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Coming dissertations at Uppsala university

  • Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs Author: Khadijah Edueng Link: Publication date: 2019-09-04 14:13

    Crystallisation is a concern for amorphous formulation because it compromises the solubility-enhancing benefit gained from amorphisation. Traditionally, amorphous formulation had been designed primarily based on trial-and-error approach. The success rate for amorphous formulation is unimpressive, due to a poor understanding of the formulation itself, especially with regard to its crystallisation behaviour. Therefore, this thesis aimed to propose a strategic approach for rational design of amorphous formulations, as opposed to the trial-and-error approach. This can be achieved by understanding what drives the crystallisation of amorphous drug, and when and how the amorphous drug crystallises. The information can guide the selection of drugs, excipients and preparation method to achieve amorphous formulations with favourable features.

    In the first part of the thesis, a systematic protocol was proposed to identify mechanisms via which crystallisation takes place when amorphous drug is dissolved. The stabilisation strategy of supersaturation produced upon dissolution of amorphous drug was then recommended depending on the crystallisation mechanisms. A molecular dynamics (MD) simulations was used to understand drug-polymer interaction during supersaturation. It was revealed that hydrogen bond interaction is an important in stabilising supersaturation. The factors affecting glass-forming ability and long-term physical stability such as preparation method and humidity were then highlighted in the second study. A follow-up study was performed to elucidate the potential complications in using a standardised differential scanning calorimetry to classify promiscuous glass formers into any specific glass-forming ability/glass stability class. In the subsequent study, the effect of physical aging and/or crystallisation of amorphous drugs during storage on supersaturation potential was addressed. It was shown that, minor crystallisation of amorphous drug upon storage did not have a significant impact on the supersaturation potential during dissolution. Instead, the crystallisation pathway of the amorphous drug during dissolution plays a more important role in determining the supersaturation behaviour of some drugs. Finally, the impact of (i) drug loading on physical stability, supersaturation, drug/polymer miscibility, and (ii) the physical aging and/or crystallisation upon storage on supersaturation potential of spray-dried solid dispersions with HPMC-AS were discussed in the last study. It was observed that the effect of drug loading on physical stability and supersaturation, and the effect of physical aging and/or crystallisation during storage on supersaturation potential is highly drug-dependent. Similarly, the stabilisation effect of HPMC-AS varied across model drugs, drug loadings and crystallisation pathways (i.e. in solid or during dissolution). The Flory-Huggins interaction parameter calculated using MD simulations revealed good miscibility between the drugs and HPMC-AS at drug loadings investigated. In the presence of water molecules, various structural organizations of the drugs and HPMC-AS complexes were observed. Taken together, this thesis provides an improved understanding of crystallisation behaviour of amorphous formulations, which is useful to guide a rational design of amorphous formulations.

  • Design flood estimation under uncertainty Author: Kenechukwu Okoli Link: Publication date: 2019-09-04 10:29

    Att bestämma dimensionerande flöden, d.v.s. sannolikheten för att vat-tenföringen i ett vattendrag överskrider ett givet värde, är ett allmänt hydrologiskt problem som exempelvis används för att utvärdera över-svämningsrisker i vattendrag samt för att dimensionera hydrauliska kon-struktioner. Vanliga tillvägagångsätt för att bestämma dimensionerande flöden är baserade på: (i) hydrologiska metoder (t.ex. avrinningsmodel-lering), eller (ii) statistiska metoder (t.ex. anpassning av en sannolikhets-fördelning till en tidsserie med årliga vattenföringstoppar). I denna av-handling så jämförs dessa två tillvägagångssätt då olika osäkerhetskällor för dimensionerande flöden tillgodoses; valet av tillvägagångsätt, osä-kerhet i modellens uppbyggnad, osäkerheter i vattenföringsmätningar, samt mätfrekvens av dimensionerande flöden, begrundades i denna avhandling. Sannolikhetsfördelningen av vattenföringen i ett hypotetisk vattendrag antogs vara känt sedan tidigare; en uppsättning av virtuella experiment (’numeriska experiment där modellen antas vara sann och beskriva den modellerade processen korrekt’) utvecklades och tillämpa-des för båda tillvägagångssätten som utvärderades utifrån hur väl de uppskattade den sedan tidigare kända sannolikhetsfördelningen av vat-tenföringen. Resultaten visar att användningen av enklare avrinnings-modeller för att bestämma dimensionerande flöden har en lägre osäker-het än då statistiska metoder används, även för längre återkomstperi-oder. Båda tillvägagångsätten bör dock användas som komplement till varandra för att bestämma dimensionerande flöden, givet osäkerheten i båda.

  • A search for leptoquarks with the ATLAS detector and hardware tracking at the High-Luminosity LHC Author: Mikael Mårtensson Link: Publication date: 2019-09-04 09:36

    This thesis presents a search for pair-production of scalar leptoquarks, decaying into third-generation particles, using proton-proton collisions delivered by the Large Hadron Collider (LHC) and recorded by the ATLAS detector. It also presents the development of a hardware track trigger for the Phase-II upgrade of the ATLAS experiment.

    The search for pair-production of leptoquarks is performed using data collected by the ATLAS detector in 2015 and 2016 at a center-of-mass energy of 13 TeV. The total integrated luminosity of this data set amounts to 36.1 fb−1 . The search sensitivity is optimized for up-type leptoquarks where both leptoquarks decay to a b-quark and a τ -lepton. However, it also proves sensitive to down-type leptoquarks where both leptoquarks decay to a top-quark and a τ -lepton. The data is found to be compatible with the Standard Model, so exclusion limits are set on the leptoquark mass.

    After the High Luminosity upgrade of the LHC, the ATLAS detector faces a 5–7 times increase in the number of simultaneous proton-proton collisions. To benefit from this increase in luminosity, the ATLAS detector has to maintain low trigger thresholds while keeping manageable trigger rates. A crucial part of the solution is the development of Hardware Tracking for the Trigger (HTT). The HTT first selects hit clusters in the inner tracking detector using associative memories and uses the selected clusters to perform linearized track-fits. This thesis presents the HTT system with focus on using the Hough transform as an alternative to associative memories to select clusters in the inner detector. The performance of the Hough transform is studied and a hardware implementation is discussed.