Process Analytical Technology Approach on Fluid Bed Granulation and Drying : Identifying Critical Relationships and Constructing the Design Space

Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

Space in Musical Semiosis : An Abductive Theory of the Musical Composition Process

Space in musical semiosis is a study of musical meaning, spatiality and composition. Earlier studies on musical composition have not adequately treated the problems of musical signification. Here, composition is considered an epitomic process of musical signification. Hence the core problems of composition theory are core problems of musical semiotics. The study employs a framework of naturalist pragmatism, based on C. S. Peirce’s philosophy. It operates on concepts such as subject, experience, mind and inquiry, and incorporates relevant ideas of Aristotle, Peirce and John Dewey into a synthetic view of esthetic, practic, and semiotic for the benefit of grasping musical signification process as a case of semiosis in general. Based on expert accounts, music is depicted as real, communicative, representational, useful, embodied and non-arbitrary. These describe how music and the musical composition process are mental processes. Peirce’s theories are combined with current morphological theories of cognition into a view of mind, in which space is central. This requires an analysis of space, and the acceptance of a relativist understanding of spatiality. This approach to signification suggests that mental processes are spatially embodied, by virtue of hard facts of the world, literal representations of objects, as well as primary and complex metaphors each sharing identities of spatial structures. Consequently, music and the musical composition process are spatially embodied. Composing music appears as a process of constructing metaphors—as a praxis of shaping and reshaping features of sound, representable from simple quality dimensions to complex domains. In principle, any conceptual space, metaphorical or literal, may set off and steer elaboration, depending on the practical bearings on the habits of feeling, thinking and action, induced in musical communication. In this sense, it is evident that music helps us to reorganize our habits of feeling, thinking, and action. These habits, in turn, constitute our existence. The combination of Peirce and morphological approaches to cognition serves well for understanding musical and general signification. It appears both possible and worthwhile to address a variety of issues central to musicological inquiry in the framework of naturalist pragmatism. The study may also contribute to the development of Peircean semiotics.

Toiminta ja tarkoite : Tutkimus suomen pronominista

The study describes the use and meaning of the Finnish demonstrative pronouns, focus being on the pronoun "tämä" (roughly 'this'). The Finnish demonstrative system is a three way one, the other two demonstratives are "tuo" ('that') and "se" ('it'). The data consisted of 12 half hours of video- and tape-recorded face-to-face and telephone conversations. The method for the study was ethnomethodological conversation analysis (CA); in addition to CA, the theoretical framework consisted of functional linguistics and linguistic anthropology. First, the study dealt with the syntactic distribution of the three demonstratives. The pronouns were analysed according to whether they are before or after the verb, and whether they compose an NP on their own or are determinants of a lexical NP. The study suggested that the form and the placement of the NP presents the referent as continuous/discontinuous or given/new. Givenness of a referent was defined as "identified adequately for the purposes of the on-going action". The so-called dislocated utterances were considered separately. It was found that left-dislocations are used for inserting referents in a particular relation to the on-going activity. Right-dislocations offer a solution for the sometimes competing motivations of newness and continuity: they are used for securing the identifiability of a referent that is implied to be continuous. Second, the study focussed on analysing the meaning of the pronouns according to three dimensions of reference: referential, indexical and relational. It was found that the demonstratives can organize interactional or spatial context. When organizing interactional context, the demonstrative pronouns express the role of identifying the referent in relation to the on-going activity. The pronoun "tämä" expresses that the referent is referentially open and the characterization of the referent is given in the on-going turn. Furthermore, it expresses asymmetry of the indexical ground: it expresses that the participants of a conversation do not share a mutual understanding of the activity at that particular time. In addition, the referent of the pronoun "tämä" is central for understanding the on-going action. Centrality could be understood as the relational feature of the pronoun. However, it is a consequence of the referential and indexical features of "tämä". The pronoun "tuo" also expresses referential openness, but it implies indexical symmetry. The pronoun "se" implies that the referent is known enough, and implies indexical symmetry. When used spatially, the pronouns may refer to a physical space or to a situation. They express or imply that the speaker is inside or outside the referent. The pronoun "tämä" implies inclusion, and the pronoun "tuo" expresses exclusion.

