Low water solubility of drug compounds limits their dissolution in the aqueous body fluids. When formulated using conventional methods, those poorly water-soluble drugs often results in low and erratic bioavailability. The use of nanoparticle engineering technologies for the formulation of poorly water-soluble drugs is a valuable strategy to enhance dissolution rates and thus bioavailability. In Chapter 2, a nanoparticle engineering process, Evaporative Precipitation into Aqueous Solution (EPAS), was modified to provide improved control over the size of precipitated particles. The improved process, Advanced EPAS, was employed to prepare nanoparticles of the poorly water-soluble drug itraconazole (ITZ). The influence of processing parameters and formulation aspects on the size of suspended ITZ-particles was investigated. The process was shown to be robust such that the size distribution of dispersed nanoparticles was largely independent across the different parameters. In Chapter 3, aqueous nanoparticulate dispersions of the poorly soluble drug mefenamic acid (MFA) were developed and subsequently incorporated into controlled release formulations employing spray-drying. Release of MFA from spray-dried formulations was sustained and complete demonstrating the feasibility of using nanoparticulates for the preparation of controlled release systems. In Chapter 4, the nanoparticle engineering process, Rapid Freezing (RF), was utilized to produce nanostructured, amorphous aggregates of the poorly water soluble drug ketoprofen (RF-KET). The stability of RF-KET against recrystallization was improved through the deposition of a hydrophobic plasma-polymerized film. The coating presented an effective barrier against surface mobility and moisture uptake resulting in enhanced stability of RF-KET for up to six months at accelerated storage conditions as compared to three days for uncoated RF-KET. / text

