artificially propagated in the laboratory and subsequently release into a fish hatchery raceway during June, September and March. Juveniles released in June experienced a gradual decline in survival rate, with 50% survival after 72 days and stable survival thereafter until 200 days. Juveniles released in September and March experienced high mortality within the first month, and were unsuccessful in surviving the cold water conditions typical of those seasons. Temperature was strongly associated with growth; thus, juveniles released in June exhibited considerably greater growth than those released in September and March. Survival was positively correlated with shell length in the first 32 days post-metamorphosis. Fall and spring survival values, shell length-frequency data, and a significant increase in overwinter mean shell length (p = 0.045) suggest that overwinter survival is size-dependent. Survival rates of juveniles released in June exceed those of previous culture studies reported in the literature. From these results, I suggest that the best time for release of propagated juvenile freshwater mussels should be at the beginning of the growing season in late spring, when water temperatures exceed 15 degrees C (plus/minus 1°C). Offspring of four, gravid female <I>L. fasciola</I> were tested to evaluate the extent of variability in growth and survival among brood stock. Comparison of growth and survival of progeny showed significantly lower performance of only one female (p < 0.05). Although results indicate variability in growth and survival among broods, it is not known whether heritabilities or physiological fitness caused this variability. Infested fish (IF), newly metamorphosed juveniles (NMJ) and juveniles cultured for 1 month (CJ) were released to a fish hatchery raceway in order to determine the most appropriate developmental stage to release juveniles. Significant differences were recorded among the three release methods, with CJ attaining the greatest growth (2.47 mm plus/minus 0.02), NMJ with the next best growth (1.86 mm plus/minus 0.02), and IF exhibiting the least growth (1.34 mm plus/minus 0.02) (p < 0.0001). Survival among release methods was not statistically different because of high variability within each release method. High mortality from predacious fish was presumably the cause of this variability. With minimal predation, L. fasciola experienced 82.2% (plus/minus 3.6) survival at 90 days. Survival of hatchery-reared juveniles was comparably higher than laboratory-reared juveniles, suggesting that culturing freshwater mussels in a hatchery raceway is a preferable alternative to laboratory culture. An experiment was conducted to compare growth of confined and unconfined juvenile L. fasciola released to a fish hatchery raceway. After 72 days, juveniles confined to small open dishes within the raceway (1.04 mm plus/minus 0.08) exhibited significantly less growth than juveniles released to the raceway that were not held in containers (2.15 mm plus/minus 0.07) (p < 0.0001). Results of additional comparisons with compiled growth data suggest that juvenile growth is retarded when cultured in small dishes. / Master of Science

The goal of this dissertation was to investigate the role of μ-opioid receptors in the mechanism of ethanol-stimulated dopamine release in the nucleus accumbens shell (NAcS) of rats. The underlying hypothesis is that blockade of the μ-opioid receptors leads to an attenuation of ethanol-stimulated mesolimbic dopamine release. We prepared ethanol-naïve male Long Evans rats (n = 95) for intravenous (i.v.) drug administration and in vivo microdialysis (in awake, freely moving animals), and analyzed our samples using HPLC and GC for dopamine and ethanol detection, respectively. In one set of experiments, we looked at the effects of naltrexone, a non-selective opioid antagonist, on ethanol-stimulated mesolimbic dopamine release. First of all, we checked to see if naltrexone affected basal dopamine levels in the NAcS. Thereafter, we looked for a dose of naltrexone (i.v.) that was effective in suppressing the release of dopamine in the NAcS evoked by morphine (1 mg/kg, i.v.). Subsequently, we checked to see if doses of naltrexone that inhibited morphine-evoked dopamine were also effective in attenuating dopamine release due to ethanol (1g/kg, 10% w/v, i.v.). To do this, we pretreated rats with naltrexone doses, followed 20 min later by morphine, ethanol or saline (all drugs were administered i.v.). In another set of experiments, we looked at the effect of β-funaltrexamine, a selective μ-opioid antagonist, on ethanol-stimulated dopamine release in the NAcS. Similarly to the previous set of experiments, we looked for a dose of β-funaltrexamine (s.c.) that was effective in suppressing the release of dopamine the NAcS evoked by morphine (1 mg/kg, i.v.), and checked to see if this dose of β-funaltrexamine was also effective in