| 1. |
- Fagerberg, Jonas H.
(författare)
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Experimental and Computational Predictions of Drug Solubility in Human Gastrointestinal Fluids
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aqueous solubility of a drug is viewed as a pivotal property for its oral absorption since only dissolved molecules can permeate the gut wall and reach the systemic circulation. The fluids in the intestine, however, do not only consist of water and therefore poor water solubility may not necessarily imply a poor solubility in the intestinal fluids and resulting low bioavailability. This thesis addresses the determination of drug solubility and dissolution rates in biorelevant dissolution media (BDM) with the aim of applying these methods to the early stages of drug discovery, where there is a need to reduce the volume of the medium and the amount of solid drug used in testing. The thesis also addresses the need for computational methods for predicting solubility in intestinal fluids and, hence, allowing in silico screening of drugs yet to be synthesized. The apparent solubility and dissolution behavior of large series of lipophilic and other diverse compounds in BDM were studied using a miniaturized method developed herein. The media used in the experimental design provided an opportunity to assess the effects of charge, solubilization in mixed lipid aggregates, and ethanol in BDM. Highly lipophilic and uncharged drugs were efficiently solubilized by aggregates in the BDM while solubilization was decreased with charge. The decrease was more pronounced for negatively charged drugs. The solubility of anionic and neutral drugs was significantly increased by the addition of ethanol to the medium and absorption simulations showed that intake of alcohol could lead to increased plasma concentrations of neutral compounds. Statistical models based on calculated molecular descriptors that accurately predicted the apparent solubility in fasted-state simulated intestinal fluid and in aspirated human intestinal fluid were also developed. In summary, the work undertaken in this thesis has resulted in new experimental and computational models for assessment of the dissolution and solubility of poorly water-soluble compounds in BDM. The models are applicable in the early discovery and development phases for predicting physiologically relevant solubility and the effects thereof on drug absorption.
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| 2. |
- Lindblom, Magnus, 1977-
(författare)
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Nanofabrication of Diffractive Soft X-ray Optics
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis summarizes the present status of the nanofabrication of diffractive optics, i.e. zone plates, and test objects for soft x-ray microscopy at KTH. The emphasis is on new and improved fabrication processes for nickel and germanium zone plates. A new concept in which nickel and germanium are combined in a zone plate is also presented. The main techniques used in the fabrication are electron beam lithography for the patterning, followed by plasma etching and electroplating for the structuring of the optical materials. The process for fabricating nickel zone plates has been significantly improved. The reproducibility of the electroplating step has been increased by the implementation of an in-situ rate measurement and an end-point detection method. We have also shown that pulse plating can be used to obtain zone plates with a uniform height profile. New plating mold materials have been introduced and electron-beam curing of the molds has been investigated and implemented to increase their mechanical stability so that pattern collapse in the electroplating step can be avoided. The introduction of cold development has improved the achievable resolution of the process. This has enabled the fabrication of zone plates with outermost zone widths down to 16 nm. The nickel process has also recently been adapted to fabrication of gold structures intended for test objects and hard x-ray zone plates. For the fabrication of germanium zone plates we developed a highly anisotropic plasma-etch process using Cl2 feed and sidewall passivation. Germanium zone plates have been fabricated with zone widths down to 30 nm. The diffraction efficiency is comparable to that of nickel zone plates, but the process does not involve electroplating and thus has for potential for highyield fabrication. The combination of nickel and germanium is a new fabrication concept that provides a means to achieve high diffraction efficiency even for thin nickel. The idea is to fabricate a nickel zone plate on a germanium film. The nickel zone plate itself is then used as etch mask for a highly selective CHF3- plasma etch into the germanium layer. Proof of principle experiments showed an efficiency increase of about a factor of two for nickel zone plates with a 50- nm nickel thickness.
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| 3. |
- Nemati, Farhang
(författare)
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Resource Sharing in Real-Time Systems on Multiprocessors
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years multiprocessor architectures have become mainstream, and multi-core processors are found in products ranging from small portable cell phones to large computer servers. In parallel, research on real-time systems has mainly focused on traditional single-core processors. Hence, in order for real-time systems to fully leverage on the extra capacity offered by new multi-core processors, new design techniques, scheduling approaches, and real-time analysis methods have to be developed. In the multi-core and multiprocessor domain there are mainly two scheduling approaches, global and partitioned scheduling. Under global scheduling each task can execute on any processor at any time while under partitioned scheduling tasks are statically allocated to processors and migration of tasks among processors is not allowed. Besides simplicity and efficiency of partitioned scheduling protocols, existing scheduling and synchronization techniques developed for single-core processor platforms can more easily be extended to partitioned scheduling. This also simplifies migration of existing systems to multi-cores. An important issue related to partitioned scheduling is the distribution of tasks among the processors, which is a bin-packing problem. In this thesis we propose a blocking-aware partitioning heuristic algorithm to distribute tasks onto the processors of a multi-core architecture. The objective of the proposed algorithm is to decrease the blocking overhead of tasks, which reduces the total utilization and has the potential to reduce the number of required processors. In industrial embedded software systems, large and complex systems are usually divided into several components (applications) each of which is developed independently without knowledge of each other, and potentially in parallel. However, the applications may share mutually exclusive resources when they co-execute on a multi-core platform which introduce a challenge for the techniques needed to ensure predictability. In this thesis we have proposed a new synchronization protocol for handling mutually exclusive resources shared among real-time applications on a multi-core platform. The schedulability analysis of each application is performed in isolation and parallel and the requirements of each application with respect to the resources it may share are included in an interface. The protocol did not originally consider any priorities among the applications. We have proposed an additional version of the protocol which grants access to resources based on priorities assigned to the applications. We have also proposed an optimal priority assignment algorithm to assign unique priorities to the applications sharing resources. Our evaluations confirm that the protocol together with the priority assignment algorithm outperforms existing alternatives in most cases. In the proposed synchronization protocol each application is assumed to be allocated on one dedicated core. However, in this thesis we have further extended the synchronization protocol to be applicable for applications allocated on multiple dedicated cores of a multi-core platform. Furthermore, we have shown how to efficiently calculate the resource hold times of resources for applications. The resource hold time of a resource for an application is the maximum duration of time that the application may lock the resource whenever it requests the resource. Finally, the thesis discusses and proposes directions for future work.
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