Malaria is a parasitic disease claiming one million lives worldwide annually. Unfortunately, malaria-endemic countries in need of good quality medicines are also overwhelmed with counterfeit or substandard medicine. This results in treatment inefficacy, resistance towards treatment and death. Counterfeit or substandard quinine sulfate tablets are known to have infiltrated the market, however at this point in time, treatment efficacy of quinine sulfate has fortunately not yet been significantly impaired by resistance, but immediate action is required to prevent it from becoming obsolete. Validated analytical methods with justified specifications are effective in controlling the quality of medicines and to minimise the effect of poor quality medicines. Pharmacopoeia specifies analytical quality control procedures and accompanying specifications to standardise acceptable levels of product quality. Understandably, different monographs of different pharmacopoeias are developed by different independent laboratories and therefore their respective test procedures/specifications for the same FPP may differ from each other. Institutions such as the Pharmacopoeial Dicussion Group (PDG) aim to harmonise pharmacopoeia in order to synchronise final outcomes. This study evaluated the relevancy of differences in analytical procedures, results and specifications for quinine sulfate tablets set by the United States Pharmacopoeia (USP), British Pharmacopoeia (BP) and International Pharmacopoeia (Ph.Int.) in an aim to ensure that these different methods all provide with similar final outcomes and that they be effective in successfully evaluating the quality of quinine sulfate tablets. Four quinine sulfate tablet products were obtained from different manufacturers and were subjected to the tests of all three pharmacopoeia – BP, USP and Ph.Int. The results from identification, assay and related substance testing concluded that the outcomes were the same between the pharmacopoeia despite their differences in techniques/procedures/specifications. The assay, identification and related substances methods and specifications set by each respective monograph were deemed appropriate to evaluate the quality of quinine sulfate tablets. Even with differences in methodology, quantitative techniques and specifications, the USP and BP dissolution methods for quinine sulfate tablets shared the same final outcome at the first stage of dissolution, whereas none of the products achieved a compliant outcome using the Ph.Int. dissolution method. Possible reasons for the poor dissolution (when using the Ph.Int. method) were identified and investigated. Investigation into the solubility of quinine sulfate found the Ph.Int. dissolution method conditions to be too stringent, as the solubility of quinine sulfate in phosphate buffer pH 6.8 (dissolution medium specified by the Ph.Int.) was found to be much less than in acidic media (as proposed by the BP and USP dissolution methods). Several adapted dissolution methods (called developmental studies) were investigated to serve as potential alternatives for the Ph.Int. dissolution method. The developmental studies investigated an alternative dissolution medium, agitation rates (50 rpm, 75 rpm, 100 rpm) and medium volumes (500 ml, 750 ml, 900 ml and 1000 ml). Developmental study 6 was proposed as an alternative dissolution method. Developmental study 6 stipulates the use of the same medium as the original Ph.Int. method, as it was deemed the medium of choice for its discriminatory ability. To address the impaired solubility of quinine sulfate in phosphate buffer, the medium volume and agitation were increased (in reference to the original method) to 900 ml and 100 rpm respectively. The same analytical quantitation technique (UV-Vis spectroscopy) is proposed for Developmental study 6. The newly proposed method provided with final outcomes comparable to that of the USP and BP, however having more discriminatory power than the USP and BP. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Flows of fluids and solid particles through microchannels have a very wide range of applications in biological and medical science and engineering. Understanding the mechanism of microflows will help to improve the development of the devices and systems in those applications. The aim of this study is to develop a sophisticated simulation and analysis technique for the study of fluid-particle flow through microchannels. This work involves construction of mathematical models, development of analytical methods and numerical algorithms, and numerical investigation and analysis. / The study consists of three parts. The first part of the research focuses on the transient flow of an incompressible Newtonian fluid through a micro-annual with a slip boundary. The flow of the fluid is governed by the continuity equation and the Navier-Stokes equations, and is driven by the pressure field with a timevarying pressure gradient. By using the Fourier series expansion in time and Bessel functions in space, an exact solution is derived for the velocity field. The velocity solution is then used to obtain the exact solutions for the flow rate and the stress field. Based on the exact solutions, the influence of the slip parameter on the flow behaviour is then investigated. / The second part of the research focuses on the particle-fluid flow in microchannels. The transport of fluid in the vessel is governed by the continuity equation and the transient Navier-Stokes equations, while the motion of the particles is governed by Newton’s laws. The particle-wall and particle-particle interactions are modelled by the interacting forces, while the particle-fluid interaction is described by the fluid drag force. A numerical scheme based on the finite element method and the Arbitary Lagrangian-Eulerian method is developed to simulate the motion of the particles and the fluid flow in the vessels. The influence of boundary slip on the velocity field in the fluid is also investigated numerically. / Based on the work in the second part, the third part of the research focuses onthe control of the movement of particles in the fluid by applying an external magneticfield to the system. Maxwell’s equations are used to model the magnetic fieldgenerated by the external magnetic source, and a finite element based numericalscheme is developed to solve the underlying boundary value problem for the magneticflux density generated. From the computed flux density and magnetic vectorpotential, the magnetic forces acting on the particles are determined. These magneticforces together with the drag force and the particle-particle interacting forcesdominate the behaviour of the particle motion. A numerical scheme, similar to thatfor the second part of the research, is then developed to study the fluid-particle flowin microchannels under magnetic forces, followed by a numerical investigation onthe influence of the magnetic forces on the particle flow behaviour.

