Understanding solid-state transformations during dehydration: new insights using vibrational spectroscopy and multivariate modelling

Many active pharmaceutical ingredients (APIs) have both anhydrate and hydrate forms. Due to the different physicochemical properties of solid forms, the changes in solid-state may result in therapeutic, pharmaceutical, legal and commercial problems. In order to obtain good solid dosage form quality and performance, there is a constant need to understand and control these phase transitions during manufacturing and storage. Thus it is important to detect and also quantify the possible transitions between the different forms. In recent years, vibrational spectroscopy has become an increasingly popular tool to characterise the solid-state forms and their phase transitions. It offers several advantages over other characterisation techniques including an ability to obtain molecular level information, minimal sample preparation, and the possibility of monitoring changes non-destructively in-line. Dehydration is the phase transition of hydrates which is frequently encountered during the dosage form production and storage. The aim of the present thesis was to investigate the dehydration behaviour of diverse pharmaceutical hydrates by near infrared (NIR), Raman and terahertz pulsed spectroscopic (TPS) monitoring together with multivariate data analysis. The goal was to reveal new perspectives for investigation of the dehydration at the molecular level. Solid-state transformations were monitored during dehydration of diverse hydrates on hot-stage. The results obtained from qualitative experiments were used to develop a method and perform the quantification of the solid-state forms during process induced dehydration in a fluidised bed dryer. Both in situ and in-line process monitoring and quantification was performed. This thesis demonstrated the utility of vibrational spectroscopy techniques and multivariate modelling to monitor and investigate dehydration behaviour in situ and during fluidised bed drying. All three spectroscopic methods proved complementary in the study of dehydration. NIR spectroscopy models could quantify the solid-state forms in the binary system, but were unable to quantify all the forms in the quaternary system. Raman spectroscopy models on the other hand could quantify all four solid-state forms that appeared upon isothermal dehydration. The speed of spectroscopic methods makes them applicable for monitoring dehydration and the quantification of multiple forms was performed during phase transition. Thus the solid-state structure information at the molecular level was directly obtained. TPS detected the intermolecular phonon modes and Raman spectroscopy detected mostly the changes in intramolecular vibrations. Both techniques revealed information about the crystal structure changes. NIR spectroscopy, on the other hand was more sensitive to water content and hydrogen bonding environment of water molecules. This study provides a basis for real time process monitoring using vibrational spectroscopy during pharmaceutical manufacturing.

Contributions to the Theory of Finite-State Based Grammars

This dissertation is a theoretical study of finite-state based grammars used in natural language processing. The study is concerned with certain varieties of finite-state intersection grammars (FSIG) whose parsers define regular relations between surface strings and annotated surface strings. The study focuses on the following three aspects of FSIGs: (i) Computational complexity of grammars under limiting parameters In the study, the computational complexity in practical natural language processing is approached through performance-motivated parameters on structural complexity. Each parameter splits some grammars in the Chomsky hierarchy into an infinite set of subset approximations. When the approximations are regular, they seem to fall into the logarithmic-time hierarchyand the dot-depth hierarchy of star-free regular languages. This theoretical result is important and possibly relevant to grammar induction. (ii) Linguistically applicable structural representations Related to the linguistically applicable representations of syntactic entities, the study contains new bracketing schemes that cope with dependency links, left- and right branching, crossing dependencies and spurious ambiguity. New grammar representations that resemble the Chomsky-Schützenberger representation of context-free languages are presented in the study, and they include, in particular, representations for mildly context-sensitive non-projective dependency grammars whose performance-motivated approximations are linear time parseable. (iii) Compilation and simplification of linguistic constraints Efficient compilation methods for certain regular operations such as generalized restriction are presented. These include an elegant algorithm that has already been adopted as the approach in a proprietary finite-state tool. In addition to the compilation methods, an approach to on-the-fly simplifications of finite-state representations for parse forests is sketched. These findings are tightly coupled with each other under the theme of locality. I argue that the findings help us to develop better, linguistically oriented formalisms for finite-state parsing and to develop more efficient parsers for natural language processing. Avainsanat: syntactic parsing, finite-state automata, dependency grammar, first-order logic, linguistic performance, star-free regular approximations, mildly context-sensitive grammars

Musiikki ahdistuksen taitona : Filosofinen tutkimus musiikin eksistentiaalis-ontologisesta merkityksestä