Teacher Education, School Effectiveness and Improvement : A Study of Academic and Professional Qualification on Teachers' Job Effectiveness in Nigerian Secondary Schools

This academic work begins with a compact presentation of the general background to the study, which also includes an autobiography for the interest in this research. The presentation provides readers who know little of the topic of this research and of the structure of the educational system as well as of the value given to education in Nigeria. It further concentrates on the dynamic interplay of the effect of academic and professional qualification and teachers' job effectiveness in secondary schools in Nigeria in particular, and in Africa in general. The aim of this study is to produce a systematic analysis and rich theoretical and empirical description of teachers' teaching competencies. The theoretical part comprises a comprehensive literature review that focuses on research conducted in the areas of academic and professional qualification and teachers' job effectiveness, teaching competencies, and the role of teacher education with particular emphasis on school effectiveness and improvement. This research benefits greatly from the functionalist conception of education, which is built upon two emphases: the application of the scientific method to the objective social world, and the use of an analogy between the individual 'organism' and 'society'. To this end, it offers us an opportunity to define terms systematically and to view problems as always being interrelated with other components of society. The empirical part involves describing and interpreting what educational objectives can be achieved with the help of teachers' teaching competencies in close connection to educational planning, teacher training and development, and achieving them without waste. The data used in this study were collected between 2002 and 2003 from teachers, principals, supervisors of education from the Ministry of Education and Post Primary Schools Board in the Rivers State of Nigeria (N=300). The data were collected from interviews, documents, observation, and questionnaires and were analyzed using both qualitative and quantitative methods to strengthen the validity of the findings. The data collected were analyzed to answer the specific research questions and hypotheses posited in this study. The data analysis involved the use of multiple statistical procedures: Percentages Mean Point Value, T-test of Significance, One-Way Analysis of Variance (ANOVA), and Cross Tabulation. The results obtained from the data analysis show that teachers require professional knowledge and professional teaching skills, as well as a broad base of general knowledge (e.g., morality, service, cultural capital, institutional survey). Above all, in order to carry out instructional processes effectively, teachers should be both academically and professionally trained. This study revealed that teachers are not however expected to have an extraordinary memory, but rather looked upon as persons capable of thinking in the right direction. This study may provide a solution to the problem of teacher education and school effectiveness in Nigeria. For this reason, I offer this treatise to anyone seriously committed in improving schools in developing countries in general and in Nigeria in particular to improve the lives of all its citizens. In particular, I write this to encourage educational planners, education policy makers, curriculum developers, principals, teachers, and students of education interested in empirical information and methods to conceptualize the issue this study has raised and to provide them with useful suggestions to help them improve secondary schooling in Nigeria. Though, multiple audiences exist for any text. For this reason, I trust that the academic community will find this piece of work a useful addition to the existing literature on school effectiveness and school improvement. Through integrating concepts from a number of disciplines, I aim to describe as holistic a representation as space could allow of the components of school effectiveness and quality improvement. A new perspective on teachers' professional competencies, which not only take into consideration the unique characteristics of the variables used in this study, but also recommend their environmental and cultural derivation. In addition, researchers should focus their attention on the ways in which both professional and non-professional teachers construct and apply their methodological competencies, such as their grouping procedures and behaviors to the schooling of students. Keywords: Professional Training, Academic Training, Professionally Qualified, Academically Qualified, Professional Qualification, Academic Qualification, Job Effectiveness, Job Efficiency, Educational Planning, Teacher Training and Development, Nigeria.

Characterization of the mitochondrial active-site serine protein LACTB: filaments in the mitochondrial intermembrane space

Mitochondria have evolved from endosymbiotic alpha-proteobacteria. During the endosymbiotic process early eukaryotes dumped the major component of the bacterial cell wall, the peptidoglycan layer. Peptidoglycan is synthesized and maintained by active-site serine enzymes belonging to the penicillin-binding protein and the β-lactamase superfamily. Mammals harbor a protein named LACTB that shares sequence similarity with bacterial penicillin-binding proteins and β-lactamases. Since eukaryotes lack the synthesis machinery for peptidoglycan, the physiological role of LACTB is intriguing. Recently, LACTB has been validated in vivo to be causative for obesity, suggesting that LACTB is implicated in metabolic processes. The aim of this study was to investigate the phylogeny, structure, biochemistry and cell biology of LACTB in order to elucidate its physiological function. Phylogenetic analysis revealed that LACTB has evolved from penicillin binding-proteins present in the bacterial periplasmic space. A structural model of LACTB indicates that LACTB shares characteristic features common to all penicillin-binding proteins and β-lactamases. Recombinat LACTB protein expressed in E. coli was recovered in significant quantities. Biochemical and cell biology studies showed that LACTB is a soluble protein localized in the mitochondrial intermembrane space. Further analysis showed that LACTB preprotein underwent proteolytic processing disclosing an N-terminal tetrapeptide motif also found in a set of cell death-inducing proteins. Electron microscopy structural studies revealed that LACTB can polymerize to form stable filaments with lengths ranging from twenty to several hundred nanometers. These data suggest that LACTB filaments define a distinct microdomain in the intermembrane space. A possible role of LACTB filaments is proposed in the intramitochondrial membrane organization and microcompartmentation. The implications of these findings offer novel insight into the evolution of mitochondria. Further studies of the LACTB function might provide a tool to treat mitochondria-related metabolic diseases.