attenuating ethanol-stimulated dopamine release in the NAcS. For the β- funaltrexamine experiments, rats were pretreated with β-funaltrexamine (s.c.) 20- 25 h before i.v. infusions of saline, morphine and ethanol. Morphine increased dopamine release in the NAcS. Naltrexone and β- funaltrexamine significantly attenuated morphine-evoked dopamine release. Also, ethanol increased dopamine release in the NAcS. Naltrexone and β- funaltrexamine, at doses effective in attenuating morphine-evoked dopamine release, suppressed the prolongation, but not the initiation of dopamine release in the NAcS due to ethanol. Naltrexone and β-funaltrexamine did not affect the peak concentration and clearance of ethanol in the brain. The conclusion of this study is that the μ-opioid receptors are involved in a delayed component of ethanol-stimulated dopamine release in the NAcS in ethanol-naïve rats. This is the first study to show that the ethanol-stimulated dopamine response consists of a delayed μ-opioid mechanism. / text

The influence of plasticization and other formulation factors on the properties of hot-melt extruded dosage forms for the controlled release of water-soluble active compounds was investigated. Citric acid monohydrate was demonstrated to function as a solid-state plasticizer in hot-melt extruded Eudragit® RS PO tablets and in cast films when concentrations below the compatibility limit were employed. Melting of the organic acid and solubilization in the polymer during extrusion were necessary to observe the plasticizing effect. The release rate of diltiazem hydrochloride, used as a high-melting, water-soluble model drug, from melt extruded Eudragit® RS PO matrix tablets increased and became independent of the original drug particle size in the presence of citric acid monohydrate. Thermal analysis of physical mixtures demonstrated that citric acid promoted drug melting during extrusion by interaction and melting point depression. Diltiazem hydrochloride remained amorphous in the final dosage form, and leaching of citric acid monohydrate enhanced drug diffusion by increasing the matrix porosity. Delayed-release matrix pellets with particle sizes below one mm were prepared by hot-melt extrusion, and the influence of the matrix forming polymer and the type and level of plasticizer on the processibility and release properties was investigated. Pellets complied with the USP requirement for delayed release articles to release less than 10% drug at pH 1.2 after 2 hours when plasticized Eudragit® S100 was used as the release-controlling material. High levels of efficient plasticizers had to be employed to decrease the polymeric melt viscosity, increase the process yield and enable extrusion at moderate temperatures to avoid instabilities during processing and storage. The aqueous solubility of the plasticizer further impacted the drug release rate in acid. A novel application of hot-melt extrusion for the preparation of monolithic matrices comprising enteric coated particles was studied. The influence of the mechanical strength of the multiparticulates, pellet loading and nature of the hydrophilic carrier material on the preservation of the delayed-release properties after extrusion was investigated. Soft particles coated with brittle films remained intact when low-melting carriers that did not solubilize the enteric film during extrusion were used, and the dissolution profile was stable over one year. / text

Chronic diseases can often be managed by constantly delivering therapeutic amounts of drug for prolonged periods. A controlled release for extended duration would replace the need for multiple and frequent dosing. Local drug release would provide added benefit as a lower dose of drug at the target site will be needed as opposed to higher doses required by whole body administration. This would provide maximum efficacy with minimum side effects. Nonetheless, a problem with the known implantable drug delivery devices is that the delivery rate cannot be controlled, which leads to drug being released in an unpredictable pattern resulting in poor therapeutic management of patients. This dissertation is the result of development of an implantable drug delivery system that is capable of long-term zero order local release of drugs. The device can be optimized to deliver any pharmaceutical agent for any time period up to several years maintaining a controlled and desired rate. Initially significant efforts were dedicated to the characterization, biocompatibility, and loading capacity of nanoporous metal surfaces for controlled release of drugs. The physical characterization of the nanoporous wafers using Scanning electron microscropy (SEM) and atomic force microscopy techniques (AFM) yielded 3.55 x 10⁴ nm³ of pore volume / μm² of wafer surface. In vitro drug release study using 2 - octyl cyanoacrylate and methyl orange as the polymer-drug matrix was conducted and after 7 days, 