Music as the Art of Anxiety: A Philosophical Approach to the Existential-Ontological Meaning of Music. The present research studies music as an art of anxiety from the points of view of both Martin Heidegger s thought and phenomenological philosophy in general. In the Heideggerian perspective, anxiety is understood as a fundamental mode of being (Grundbefindlichkeit) in human existence. Taken as an existential-ontological concept, anxiety is conceived philosophically and not psychologically. The central research questions are: what is the relationship between music and existential-ontological anxiety? In what way can music be considered as an art of anxiety? In thinking of music as a channel and manifestation of anxiety, what makes it a special case? What are the possible applications of phenomenology and Heideggerian thought in musicology? The main aim of the research is to develop a theory of music as an art of existential-ontological anxiety and to apply this theory to musicologically relevant phenomena. Furthermore, the research will contribute to contemporary musicological debates and research as it aims to outline the phenomenological study of music as a field of its own; the development of a specific methodology is implicit in these aims. The main subject of the study, a theory of music as an art of anxiety, integrates Heideggerian and phenomenological philosophies with critical and cultural theories concerning violence, social sacrifice, and mimetic desire (René Girard), music, noise and society (Jacques Attali), and the affect-based charme of music (Vladimir Jankélévitch). Thus, in addition to the subjective mood (Stimmung) of emptiness and meaninglessness, the philosophical concept of anxiety also refers to a state of disorder and chaos in general; for instance, to noise in the realm of sound and total (social) violence at the level of society. In this study, music is approached as conveying the existentially crucial human compulsion for signifying i.e., organizing chaos. In music, this happens primarily at the immediate level of experience, i.e. in affectivity, and also in relation to all of the aforementioned dimensions (sound, society, consciousness, and so on). Thus, music s existential-ontological meaning in human existence, Dasein, is in its ability to reveal different orders of existence as such. Indeed, this makes music the art of anxiety: more precisely, music can be existentially significant at the level of moods. The study proceeds from outlining the relevance of phenomenology and Heidegger s philosophy in musicology to the philosophical development of a theory of music as the art of anxiety. The theory is developed further through the study of three selected specific musical phenomena: the concept of a musical work, guitar smashing in the performance tradition of rock music, and Erik Bergman s orchestral work Colori ed improvvisazioni. The first example illustrates the level of individual human-subject in music as the art of anxiety, as a means of signifying chaos, while the second example focuses on the collective need to socio-culturally channel violence. The third example, being music-analytical, studies contemporary music s ability to mirror the structures of anxiety at the level of a specific musical text. The selected examples illustrate that, in addition to the philosophical orientation, the research also contributes to music analysis, popular music studies, and the cultural-critical study of music. Key words: music, anxiety, phenomenology, Martin Heidegger, ontology, guitar smashing, Erik Bergman, musical work, affectivity, Stimmung, René Girard

Epidemiological data of seasonal variation in mood and behaviour

The aim of this study was to measure seasonal variation in mood and behaviour. The dual vulnerability and latitude effect hypothesis, the risk of increased appetite, weight and other seasonal symptoms to develop metabolic syndrome, and perception of low illumination in quality of life and mental well-being were assessed. These variations are prevalent in persons who live in high latitudes and need balancing of metabolic processes to adapt to environmental changes due to seasons. A randomized sample of 8028 adults aged 30 and over (55% women) participated in an epidemiological health examination study, The Health 2000, applying the probability proportional to population size method for a range of socio-demographic characteristics. They were present in a face-to-face interview at home and health status examination. The questionnaires included the modified versions of the Seasonal Pattern Assessment Questionnaire (SPAQ) and Beck Depression Inventory (BDI), the Health Related Quality of Life (HRQoL) instrument 15D, and the General Health Questionnaire (GHQ). The structured and computerized Munich Composite International Diagnostic Interview (M-CIDI) as part of the interview was used to assess diagnoses of mental disorders, and, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria were assessed using all the available information to detect metabolic syndrome. A key finding was that 85% of this nationwide representative sample had seasonal variation in mood and behaviour. Approximately 9% of the study population presented combined seasonal and depressive symptoms with a significant association between their scores, and 2.6% had symptoms that corresponded to Seasonal Affective Disorder (SAD) in severity. Seasonal variations in weight and appetite are two important components that increase the risk of metabolic syndrome. Other factors such as waist circumference and major depressive disorder contributed to the metabolic syndrome as well. Persons reported of having seasonal symptoms were associated with a poorer quality of life and compromised mental well-being, especially if indoors illumination at home and/or at work was experienced as being low. Seasonal and circadian misalignments are suggested to associate with metabolic disorders, and could be remarked if individuals perceive low illumination levels at home and/or at work that affect the health-related quality of life and mental well-being. Keywords: depression, health-related quality of life, illumination, latitude, mental well-being, metabolic syndrome, seasonal variation, winter.

Computational studies on new chemical species in the gas-phase and the solid-state.

