Investigating physical properties of solid dosage forms during pharmaceutical processing : Process analytical applications of vibrational spectroscopy

In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms

Aritmetiikasta algebraan : Muutoksia osaamisessa peruskoulun päättöluokalla 20 vuoden aikana

From Arithmetic to Algebra. Changes in the skills in comprehensive school over 20 years. In recent decades we have emphasized the understanding of calculation in mathematics teaching. Many studies have found that better understanding helps to apply skills in new conditions and that the ability to think on an abstract level increases the transfer to new contexts. In my research I take into consideration competence as a matrix where content is in a horizontal line and levels of thinking are in a vertical line. The know-how is intellectual and strategic flexibility and understanding. The resources and limitations of memory have their effects on learning in different ways in different phases. Therefore both flexible conceptual thinking and automatization must be considered in learning. The research questions that I examine are what kind of changes have occurred in mathematical skills in comprehensive school over the last 20 years and what kind of conceptual thinking is demonstrated by students in this decade. The study consists of two parts. The first part is a statistical analysis of the mathematical skills and their changes over the last 20 years in comprehensive school. In the test the pupils did not use calculators. The second part is a qualitative analysis of the conceptual thinking of pupils in comprehensive school in this decade. The study shows significant differences in algebra and in some parts of arithmetic. The largest differences were detected in the calculation skills of fractions. In the 1980s two out of three pupils were able to complete tasks with fractions, but in the 2000s only one out of three pupils were able to do the same tasks. Also remarkable is that out of the students who could complete the tasks with fractions, only one out of three pupils was on the conceptual level in his/her thinking. This means that about 10% of pupils are able to understand the algebraic expression, which has the same isomorphic structure as the arithmetical expression. This finding is important because the ability to think innovatively is created when learning the basic concepts. Keywords: arithmetic, algebra, competence

Developing and Integrating HRM Practices in MNC Subsidiaries in China

Whilst previous research on Human Resource Management (HRM) in subsidiaries of multinational companies (MNCs) has focused extensively on the HRM practices that exist in foreign subsidiaries and the extent to which they resemble MNC home country and/or local host country practices, considerably less attention has been directed at the question of how these practices come to exist. Accordingly, this thesis aims to shed light on the processes that shape HRM practices and capabilities in MNC subsidiaries. The main contribution of the thesis is the focus on how; how HRM practices are integrated in MNC subsidiaries, and how subsidiary HRM capabilities are developed through involvement in social networks. Furthermore, this thesis includes a time aspect which, despite not being purely longitudinal, provides an indication of the ongoing changes in HRM in MNC subsidiaries in China. Data for this study were collected in 2005-2006 through structured face to face interviews with 153 general managers and HR managers in 87 subsidiaries of European MNCs located in China. Five of the six thesis papers build on this questionnaire data and one paper builds on qualitative data collected at the same time. Two papers build on dual data sets, meaning that they in addition to the abovementioned data include quantitative questionnaire data from 1996 and 1999 respectively. The thesis focuses on the following four sub-questions i) To what extent do subsidiary HRM practices resemble parent MNC and host country practices? How has this changed over time and why? ii) How are HRM practices integrated into MNC subsidiaries and why are certain integration mechanisms used? iii) How does involvement in internal and external social networks influence subsidiary HRM capabilities? iv) What factors influence the strategic role of the subsidiary HR department? Regarding the first sub-question the findings indicate that the HRM practices of MNC subsidiaries in China are converging with both local company practices and parent MNC practices. This is interesting in the sense that it suggests that the isomorphic pressures the subsidiary faces from the MNC and from its local host environment are not always in conflict with each other. Concerning the question of how HRM practices are integrated into MNC subsidiaries and why certain integration mechanisms are used, the thesis provides a fine-grained examination of four mechanisms that MNCs use to integrate HRM practices in subsidiaries. The findings suggest that MNCs use a variety of different integration mechanisms as complements rather than as substitutes for each other. Furthermore, it is apparent that different contextual factors in the subsidiary and the subsidiary-headquarters relationship influence why certain mechanisms are or are not used. The most interesting contribution of the thesis in regard to the third question is that it highlights the importance of network involvement for learning about HRM practices in the Chinese context. Networks with other MNCs in China clearly emerged as particularly important contributors to enhanced HRM capabilities. Finally, concerning the fourth sub-question the findings indicate that the role of the HR department in MNC subsidiaries in China had become more strategic between 1999 and 2006.