Background No data exist about caregivers’ beliefs surrounding a diagnosis of cerebral palsy (CP), its causes and how this influences caregivers’ perceptions of therapy in poorly-resourced South African settings. Neither is there any information about how rehabilitation therapy influences the life of the child or the caregiver. The appropriateness, the outcomes and the effectiveness of therapy for children with CP in a South African setting have not been studied. Numerous tools and scales for measuring outcomes of rehabilitation relating to both the child and the caregiver are available internationally but none have been validated for use in South Africa. Caregiver-related outcomes were the focus of this study and included maternal well-being and mental health, personal quality of life, availability of support and interaction with the child. These are factors known to potentially be influenced through contact with rehabilitation services. Aims The aims of this study were firstly to ascertain whether caregiver-related outcome measures developed in high-income settings were appropriate for a poorly-resourced South African setting; and secondly, to describe parental perceptions and experiences of rehabilitation therapy received in public service hospitals in disadvantaged areas. Methodology The study was undertaken in two phases. Phase One was a quantitative cross-sectional, analytical study and addressed the first aim. Five scales were identified from the literature as being suitable for measuring the caregiver-related outcomes of interest in this study: the Caregiver-Child Scale, the Family Support Scale, the Personal Quality of Life Scale, the Mental Health Subscale of the Medical Outcomes Study (MOS) Short-form 20 Health Survey, and the Measure of Processes of Care (MPOC) Scale. The first four scales measure aspects of maternal well-being and interaction with the child whilst the MPOC assesses caregivers’ reported experiences of family-centred behaviours of rehabilitation service providers. These scales were modified and adapted to make them relevant to a South African setting through a process that included focus groups with caregivers and experienced therapists. After the modified scales had been translated into six local languages and then back-translated into English, the translators, researcher and interviewers met to discuss discrepancies between the two versions (the original modified English version and the back-translation) and to reach consensus on the final translation. The scales were further refined during a pilot study where two trained interviewers administered the modified scales to 24 caregivers of children attending public service hospitals for therapy. Items in the scales which were confusing for caregivers or which they found difficult to understand were clarified. In addition, where necessary, concrete examples were given of the type of behaviour or action being asked about in the scale. Following the pilot study, two trained interviewers administered the modified scales to a convenience sample of caregivers attending rehabilitation therapy in public service hospitals in Gauteng and Limpopo. The reliability and validity of each scale was assessed using multi-trait scaling and factor analysis. Phase Two employed qualitative methodology to address the second aim of the study. A purposive sample of 24 information-rich caregivers attending therapy in public service hospitals in Gauteng and Limpopo participated in one of five focus groups. The discussions were conducted in local languages. Taped recordings were transcribed and translated into English before being analysed using a grounded theory approach. Results Two hundred and sixty three caregivers from 31 hospitals in Gauteng and Limpopo provinces were interviewed during the first phase of the study. The mean age of their children was 3.3 years (± 2.6).Two-thirds of the children (66%) had severe limitations in motor function and few (15%) could communicate verbally. Only one of the five scales, the Mental Health Subscale, proved to be both reliable and valid in South African settings. A second scale - the MPOC - was potentially useful if reduced to an eight item scale (from the original 20 items). The Family Support Scale was reliable but not valid whilst the Caregiver-Child and Personal Quality of Life Scales were neither reliable nor valid. The process of administering the scales combined with the qualitative data helped to explain why the scales did not perform as well as expected in a South African setting. Reasons for these findings included the caregivers’ inexperience in completing these kinds of questionnaires; their difficulty with the concept of grading their responses which meant that Likert-type scales were difficult for them to complete; and thirdly language and cross-cultural applicability. This was because the scales were developed for very different cultural groups. It was not the questions or scale items that were the problem; it was rather finding the language and words that caregivers themselves would use to express the underlying concepts. The study found that caregivers living in disadvantaged South African settings live very differently from their counterparts in well-resourced areas. They lived in poverty; were beset by financial concerns; often abandoned and rejected by their partners; and endured gossip and ignorant attitudes from their neighbours and the community. The burden of daily care-giving was high as most of the children were severely disabled. This was compounded by concern about the child’s health and the future. Despite this, the study found that they were happy, healthy and generally well satisfied with their lives. Support from informal support structures such as relatives and close family members, together with formal support structures, was an important dimension in helping caregivers cope. Qualitative data from the focus groups yielded information regarding caregivers’ beliefs surrounding the perceived cause of the child’s disability. These ranged from traditional and cultural beliefs to medical explanations, and to frank confusion between the two. This was accompanied by misconceptions about therapy and the outcome thereof. Parental perceptions and experiences of rehabilitation were positive although many caregivers initially expected therapy to provide a cure. Respectful and caring attitudes, “hands on” therapy, practical help and assistance with assistive devices and school placements were aspects of service most valued by caregivers. The study helped define the components of an “ideal” therapy service in disadvantaged South African settings. They would include the availability of parent support groups; greater involvement of fathers, close family members and traditional healers in the rehabilitation process as well as the implementation of innovative strategies to ensure clearer communication and understanding between therapists and caregivers operating in a cross-cultural setting. Elements of care not traditionally perceived as part of therapy such as promoting supportive networks and taking on advocacy role for children with disabilities may offer additional advantages. Conclusion The study confirms the view that scales developed in high-income settings are not necessarily immediately applicable to less well-resourced settings and often require extensive modifications to ensure reliability and validity. Whilst the Mental Health Scale is a reliable and valid tool for caregivers attending public service hospitals in South Africa, other scales, such as the MPOC, a popular scale in North American and Europe, require substantial modification for a South African setting. In addition to highlighting the challenges involved in finding suitable outcome measures of therapy intervention for this population, this study has objectively documented the lives and experiences of caregivers of children with CP in South Africa for the first time together with their experiences and perceptions of rehabilitation therapy. Using this information, the components of an “ideal” rehabilitation service in a disadvantaged South African setting have been identified and described. This may facilitate the establishment of a more effective and appropriate therapy service for caregivers and children with CP living in poor areas.

No / Of particular importance in recent years has been the development of techniques for producing nanoparticles (NPs) of poorly-water soluble drugs with dimensions less than 1000 nm for which their high surface area can lead to improvements in bioavailability. Furthermore, the small size of these particles can also enable cellular uptake, particularly for positively charged systems. Therefore, an overall objective of this part of the project was to produce nanoparticles with different levels of positive surface charge using the bottom-up method.

Poor aqueous solubilities of drug candidates limit the biopharmaceutical usefulness in either oral or parenteral dosage forms. Lipid assemblies, such as micelles, may provide a means of enhancing solubility. Despite their usefulness, little is known about the means by which micelles accomplish this result. The goal of the current dissertation is to provide the molecular level understanding of the mechanism by which simple micelle systems solubilize drugs. Specifically, the location, orientation and amount of the drug molecules in micelle systems are the focuses of the work. Three series of model drugs, steroids, benzodiazepines and parabens, in three surfactant systems with anionic, cationic and neutral hydrophilic headgroups were studied. Solubilization power of each micelle system for each model drug was determined by equilibrium solubility. The observed strong surface activities of model drug at hydrocarbon/water interface and the ability of the drugs to compete with surfactants for the model oil/water interface lend support to the hypothesis that drug molecules are mainly solubilized in the interfacial region of the micelles. A surface-localized thermodynamic model that considered the surfactant-drug competition at micelle surface was successfully applied to predict the micelle/water partitioning coefficients. The predictions were made without the use of adjustable parameters in the case of both dilute and concentrated solutions. The orientation of drug at micelle surface was determined by matching calculated occupied areas by solutes at oil/water interface using molecular modeling method to the experimental values. To look into the micro-structure of micelles, twodimensional and diffusion (or PGSE) NMR techniques were employed to detect the specific drug-surfactant interactions and the micelle sizes influenced by model drugs and electrolytes.