Aspects and Applications of Pulse Sequence Design for Solution-State Nuclear Magnetic Resonance Spectroscopy

NMR spectroscopy enables the study of biomolecules from peptides and carbohydrates to proteins at atomic resolution. The technique uniquely allows for structure determination of molecules in solution-state. It also gives insights into dynamics and intermolecular interactions important for determining biological function. Detailed molecular information is entangled in the nuclear spin states. The information can be extracted by pulse sequences designed to measure the desired molecular parameters. Advancement of pulse sequence methodology therefore plays a key role in the development of biomolecular NMR spectroscopy. A range of novel pulse sequences for solution-state NMR spectroscopy are presented in this thesis. The pulse sequences are described in relation to the molecular information they provide. The pulse sequence experiments represent several advances in NMR spectroscopy with particular emphasis on applications for proteins. Some of the novel methods are focusing on methyl-containing amino acids which are pivotal for structure determination. Methyl-specific assignment schemes are introduced for increasing the size range of 13C,15N labeled proteins amenable to structure determination without resolving to more elaborate labeling schemes. Furthermore, cost-effective means are presented for monitoring amide and methyl correlations simultaneously. Residual dipolar couplings can be applied for structure refinement as well as for studying dynamics. Accurate methods for measuring residual dipolar couplings in small proteins are devised along with special techniques applicable when proteins require high pH or high temperature solvent conditions. Finally, a new technique is demonstrated to diminish strong-coupling induced artifacts in HMBC, a routine experiment for establishing long-range correlations in unlabeled molecules. The presented experiments facilitate structural studies of biomolecules by NMR spectroscopy.

Renormalization methods in KAM theory

It is well known that an integrable (in the sense of Arnold-Jost) Hamiltonian system gives rise to quasi-periodic motion with trajectories running on invariant tori. These tori foliate the whole phase space. If we perturb an integrable system, the Kolmogorow-Arnold-Moser (KAM) theorem states that, provided some non-degeneracy condition and that the perturbation is sufficiently small, most of the invariant tori carrying quasi-periodic motion persist, getting only slightly deformed. The measure of the persisting invariant tori is large together with the inverse of the size of the perturbation. In the first part of the thesis we shall use a Renormalization Group (RG) scheme in order to prove the classical KAM result in the case of a non analytic perturbation (the latter will only be assumed to have continuous derivatives up to a sufficiently large order). We shall proceed by solving a sequence of problems in which theperturbations are analytic approximations of the original one. We will finally show that the approximate solutions will converge to a differentiable solution of our original problem. In the second part we will use an RG scheme using continuous scales, so that instead of solving an iterative equation as in the classical RG KAM, we will end up solving a partial differential equation. This will allow us to reduce the complications of treating a sequence of iterative equations to the use of the Banach fixed point theorem in a suitable Banach space.

Stochastic Filtering

The stochastic filtering has been in general an estimation of indirectly observed states given observed data. This means that one is discussing conditional expected values as being one of the most accurate estimation, given the observations in the context of probability space. In my thesis, I have presented the theory of filtering using two different kind of observation process: the first one is a diffusion process which is discussed in the first chapter, while the third chapter introduces the latter which is a counting process. The majority of the fundamental results of the stochastic filtering is stated in form of interesting equations, such the unnormalized Zakai equation that leads to the Kushner-Stratonovich equation. The latter one which is known also by the normalized Zakai equation or equally by Fujisaki-Kallianpur-Kunita (FKK) equation, shows the divergence between the estimate using a diffusion process and a counting process. I have also introduced an example for the linear gaussian case, which is mainly the concept to build the so-called Kalman-Bucy filter. As the unnormalized and the normalized Zakai equations are in terms of the conditional distribution, a density of these distributions will be developed through these equations and stated by Kushner Theorem. However, Kushner Theorem has a form of a stochastic partial differential equation that needs to be verify in the sense of the existence and uniqueness of its solution, which is covered in the second chapter.