There is intense activity in the area of theoretical chemistry of gold. It is now possible to predict new molecular species, and more recently, solids by combining relativistic methodology with isoelectronic thinking. In this thesis we predict a series of solid sheet-type crystals for Group-11 cyanides, MCN (M=Cu, Ag, Au), and Group-2 and 12 carbides MC2 (M=Be-Ba, Zn-Hg). The idea of sheets is then extended to nanostrips which can be bent to nanorings. The bending energies and deformation frequencies can be systematized by treating these molecules as an elastic bodies. In these species Au atoms act as an 'intermolecular glue'. Further suggested molecular species are the new uncongested aurocarbons, and the neutral Au_nHg_m clusters. Many of the suggested species are expected to be stabilized by aurophilic interactions. We also estimate the MP2 basis-set limit of the aurophilicity for the model compounds [ClAuPH_3]_2 and [P(AuPH_3)_4]^+. Beside investigating the size of the basis-set applied, our research confirms that the 19-VE TZVP+2f level, used a decade ago, already produced 74 % of the present aurophilic attraction energy for the [ClAuPH_3]_2 dimer. Likewise we verify the preferred C4v structure for the [P(AuPH_3)_4]^+ cation at the MP2 level. We also perform the first calculation on model aurophilic systems using the SCS-MP2 method and compare the results to high-accuracy CCSD(T) ones. The recently obtained high-resolution microwave spectra on MCN molecules (M=Cu, Ag, Au) provide an excellent testing ground for quantum chemistry. MP2 or CCSD(T) calculations, correlating all 19 valence electrons of Au and including BSSE and SO corrections, are able to give bond lengths to 0.6 pm, or better. Our calculated vibrational frequencies are expected to be better than the currently available experimental estimates. Qualitative evidence for multiple Au-C bonding in triatomic AuCN is also found.

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.

From Francovich to Köbler and beyond : The evolution of a State liability regime for the EC

The aim of this paper is to present the evolution of the Francovich doctrine within the European legal order. The first part deals with the gradual development of the ECJ's case law on State liability in damages for breach of EC law. Starting from the seminal Francovich and Brasserie du Pêcheur, the clarification of the criteria set by the Court is attempted with reference to subsequent case law, whereas issues concerning the extent and form of the compensation owned are also mentioned. The second part concerns one of the more recent developments in the field, namely State liability for breaches of Community law attributed to national judiciary. The Court's ruling in Köbler is examined in connection with two other recent judgments, namely Commission v. Italy of 2003 and Kühne & Heitz, as an attempt of the ECJ to reframe its relationships with national supreme courts and appropriate for itself the position of the Supreme Court in the European legal order. The implications on State liability claims by the ruling in Commission v. France of 1997 constitute the theme of the third part, where it is submitted that Member States can also be held liable for disregard of Community law by private individuals within their respected territories. To this extent, Schmidberger is viewed as a manifestation of this opinion, with fundamental rights acquiring a new dimension, being invoked by the States, contra the individuals as a shield to liability claims. Finally, the third part examines the relationship between the Francovich doctrine and the principle of legal certainty and concludes that the solutions employed by the ECJ have been both predictable and acceptable by the national legal orders. Keywords: State liability, damages, Francovich, Köbler, Schmidberger

Small State Cultures of Consensus : State Traditions and Consensus-Seeking in the Neo-Corporatist and Neutrality Policies in Post-1945 Austria and Finland

Austria and Finland are persistently referred to as the “success stories” of post-1945 European history. Notwithstanding their different points of departure, in the course of the Cold War both countries portrayed themselves as small and neutral border-states in the world dictated by superpower politics. By the 1970s, both countries frequently ranked at the top end in various international classifications regarding economic development and well-being in society. This trend continues today. The study takes under scrutiny the concept of consensus which figures centrally in the two national narratives of post-1945 success. Given that the two domestic contexts as such only share few direct links with one another and are more obviously different than similar in terms of their geographical location, historical experiences and politico-cultural traditions, the analogies and variations in the anatomies of the post-1945 “cultures of consensus” provide an interesting topic for a historical comparative and cross-national examination. The main research question concerns the identification and analysis of the conceptual and procedural convergence points of the concepts of the state and consensus. The thesis is divided into six main chapters. After the introduction, the second chapter presents the theoretical framework in more detail by focusing on the key concepts of the study – the state and consensus. Chapter two also introduces the comparative historical and cross-national research angles. Chapter three grounds the key concepts of the state and consensus in the historical contexts of Austria and Finland by discussing the state, the nation and democracy in a longer term comparative perspective. The fourth and fifth chapter present case studies on the two policy fields, the “pillars”, upon which the post-1945 Austrian and Finnish cultures of consensus are argued to have rested. Chapter four deals with neo-corporatist features in the economic policy making and chapter five discusses the building up of domestic consensus regarding the key concepts of neutrality policies in the 1950s and 1960s. The study concludes that it was not consensus as such but the strikingly intense preoccupation with the theme of domestic consensus that cross-cut, in a curiously analogous manner, the policy-making processes studied. The main challenge for the post-1945 architects of Austrian and Finnish cultures of consensus was to find strategies and concepts for consensus-building which would be compatible with the principles of democracy. Discussed at the level of procedures, the most important finding of the study concerns the triangular mechanism of coordination, consultation and cooperation that set into motion and facilitated a new type of search for consensus in both post-war societies. In this triangle, the agency of the state was central, though in varying ways. The new conceptions concerning a small state’s position in the Cold War world also prompted cross-nationally perceivable willingness to reconsider inherited concepts and procedures of the state and the nation. At the same time, the ways of understanding the role of the state and its relation to society remained profoundly different in Austria and Finland and this basic difference was in many ways reflected in the concepts and procedures deployed in the search for consensus and management of domestic conflicts. For more detailed information, please consult the author.