The majority of pharmacologically active chemotherapeutics are poorly water soluble. Solubilization enhancement by the utilization of organic solvents often leads to adverse side effects. Nanoparticle-based cancer therapy, which is passively targeted to the tumor tissue via the enhanced permeation and retention effect, has been vastly developed in recent years. Nanocrystals, which exist as crystalline and carry nearly 100% drug loading, has been explored for delivering antineoplastic agents. Additionally, the hybrid nanocrystal concept offers a novel and simple way to integrate imaging agents into the drug crystals, enabling the achievement of theranostics. The overall objective of this dissertation is to formulate both pure and hybrid nanocrystals, evaluate their performance in vitro and in vivo, and investigate the extent of tissue distribution and tumor accumulation in a murine model. Pure and hybrid nanocrystals of several model drugs, including paclitaxel (PTX), camptothecin, and ZSTK474, were precipitated by the antisolvent method in the absence of stabilizer, and their size was further minimized by homogenization. The nanocrystals of PTX, which is the focus of the study, had particle size of approximately 200 nm and close-to-neutral surface charge. Depending on the cell type, PTX nanocrystals exerted different level of cytotoxicity. In human colon and breast cancer xenograft models, nanocrystals yielded similar efficacy as the conventional formulation, Taxol, at a dose of 20 mg/kg, yet induced a reduced toxicity. Biodistribution study revealed that 3H-PTX nanocrystals were sequestered rapidly by the macrophages upon intravenous injection. Yet, apparent toxicity was not observed even after four weekly injections. The sequestered nanocrystals were postulated to be released slowly into the blood circulation and reached the tumor. Tritium-labeled-taxol, in contrast, was distributed extensively to all the major organs, inducing systemic toxicity as observed in significant body weight loss. The biodistribution results obtained from radioactive analysis and whole-body optical imaging was compared. To some degree, the correlation was present, but divergence in the quantitative result, due to nanocrystal integrity and limitations associated with the optical modality, existed. Despite their promising properties, nanocrystal suspensions must be securely stabilized by stealth polymers in order to minimize opsonization, extend blood-circulation time, and efficiently target the tumor.