A Decentralized Session Management Framework for Heterogeneous Ad-Hoc and Fixed Networks

Wireless technologies are continuously evolving. Second generation cellular networks have gained worldwide acceptance. Wireless LANs are commonly deployed in corporations or university campuses, and their diffusion in public hotspots is growing. Third generation cellular systems are yet to affirm everywhere; still, there is an impressive amount of research ongoing for deploying beyond 3G systems. These new wireless technologies combine the characteristics of WLAN based and cellular networks to provide increased bandwidth. The common direction where all the efforts in wireless technologies are headed is towards an IP-based communication. Telephony services have been the killer application for cellular systems; their evolution to packet-switched networks is a natural path. Effective IP telephony signaling protocols, such as the Session Initiation Protocol (SIP) and the H 323 protocol are needed to establish IP-based telephony sessions. However, IP telephony is just one service example of IP-based communication. IP-based multimedia sessions are expected to become popular and offer a wider range of communication capabilities than pure telephony. In order to conjoin the advances of the future wireless technologies with the potential of IP-based multimedia communication, the next step would be to obtain ubiquitous communication capabilities. According to this vision, people must be able to communicate also when no support from an infrastructured network is available, needed or desired. In order to achieve ubiquitous communication, end devices must integrate all the capabilities necessary for IP-based distributed and decentralized communication. Such capabilities are currently missing. For example, it is not possible to utilize native IP telephony signaling protocols in a totally decentralized way. This dissertation presents a solution for deploying the SIP protocol in a decentralized fashion without support of infrastructure servers. The proposed solution is mainly designed to fit the needs of decentralized mobile environments, and can be applied to small scale ad-hoc networks or also bigger networks with hundreds of nodes. A framework allowing discovery of SIP users in ad-hoc networks and the establishment of SIP sessions among them, in a fully distributed and secure way, is described and evaluated. Security support allows ad-hoc users to authenticate the sender of a message, and to verify the integrity of a received message. The distributed session management framework has been extended in order to achieve interoperability with the Internet, and the native Internet applications. With limited extensions to the SIP protocol, we have designed and experimentally validated a SIP gateway allowing SIP signaling between ad-hoc networks with private addressing space and native SIP applications in the Internet. The design is completed by an application level relay that permits instant messaging sessions to be established in heterogeneous environments. The resulting framework constitutes a flexible and effective approach for the pervasive deployment of real time applications.

Efficient search for statistically significant dependency rules in binary data

Analyzing statistical dependencies is a fundamental problem in all empirical science. Dependencies help us understand causes and effects, create new scientific theories, and invent cures to problems. Nowadays, large amounts of data is available, but efficient computational tools for analyzing the data are missing. In this research, we develop efficient algorithms for a commonly occurring search problem - searching for the statistically most significant dependency rules in binary data. We consider dependency rules of the form X->A or X->not A, where X is a set of positive-valued attributes and A is a single attribute. Such rules describe which factors either increase or decrease the probability of the consequent A. A classical example are genetic and environmental factors, which can either cause or prevent a disease. The emphasis in this research is that the discovered dependencies should be genuine - i.e. they should also hold in future data. This is an important distinction from the traditional association rules, which - in spite of their name and a similar appearance to dependency rules - do not necessarily represent statistical dependencies at all or represent only spurious connections, which occur by chance. Therefore, the principal objective is to search for the rules with statistical significance measures. Another important objective is to search for only non-redundant rules, which express the real causes of dependence, without any occasional extra factors. The extra factors do not add any new information on the dependence, but can only blur it and make it less accurate in future data. The problem is computationally very demanding, because the number of all possible rules increases exponentially with the number of attributes. In addition, neither the statistical dependency nor the statistical significance are monotonic properties, which means that the traditional pruning techniques do not work. As a solution, we first derive the mathematical basis for pruning the search space with any well-behaving statistical significance measures. The mathematical theory is complemented by a new algorithmic invention, which enables an efficient search without any heuristic restrictions. The resulting algorithm can be used to search for both positive and negative dependencies with any commonly used statistical measures, like Fisher's exact test, the chi-squared measure, mutual information, and z scores. According to our experiments, the algorithm is well-scalable, especially with Fisher's exact test. It can easily handle even the densest data sets with 10000-20000 attributes. Still, the results are globally optimal, which is a remarkable improvement over the existing solutions. In practice, this means that the user does not have to worry whether the dependencies hold in future data or if the data still contains better, but undiscovered dependencies.