88.1 ± 5.0 % drug was released. However, the initial goal to achieve zero order drug release rates for long periods of time was not achieved. The search for a better delivery system led to the design of a perforated microtube. The delivery system was designed and appropriate dimensions for the device size and hole size were estimated. Polyimide microtubes in different sizes (125-1000 μm) were used. Micro holes with dimensions ranging from 20-600 μm were fabricated on these tubes using photolithography, laser drilling, or manual drilling procedures. Small molecules such as crystal violet, prednisolone, and ethinyl estradiol were successfully loaded inside the tubes in powder or solution using manual filling or capillary filling methods. A drug loading of 0.05 – 5.40 mg was achieved depending on the tube size and the drug filling method used. The delivery system in different dimensions was characterized by performing in vitro release studies in phosphate buffered saline (pH 7.1-7.4) and in vitreous humor from the rabbit’s eye at 37.0 ± 1.0°C for up to four weeks. The number of holes was varied between 1 and 3. The tubes were loaded with crystal violet (CV) and ethinyl estradiol (EE). Linear release rates with R²>0.9900 were obtained for all groups with CV and EE. Release rates of 7.8±2.5, 16.2±5.5, and 22.5±6.0 ng/day for CV and 30.1±5.8 ng/day for EE were obtained for small tubes (30 μm hole diameter; 125 μm tube diameter). For large tubes (362-542 μm hole diameter; 1000 μm tube diameter), a release rate of 10.8±4.1, 15.8±4.8 and 22.1±6.7 μg/day was observed in vitro in PBS and a release rate of 5.8±1.8 μg/day was observed ex vivo in vitreous humor. The delivery system was also evaluated for its ability to produce a biologically significant amounts in cells stably transfected with an estrogen receptor/luciferase construct (T47D-KBluc cells). These cells are engineered to produce a constant luminescent signal in proportion to drug exposure. The average luminescence of 1144.8±153.8 and 1219.9±127.7 RLU/day, (RLU = Relative Luminescence Units), yet again indicating the capability of the device for long-term zero order release. The polyimide device was characterized for biocompatibility. An automated goniometer was used to determine the contact angle for the device, which was found to be 63.7±3.7degreees indicating that it is hydrophilic and favors cell attachment. In addition, after 72 h incubation with mammalian cells (RAW 267.4), a high cell distribution was observed on the device’s surface. The polyimide tubes were also investigated for any signs of inflammation using inflammatory markers, TNF-α and IL-1β. No significant levels of either TNF-α or IL-1β were detected in polyimide device. The results indicated that polyimide tubes were biocompatible and did not produce an inflammatory response. / text

The purpose of this project was to fabricate biodegradable ophthalmic inserts for controlled delivery of pilocarpine and evaluate them by both in-vitro and in-vivo studies. Emphasis was placed on the use of an inexpensive material as a drug carrier and on the ease of fabrication of the device. Based on these criteria, absorbable gelatin was selected to fabricate a matrix system. Absorbable gelatin can be obtained by either thermal treatment or chemical crosslinking of gelatin. In the first part of this project, we fabricated an insert using Gelfoamᴿ, an absorbable gelatin sponge obtained by thermal treatment. A prolonged in-vitro release of pilocarpine from the device was achieved through pharmaceutical modification by embedding a retardant in the pores. The devices impregnated with polyethylene glycol monostearate (PMS) and cetyl esters wax (CEW) were found to be most effective. The in-vivo evaluation of the devices indicated that pharmaceutical modification of Gelfoamᴿ is an effective means of improving the biological activity of pilocarpine without altering the biodegradability of the biopolymer backbone. The CEW device produces a substantial improvement in drug bioavailability and an increase in the duration of biological effect over that from the two commercial formulations, the eyedrop and the gel. In the second part of the project, we fabricated absorbable gelatin inserts through chemical crosslinking of gelatin. The effect of selected fabrication variables on profiles of the in-vitro release of pilocarpine and the dynamic water uptake by the crosslinked gelatin devices was investigated. These results were further substantiated by the measurement of the degree of crosslinking of gelatin. The in-vivo study indicated that the modification of the structure of gelatin by crosslinking is another simple and effective way of improving bioavailability and extending the duration of effect of pilocarpine incorporated in the biopolymeric device. In addition, altering the degree of crosslinking of gelatin allows a variation of the biodegradation time of the polymer.