Para a introdução da cultura do milho como alternativa de rotação de culturas em áreas cultivadas com arroz irrigado no Rio Grande do Sul, é necessário um sistema de irrigação e drenagem eficiente, sem ocasionar problemas de manejo para o cultivo do arroz. O objetivo deste trabalho é avaliar diferentes manejos de irrigação e drenagem visando introduzir o milho como alternativa técnica e econômica para rotação de cultura em Gleissolo Háplico Distrófico Típico, onde tradicionalmente se cultiva arroz. Foram avaliados alguns indicadores de rendimento do milho e a eficiência do uso da água (EUA) nas diferentes alternativas de manejos. Foram testados quatro tratamentos: (T1) microcamalhão de 15 cm de altura com irrigação por sulco sempre que necessário, (T2) uma testemunha com microcamalhão com 15 cm de altura sem irrigação, (T3) um sem construção de microcamalhão, com irrigação por banhos sempre que necessário, e (T4) outro sem construção de microcamalhão e sem irrigação. Todos os tratamentos foram realizados com três repetições. O experimento foi conduzido nos anos agrícolas 2013/2014 e 2014/2015, na estação experimental do IRGA em Cachoeirinha-RS. Em todos os tratamentos a área foi nivelada com uma declividade de 0,08%, ao longo do comprimento das parcelas (79 m). A lâmina irrigada foi de 30 mm e as irrigações foram efetuadas de maneira complementar à chuva por sulcos ou banhos. Os resultados desta pesquisa demonstram que a drenagem foi eficientenos dois anos, pois mesmo com ocorrência de eventos de chuva superiores a 50 mm em 24 horas, não houve problema de excesso hídrico. No primeiro ano foram aplicados 300 mm de irrigação (choveu 480 mm ao longo do desenvolvimento do milho) e os resultados indicam alta produtividade do milho (superiores a 10 Mg ha-1) para o tratamento irrigado e com microcamalhão. No segundo ano foram aplicados somente 90 mm de irrigação pois foi um ano muito úmido (choveu 620 mm durante o segundo ano agrícola). Em consequência disso, não houve diferença significativa nos resultados pois todas os tratamentos mantiveram-se na umidade ideal na maioria do tempo, apresentando altas produtividades de grãos (superiores a 13 Mg ha-1). O milho cultivado em áreas cultivadas com arroz irrigado no Rio Grande do Sul é tecnicamente e economicamente viável desde que ocorra o uso de irrigação e que se utilize um sistema de drenagem eficiente. / For the introduction of corn as crop rotation alternative in areas cultivated with rice in Rio Grande do Sul, efficient irrigation and drainage system is required, without causing management problems for rice cultivation. The objective of this study is to evaluate different management of irrigation and drainage aimed at introducing corn as technical and economical alternative to crop rotation in Gleissolo Háplico Distrófico Típico, where traditionally cultivated rice. We evaluated some corn performance indicators and efficiency of water use (EWU) in the different alternatives managements. Four treatments were tested: (T1) microcamalhão 15 cm with furrow irrigation whenever necessary, (T2) a witness with microcamalhão 15 cm without irrigation, (T3) without building microcamalhão, with irrigation when necessary, and (T4) without building microcamalhão and without irrigation. All treatments were performed with three replications. The experiment was conducted in the agricultural year 2013/2014 and 2014/2015, the IRGA's experimental station in Cachoeirinha-RS. In all treatments area was capped with a slope of 0.08% along the length of the parcels (79 m). Irrigated blade was 30 mm and irrigation was made in a complementary manner to rain by grooves or baths. These results demonstrate that the drainage was efficient in both years, since even the occurrence of rain events greater than 50 mm in 24 hours, there was no excess water problem. In the first year were applied 300 mm irrigation (480 mm rain during the development of corn) and the results indicate high corn yields (above 10 Mg ha-1) for the treatment irrigated and microcamalhão. In the second year there were only applied 90 mm of irrigation because it was a very wet year (620 mm rain during the second growing season) so there was no significant difference in the results for all treatments remained at the ideal humidity most of the time, high grain yield (above 13 Mg ha-1). The corn grown in areas cultivated with rice in Rio Grande do Sul is technically and economically feasible provided that there is an efficient irrigation and drainage system.

Supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs), have been used extensively to elevate the apparent solubility and oral bioavailability of poorly water-soluble drugs. However, despite the numerous examples of success in increasing solubility and oral bioavailability using ASDs, physical stability challenges remain as formulators seek to employ high drug loading for cost reduction and improved patient compliance. Therefore, stability in both the solid and solution state must be considered for ASDs to be successful. In the solid state, the drug must remain amorphous in the solid matrix throughout the shelf life of the product. Although excipients, such as polymers, have been known to stabilize the amorphous drug in the solid state, stresses encountered during manufacturing and fluctuations in storage conditions may have a detrimental impact on the physical stability of ASDs. Numerous studies have been performed on the impact of each process on ASD stability, yet the relative quantitative impact of each process with respect to the overall energetics landscape is not well understood. Further, ASDs must dissolve after administration and maintain the intended supersaturation in the gastrointestinal (GI) tract during the GI transit time to achieve maximum oral absorption. In solution, the energetics advantage of the amorphous over the crystalline material is a “double-edged sword,” in that it produces not only a high absorption driving force but also an undesirable high crystallization potential. An approach to quantitatively measure the thermodynamic activity of amorphous materials is, thus, desirable. However, it is difficult to measure thermodynamic activity quantitatively, especially due to the speciation process induced by formulation excipients and endogenous materials. Hence, it is often difficult to assess the true enhancement in the absorption for a given ASD and to measure its crystallization tendency in solution. Overall, this dissertation aims to address the following: 1. The relative thermodynamics magnitude of various processes with respect to the crystallization energy associated with amorphous drugs 2. The development of a practical tool to measure the thermodynamic activity of amorphous materials over its crystalline counterpart in solution to assess the enhancement in absorption in the presence of excipients 3. The impact of measured thermodynamic activity on drug crystallization energetics in the presence of excipients