Diss. (sammanfattning) Stockholm : Tekn. högsk. / Härtill 6 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 6 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2008. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2009. / Härtill 5 uppsatser.

Este trabalho apresenta estudo sobre o voriconazol, antifúngico de amplo espectro liberado para tratamento de infecções fúngicas invasivas no ano de 2002, focado no controle de qualidade e estudo de estabilidade. Foram realizados testes, ainda não citados na literatura, que visaram à caracterização do fármaco tais como: espectrofotometria na região do infravermelho, espectroscopia de ressonância magnética nuclear de hidrogênio e de carbono. Os seguintes métodos de análise quantitativa do fármaco em comprimidos foram desenvolvidos e validados: espectrofotometria na região do UV, cromatografia a líquido de alta eficiência e ensaio microbiológico - método de difusão em ágar. Todos os métodos foram avaliados frente aos parâmetros de linearidade, exatidão e precisão. A especificidade foi avaliada nos métodos de CLAE e UV, pela análise de placebo (CLAE e UV) e testes de degradação forçada (CLAE). A robustez foi avaliada no método de CLAE. Os resultados obtidos através destes métodos foram comparados estatisticamente por ANOVA, que indicou não haver diferenças estatisticamente significativas entre os mesmos; no entanto, os métodos por CLAE e ensaio microbiológico possibilitam a quantificação do voriconazol em amostras degradadas. Foram estudadas as estabilidades térmica, fotoquímica e química do voriconazol. Quimicamente, o fármaco é degradado intensamente em meio alcalino e em menor extensão em meios ácido, oxidante e neutro. Na temperatura testada (60 ºC), o voriconazol é estável em estado sólido e instável em solução metanólica (teor de 25% em 21 dias). O fármaco é instável às radiações UV-C, em maior grau, e UV-A (degradação menos intensa), tanto em solução quanto em estado sólido. Em ambas, a degradação é favorecida se o fármaco estiver em solução. Também foi estudada a estabilidade da formulação injetável, como produto reconstituído e em soluções para infusão. Verificou-se que o prazo de validade da solução reconstituída de 24 horas, proposto pelo laboratório produtor, pode ser estendido para oito dias. As soluções para infusão do voriconazol em cloreto de sódio 0,9% ou glicose 5%, preparadas em bolsas de PVC, devem ser administradas logo após sua preparação, se mantidas em temperatura ambiente. Mantidas sob refrigeração, são estáveis por 11 e nove dias, respectivamente. Isolou-se e identificou-se o produto de degradação majoritário observado durante os estudos de estabilidade, que corresponde a 1- (2,4-difluorfenil)-2-(1H-1,2,4-triazol-1-il)-1-etanona. Foi constatado que os produtos de degradação do voriconazol não apresentam atividade antifúngica; sendo assim, cuidados em relação à temperatura e luz devem ser tomados ao armazenar soluções do fármaco. / This study is focused on quality control and stability evaluation of voriconazole, a broad spectrum antifungal agent, approved for treatment of invasive fungal infections in 2002. The drug was characterized by tests as IV spectrophotometry, nuclear magnetic ressonance spectrometry of hydrogen and carbon, not refered until the moment. The following methods, applied to the assay of voriconazole in tablets were developed and validated: UV spectrophotometry, HPLC assay and microbiological assay, using the cylinder-plate method. All of them were evaluated in the following parameters: linearity, accuracy and precision. The specificity was evaluated in HPLC and UV assays, by analysis of excipients and/or degradated samples. The robustness was evaluated in the HPLC assay. The results obtained in the three methods were compared by ANOVA, which indicated that they are equivalent. However, only HPLC and microbiological assays could be used in the quantitation of voriconazole in degradated samples. The stability of voriconazole under temperature, radiation and different chemical mediums was evaluated. The drug is extensively degradated under alkaline medium, being degradated in less extension under acidic, neutral and oxidant mediums. Voriconazole is stable in the tested temperature (60 ºC) in solid state, but is unstable in solution (loss of 75%, in 21 days). The drug is unstable to UV-C and UV-A radiations, both in solution or in solid state, being the degradation on UV-C more intense. The degradation is higher if the drug is in solution. The stability of the injectable formulation was studied, as reconstituted product and infusion solutions in PVC bags. Voriconazole reconstituted product was stable for eight days, stored at 4-7 ºC. As infusion solution, in 0.9% sodium chloride or in 5% dextrose, stored at room temperature, the drug should be administered only just after preparation. Stored at 4-7 ºC, the infusion solutions were stable for 11 and 9 days, respectivelly. The main degradation product observed in the stability studies was isolated and identified. It corresponds to 1-(2,4-difluorophenyl)-2-(1H-1,2,4- triazol-1-yl)-1-ethanone. It was comproved that the voriconazole degradation xxx products don’t have antifungal activity. So, special care should be taken in relation to temperature and radiation, when solutions of voriconazole are stored.