In today’s drug discovery, the number of candidate drugs based on new molecular entities with poor aqueous solubility is increasing. Since poor aqueous solubility of an active pharmaceutical ingredients (APIs) is associated with low bioavailability and thus limite their therapeutic effect, this is often a great challenge in the development of new drugs when oral administration is the preferred route of administration. A number of different strategies have been developed to circumvent this problem where salt formulations of an API is the most widely employed method. However, new strategies are needed since there is no one solution that solves this issue for all substances. In recent time, the concept of stabilizing poorly soluble APIs in their amorphous form has gained a lot of attention since amorphous compounds exhibit a higher apparent solubility compared to their crystalline counterparts. Amorphous substances are prone to crystallize if left in a non-constricted environment and thus need to be stabilized if the amorphous state is to be conserved until administration. Inorganic mesoporous materials have been proposed as an interesting type of excipients that can conserve the amorphous state of APIs. In this work, the focus was to investigate the possibilities of using a mesoporous type of magnesium carbonate to stabilize the amorphous state of different APIs. Due to the nanometer sized pores in the material, complete conservation of amorphous APIs was obtained. This resulted in both an increase in in vitro release rate and a higher solubility of the substances which may translate to both a faster onset of action and an improved therapeutic effect of the APIs in a clinical situation. The long term stability of formulations was also investigated showing promising results. The results presented in this work show that mesoporous magnesium carbonate represents an interesting type of excipient for oral formulations of APIs with poor aqueous solubility. / <p>Felaktigt ISBN 978-91-554-9702-6 i tryck version.</p>

MSc (Med),Dept of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand / Pain is the net effect of multidimensional mechanisms that engage most parts of the central nervous system (CNS) and the treatment of pain is one of the key challenges in clinical medicine (Le Bars et al., 2001; Miranda et al., 2008). Polypharmacy is seen as a barrier to analgesic treatment compliance, signifying the necessity for the development of fixed dose combinations (FDCs), which allow the number of tablets administered to be reduced, with no associated loss in efficacy or increase in the prevalence of side effects (Torres Morera, 2004). FDCs of analgesic drugs with differing mechanisms of nociceptive modulation offer benefits including synergistic analgesic effects, where the individual agents act in a greater than additive manner, and a reduced occurrence of side-effects (Raffa, 2001; Camu, 2002). This study aimed at producing a novel, rate-modulated, fixed-dose analgesic formulation for the treatment of mild to moderate pain. The fixed-dose combination (FDC) rationale of paracetamol (PC), tramadol hydrochloride (TM) and diclofenac potassium (DC) takes advantage of previously reported analgesic synergy of PC and TM as well as extending the analgesic paradigm with the addition of the anti-inflammatory component, DC. The study involved the development of a triple-layered tablet delivery system with the desired release characteristics of approximately 60% of the PC and TM being made available within 2 hours to provide an initial pain relief effect and then sustained zero-order release of DC over a period of 24 hours to combat the on-going effects of any underlying inflammatory conditions. The triple-layered tablet delivery system would thus provide both rapid onset of pain relief as well as potentially address an underlying inflammatory cause. The design of a novel triple-layered tablet allowed for the desired release characteristics to be attained. During initial development work on the polymeric matrix it was discovered that only when combined with the optimized ratio of the release retarding polymer polyethylene oxide (PEO) in combination with electrolytic-crosslinking activity, provided by the biopolymer sodium alginate and zinc gluconate, could the 24 hour zero-order release of DC be attained. It was also necessary for this polymeric matrix