Spatial patterns as well as temporal dynamics of soil moisture have a major influence on runoff generation. The investigation of these dynamics and patterns can thus yield valuable information on hydrological processes, especially in data scarce or previously ungauged catchments. The combination of spatially scarce but temporally high resolution soil moisture profiles with episodic and thus temporally scarce moisture profiles at additional locations provides information on spatial as well as temporal patterns of soil moisture at the hillslope transect scale. This approach is better suited to difficult terrain (dense forest, steep slopes) than geophysical techniques and at the same time less cost-intensive than a high resolution grid of continuously measuring sensors. Rainfall simulation experiments with dye tracers while continuously monitoring soil moisture response allows for visualization of flow processes in the unsaturated zone at these locations. Data was analyzed at different spacio-temporal scales using various graphical methods, such as space-time colour maps (for the event and plot scale) and binary indicator maps (for the long-term and hillslope scale). Annual dynamics of soil moisture and decimeterscale variability were also investigated. The proposed approach proved to be successful in the investigation of flow processes in the unsaturated zone and showed the importance of preferential flow in the Malalcahuello Catchment, a datascarce catchment in the Andes of Southern Chile. Fast response times of stream flow indicate that preferential flow observed at the plot scale might also be of importance at the hillslope or catchment scale. Flow patterns were highly variable in space but persistent in time. The most likely explanation for preferential flow in this catchment is a combination of hydrophobicity, small scale heterogeneity in rainfall due to redistribution in the canopy and strong gradients in unsaturated conductivities leading to self-reinforcing flow paths.

The number of newly developed chemical entities exhibiting poor water solubility has increased dramatically in recent years. In many cases this intrinsic property results in poor or erratic dissolution in biological fluids. Improving aqueous solubility of these compounds, even temporarily, can have a significant impact on in vivo performance. Single phase amorphous solid dispersions of a drug and polymer have emerged as a technique to not only increase the level of drug supersaturation but also maintain these levels for extended periods of time. Hot-melt extrusion (HME) has become the preferred processing technique to prepare systems such as these but has a number of limitations that prevent the successful formulation of many drug substances. Within this dissertation, the use of concentration enhancing polymers was investigated in parallel with a thorough evaluation of a novel fusion-based processing technique, KinetiSol® Dispersing (KSD), to prepare single phase amorphous solid dispersions that could not be successfully prepared by HME. Studies showed that the KSD technique is suitable for rendering thermally labile and high melting point drug substances amorphous through a combination of frictional and shearing energy. Compounds such as these were shown to degrade during HME processing due to relatively long residence times and low shear forces. Similarly, the KSD process was shown to successfully process solid dispersion compositions containing a high viscosity polymer with significantly lower levels of polymer degradation than obtained by HME processing. In the final study, KSD processing was used to prepare solid dispersions containing the hydrophilic polymer Soluplus[superscript TM] and methods were evaluated to formulate a tablet with rapid tablet disintegration characteristics, a requirement for sufficient dissolution enhancement. Combined, the studies demonstrated the effectiveness of combining proper polymer selection and formulation approaches with a suitable processing technique to form solid dispersion systems that provide rapid and extended durations of supersaturation. / text

Frac-pack design is still done on conventional hydraulic fracturing models that employ linear elastic fracture mechanics. However it has become evident that the traditional models of fracture growth are not applicable to soft rocks/unconsolidated formations due to elastoplastic material behavior and strong coupling between flow and stress model. Conventional hydraulic fracture models do not explain the very high net fracturing pressures reported in field and experiments and predict smaller fracture widths than expected. The key observations from past experimental work are that the fracture propagation in poorly consolidated sands is a strong function of fluid rheology and leak off and is accompanied by large inelastic deformation and shear failure leading to higher net fracturing pressures. In this thesis a numerical model is formulated to better understand the mechanisms governing fracture propagation in poorly consolidated sands under different conditions. The key issues to be accounted for are the low shear strength of soft rocks/unconsolidated sands making them susceptible to shear failure and the high permeabilities and subsequently high leakoff in these formations causing substantial pore pressure changes in the near wellbore region. The pore pressure changes cause poroelastic stress changes resulting in a strong fluid/solid coupling. Also, the formation of internal and external filtercakes due to plugging by particles present in the injected fluids can have a major impact on the failure mechanism and observed fracturing pressures. In the presented model the fracture propagation mechanism is different from the linear elastic fracture mechanics approach. Elastoplastic material behavior and poroelastic stress effects are accounted for. Shear failure takes place at the tip due to fluid invasion and pore pressure increase. Subsequently the tip may fail in tension and the fracture propagates. The model also accounts for reduction in porosity and permeability due to plugging by particles in the injected fluids. The key influence of pore pressure gradients, fluid leakoff and the elastic and strength properties of rock on the failure mechanisms in sands have been demonstrated and found to be consistent with experimental observations. / text