Weak Ehrenfeucht-Fraïssé Games

In this paper we define a game which is played between two players I and II on two mathematical structures A and B. The players choose elements from both structures in moves, and at the end of the game the player II wins if the chosen structures are isomorphic. Thus the difference of this to the ordinary Ehrenfeucht-Fra¨ıss´e game is that the isomorphism can be arbitrary, whereas in the ordinary EF-game it is determined by the moves of the players. We investigate determinacy of the weak EF-game for different (the length of the game) and its relation to the ordinary EF-game.

Properties of Toeplitz operators on analytic function spaces : from function symbols to distributions

Toeplitz operators are among the most important classes of concrete operators with applications to several branches of pure and applied mathematics. This doctoral thesis deals with Toeplitz operators on analytic Bergman, Bloch and Fock spaces. Usually, a Toeplitz operator is a composition of multiplication by a function and a suitable projection. The present work deals with generalizing the notion to the case where the function is replaced by a distributional symbol. Fredholm theory for Toeplitz operators with matrix-valued symbols is also considered. The subject of this thesis belongs to the areas of complex analysis, functional analysis and operator theory. This work contains five research articles. The articles one, three and four deal with finding suitable distributional classes in Bergman, Fock and Bloch spaces, respectively. In each case the symbol class to be considered turns out to be a certain weighted Sobolev-type space of distributions. The Bergman space setting is the most straightforward. When dealing with Fock spaces, some difficulties arise due to unboundedness of the complex plane and the properties of the Gaussian measure in the definition. In the Bloch-type spaces an additional logarithmic weight must be introduced. Sufficient conditions for boundedness and compactness are derived. The article two contains a portion showing that under additional assumptions, the condition for Bergman spaces is also necessary. The fifth article deals with Fredholm theory for Toeplitz operators having matrix-valued symbols. The essential spectra and index theorems are obtained with the help of Hardy space factorization and the Berezin transform, for instance. The article two also has a part dealing with matrix-valued symbols in a non-reflexive Bergman space, in which case a condition on the oscillation of the symbol (a logarithmic VMO-condition) must be added.

Structure of Relativistic States

QCD factorization in the Bjorken limit allows to separate the long-distance physics from the hard subprocess. At leading twist, only one parton in each hadron is coherent with the hard subprocess. Higher twist effects increase as one of the active partons carries most of the longitudinal momentum of the hadron, x -> 1. In the Drell-Yan process \pi N -> \mu^- mu^+ + X, the polarization of the virtual photon is observed to change to longitudinal when the photon carries x_F > 0.6 of the pion. I define and study the Berger-Brodsky limit of Q^2 -> \infty with Q^2(1-x) fixed. A new kind of factorization holds in the Drell-Yan process in this limit, in which both pion valence quarks are coherent with the hard subprocess, the virtual photon is longitudinal rather than transverse, and the cross section is proportional to a multiparton distribution. Generalized parton distributions contain information on the longitudinal momentum and transverse position densities of partons in a hadron. Transverse charge densities are Fourier transforms of the electromagnetic form factors. I discuss the application of these methods to the QED electron, studying the form factors, charge densities and spin distributions of the leading order |e\gamma> Fock state in impact parameter and longitudinal momentum space. I show how the transverse shape of any virtual photon induced process, \gamma^*(q)+i -> f, may be measured. Qualitative arguments concerning the size of such transitions have been previously made in the literature, but without a precise analysis. Properly defined, the amplitudes and the cross section in impact parameter space provide information on the transverse shape of the transition process.