to be bordered on both sides by the cellulosic polymers containing PC and TM. Thus the application of multi-layered tableting technology in the form of a triple-layered tablet were capable of attaining the rate-modulated release objectives set out in the study. The induced barriers provided by the three layers also served to physically separate TM and DC, reducing the likelihood of the bioavailability-diminishing interaction noted in United States Patent 6,558,701 and detected in the DSC analysis performed as part of this study. The designed system provided significant flexibility in modulation of release kinetics for drugs of varying solubility. The suitability of the designed triple-layered tablet delivery system was confirmed by a Design of Experiments (DoE) statistical evaluation, which revealed that Formulation F4 related closest to the desired more immediate release for PC and TM and the zero-order kinetics for DC. The results were confirmed by comparing Formulation F4 to typical release kinetic mechanisms described by Noyes-Whitney, Higuchi, Power Law, Pappas-Sahlin and Hopfenberg. Using f1 and f2 fit factors Formulation F4 compared favourably to each of the criteria defined for these kinetic models. The Ultra Performance Liquid Chromatographic (UPLC) assay method developed displayed superior resolution of the active pharmaceutical ingredient (API) combinations and the linearity plots produced indicated that the method was sufficiently sensitive to detect the concentrations of each API over the concentration ranges studied. The method was successfully validated and hence appropriate to simultaneously detect the three APIs as well as 4-aminophenol, the degradation product related to PC. Textural profile analysis in the form of swelling as well as matrix hardness analysis revealed that an increase in the penetration distance was associated with an increase in hydration time of the tablet and also an increase in gel layer thickness. The swelling complexities observed in the delivery system in terms of both the PEO, crosslinking sodium alginate and both cellulose polymers as well as the actuality of the three layers of the tablet swelling simultaneously suggests further intricacies involved in the release kinetics of the three drugs from this tablet configuration. Modified release dosage forms, such as the one developed in this study, have gained widespread importance in recent years and offer many advantages including flexible release kinetics and improved therapy and patient compliance.

O nitrogênio é um dos nutrientes mais importante para o desenvolvimento vegetal e o mais aplicado em diversos cultivos agrícolas. Dentre as fontes nitrogenadas disponíveis, a ureia se destaca pela alta concentração de nitrogênio que remete a diversas vantagens econômicas e operacionais no sistema de produção agrícola. Porém, além da alta propensão a perdas, principalmente por volatilização do gás amônia, tem-se a necessidade do aumento da produtividade de modo ao suprimento da demanda crescente de alimentos, fibras e energia. Considerando estes fatores, uma nova vertente de pesquisa está voltada a aplicação de tecnologias à ureia, os fertilizantes com tecnologia agregada, estes vêm se destacando e disponibilizando alternativas de novos produtos no mercado. Com base no exposto, buscou-se elucidar os seguintes questionamentos: As novas tecnologias aplicadas a ureia possibilitam a redução de perdas por volatilização? As novas tecnologias aplicadas a ureia modificam suas transformações inorgânicas e orgânicas no solo e, em caso de modificação, estas são positivas? O uso de tecnologias aplicadas à ureia reflete em maior longevidade na liberação do nutriente ao solo e, em caso positivo, esta longevidade é vantajosa? A combinação entre produtos de ureia convencional e com tecnologia agregada, pode trazer mais benefícios à cultura do milho do que a aplicação destes isoladamente? A substituição do uso/aplicação da ureia em sua forma tradicional pela ureia com tecnologia agregada, na cultura do milho, é viável economicamente ao produtor? Para responder a estes questionamentos, foram conduzidos três experimentos: análise das frações do nitrogênio provenientes da ureia com inibidores de urease; caracterização da dinâmica de liberação e longevidade de fertilizantes recobertos com polímero e enxofre e; análise da produtividade da cultura do milho