Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress

Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress

Functional partitioning of multi-processor architectures

Many real-time computations such as process control and robotic applications may be naturally distributed in a functional manner. One way of ensuring good performance, reliability and security of operation is to map or distribute such tasks onto a distributed, multi-processor system. The time-critical task is thus functionally partitioned into a set of cooperating sub-tasks. These sub-tasks run concurrently and asynchronously on different nodes (stations) of the system. The software design and support of such a functional distribution of sub-tasks (processes) depends on the degree of interaction of these processes among the different nodes. [Continues.

A Framework for Model-based Testing of Integrated Modular Avionics

In modern aircraft, electronics and control systems are designed based on the Integrated Modular Avionics (IMA) system architecture. While this has numerous advantages (reduction of weight, reduced power and fuel consumption, reduction of development cost and certification effort), the IMA platform also adds an additional layer of complexity. Due to the safety-critical nature of many avionics functions careful and accurate verification and testing are imperative. This thesis describes results achieved from research on model-based testing of IMA systems, in part obtained during the European research project SCARLETT. It presents a complete framework which enables IMA domain experts to design and run model-based tests on bare module, configured module, and application level in a standardised test environment. The first part of this thesis provides background information on the relevant topics: the IMA concept, domain-specific languages, model-based testing, and the TTCN-3 standard. The second part introduces the IMA Test Modelling Language (ITML) framework and its components. It describes a tailored TTCN-3 test environment with appropriate adapters and codecs. Based on MetaEdit and its meta-metamodel GOPPRR, it defines the three variants of the domain-specific language ITML, each with its abstract and concrete syntax as well as static and dynamic semantics. The process of test procedure generation from ITML models is explained in detail. Furthermore, the design and implementation of a universal Test Agent is shown. A dedicated communication protocol for controlling the agent is defined as well. The third part provides an evaluation of the framework. It shows usage scenarios in the SCARLETT project, gives a comparison to related tools and approaches, and explains the advantages of using the ITML framework for an IMA domain expert. The final part presents several example ITML models. It also provides reference material like XML schemata, framework source code, and model validators

Gene expression variability - the other dimension in transcriptome analysis:the other dimension in transcriptome analysis

Transcriptome sequencing is a powerful technique to study molecular changes that underlie the differences in physiological conditions and disease progression. A typical question that is posed in such studies is finding genes with significant changes between sample groups. In this respect expression variability is regarded as a nuisance factor that is primarily of technical origin and complicates the data analysis. However, it is becoming apparent that the biological variation in gene expression might be an important molecular phenotype that can affect physiological parameters. In this review we explore the recent literature on technical and biological variability in gene expression, sources of expression variability, (epi-) genetic hallmarks, and evolutionary constraints in genes with robust and variable gene expression. We provide an overview of recent findings on effects of external cues, such as diet and aging, on expression variability and on other biological phenomena that can be linked to it. We discuss metrics and tools that were developed for quantification of expression variability and highlight the importance of future studies in this direction. To assist the adoption of expression variability analysis, we also provide a detailed description and computer code, which can easily be utilized by other researchers. We also provide a reanalysis of recently published data to highlight the value of the analysis method

Modeling active cell movement with the Potts model

In the last decade, the cellular Potts model has been extensively used to model interacting cell systems at the tissue-level. However, in early applications of this model, cell movement was taken as a consequence of membrane fluctuations due to cell-cell interactions, or as a response to an external chemotactic gradient. Recent findings have shown that eukaryotic cells can exhibit persistent displacements across scales larger than cell size, even in the absence of external signals. Persistent cell motion has been incorporated to the cellular Potts model by many authors in the context of collective motion, chemotaxis and morphogenesis. In this paper, we use the cellular Potts model in combination with a random field applied over each cell. This field promotes a uniform cell motion in a given direction during a certain time interval, after which the movement direction changes. The dynamics of the direction is coupled to a first order autoregressive process. We investigated statistical properties, such as the mean-squared displacement and spatio-temporal correlations, associated to these self-propelled in silico cells in different conditions. The proposed model emulates many properties observed in different experimental setups. By studying low and high density cultures, we find that cell-cell interactions decrease the effective persistent time.Instituto de Investigaciones Fisicoquímicas Teóricas y AplicadasCentro Regional de Estudios Genómico

Optimal sub-arraying of compromise planar arrays through an innovative ACO-weighted procedure

In this paper, the synthesis of sub-arrayed monopulse planar arrays providing an optimal sum pattern and best compromise difference patterns is addressed by means of an innovative clustering approach based on the Ant Colony Optimizer. Exploiting the similarity properties of optimal and independent sum and difference excitation sets, the problem is reformulated into a combinatorial one where the definition of the sub-array configuration is obtained through the search of a path within a weighted graph. Such a weighting strategy allows one to effectively sample the solution space avoiding bias towards sub-optimal solutions. The sub-array weight coefficients are then determined in an optimal way by exploiting the convexity of the problem at hand by means of a convex programming procedure. Representative results are reported to assess the effectiveness of the weighted global optimization and its advantages over previous implementations. (c) The Electromagnetics Academy - The final version of this article is available at the url of the journal PIER (Progress In Electromagnetics Research): http://www.jpier.org/PIER/pier.php?paper=1009200