submetida a adubação com ureia recoberta com polímero e enxofre. O primeiro experimento permitiu concluir que o uso dos inibidores de urease tem potencial para a redução das perdas por volatilização da amônia, foi possível verificar as transformações sofridas pelo nitrogênio desde a aplicação do grânulo até a disponibilidade das formas minerais, passando a incorporação do nutriente na matéria orgânica. No segundo experimento concluiu-se que os fertilizantes recobertos com polímero e enxofre possuem dinâmica exponencial de liberação, o recobrimento é dependente da temperatura, umidade do solo, tipo de material de recobrimento e processo de recobrimento (espessura), que afetam diretamente a liberação e longevidade destes fertilizantes. O último experimento mostrou que uso dos fertilizantes recobertos com polímero e enxofre aumenta a produtividade, os parâmetros biométricos, os parâmetros nutricionais e a qualidade do grão da cultura do milho. As combinações realizadas entre os produtos recobertos com a ureia convencional são alternativas para o aumento da produtividade resultando em valores superiores a aplicação dos insumos de forma isolada. A combinações de produtos recobertos com a ureia convencional é opção para a redução do investimento e, consequentemente, custo de produção resultante da adoção destas novas tecnologias. / Nitrogen is one of the most important nutrient for plant development and the most applied nutrient in several agricultural crops. Among the available nitrogen sources, urea differ due to the high concentration of nitrogen that result to several economic and operational advantages in the agricultural production system. However, in addition to the high propensity for losses, mainly due to the ammonia volatilization, the need to increase yield in order to supply the growing demand for food, fiber and energy emerge. Considering these factors, a new research area is focused to aggregate technologies to the urea, they call fertilizers with aggregate technology, this type of fertilizers emerges and brings new alternatives about new products available in the market. Based on the above, it was tried to answer the following questions: Does the new technologies applied to urea fertilizer enable the reduction of losses by volatilization? The new technologies applied to urea modify their inorganic and organic transformations in the soil and, if modified, are these positive? Does the use of technologies applied to urea reflect in a longer longevity in the release of the nutrient to the soil and, if so, is this longevity advantageous? Can the combination of conventional urea and aggregate technology products brings more benefits to cons than the application of these alone? Is the substitution of urea in its traditional form by urea with aggregate technology in the maize crop economically viable to the producer? In order to answer these questions, three experiments were conducted: analysis of nitrogen fractions from urea and urea mixed with inhibitors; Dynamics of release and longevity of polymer sulfurcoated fertilizers; Analysis of maize yield submitted to fertilization with polymer and sulfur coated urea. The first experiment allowed concluding that the use of the urea inhibitors has potential to reduce losses by ammonia volatilization, it was possible to verify all the changes undergone by the nitrogen fertilization since the granule until the availability of the mineral forms, including the immobilization of the nutrient in organic matter. In the second experiment, it was concluded that the polymer and sulfur coated fertilizers have exponential dynamics of release, the coating depends on the temperature, soil moisture, type of coating material and coating process (thickness), which directly affects the release and longevity of these fertilizers. The last experiment showed that the use of the coated fertilizers with polymer and sulfur increases the yield, the biometric parameters, the leaf concentration and the quality of grain to the maize crop. The combinations performed between the coated products with conventional urea are alternatives for increasing the yield resulting in higher application values of the inputs in an isolated way. Combinations of coated products with conventional urea is an alternative to reduce investment and consequently the production costs, it will result the adoption of these new technologies.