Regional Integration and the State : The Changing Nature of Sovereignty in Southern Africa and Europe

The study explores the role of the state in regional integration processes. The question is approached through theoretical discussion and two case-studies - SADC (Southern African Development Community) and the EU. The main research question of the study is, what are the possibilities and problems of the integration process in Southern Africa and how do they differ from the possibilities and problems of the integration process in Europe. The undelrying question of the study is why do states decide to participate in an integration process where they have to limit their sovereignty. Review of the theoretical discussion of the integration studies shows that the integration process is affected by several factors on different levels of the international system. But the state plays a central role in integration processes - integration processes are inititated and carried on by the participatig states. The European integration process shows that the interests of the state can change over time. At the beginning of the integration process, the objective was to strengthen participating states. Later EU member states have decided that it is in their interest to deepen the process even if it has meant limitation of their sovereignty. The determinant factor has been that the member states have considered it to be in their interst to deepen the process. In Southern Africa the integration process is only at the beginning. SADC aims to establish a free trade area by 2008. The biggest challenge is how to implement the integration process so that it benefits all member states in a region that is economically dominated by South Africa. In practice this can be achieved through establishment of corrective mechanisms, which ensure equitable distribution of benefits. This would require deeper integration and South Africa to adapt responsibility towards its regional partners. African integration processes in general have not been as successful as for example the EU. African states have been reluctant to limit their sovereignty in favour of regional organisations.This can be explained by the differences between European and African states. The EU member states have been democracies while African states have been characterised by concentration of power in the executive branch. Furthermore the political systems in Africa have been characterised by vertical clientelist reltionships. As a result it has not been in the interest of the political elite to limit the state sovereignty in favour of regional organisations. In recent years SADC has been relatively succesful in its integration process and reforms, but a lot remains to be done before the implementation of the free trade area can be succesful. The institutional structure and treaties of SADC differ from the structures of the EU. Member states are the main actors of the integration processes. Their differences are reflected in the process and produce different kinds of integration in different parts of the world.

State Agent, Identity and the "New World Order" : Reconstructing Polish Defence Identity after the Cold War Era

National identity signifies and makes state s defence- and foreign policy behaviour meaningful. National consciousness is narrated into existence by narratives upon one s own exceptionalism and Otherness of the other nations. While national identity may be understood merely as a self-image of a nation, defence identity refers to the borders of Otherness and issues that have been considered as worth defending for. As national identities and all the world order models are human constructions, they may be changed by the human efforts as well; states and nations may deliberately promote communitarian or even cosmopolitan equality and tolerance without borders of Otherness. The main research question of the thesis is: How does Poland constitute herself as a nation and a state agent in the current world order and to what extent have contextual foreign and defence policy interactions changed the Polish defence identity during the post-Cold War era? The main empirical argument of the thesis is: Poland is a narrated idea of a Christian Catholic nation-state, which the Polish State, the Catholic Church of Poland, the Armed Forces of Poland as well as a majority of the Polish nation share. Polish defence identity has been almost impenetrable to contextual foreign and defence policy interactions during the post-Cold War era. While Christian religious ontology binds corporate Poland together, allowing her to survive any number of military and political catastrophes, it simultaneously brings her closer to the USA, raises tensions in the infidel EU-context, and restrains corporate Poland s pursuit of communitarian, or even cosmopolitan, global equality and tolerance. It is not the case that corporate Poland s foreign and defence policy orientation is instinctively Atlanticist by nature, as has been argued. Rather, it has been the State s rational project to overcome a habituated and reified fear of becoming geopolitically sandwiched between Russian and German Others by leaning on the USA; among the Polish nation, support for the USA has been declining since 2004. It is not corporate Poland either that has turned into a constructive European , as has been argued, but rather the Polish nation that has, at least partly, managed to emancipate itself from its habituation to a betrayal by Europe narrative, since it favours the EU as much as it favours NATO. It seems that in the Polish case a truly common European CFSP vis-à-vis Russia may offer a solution that will emancipate the Polish State from its habituated EU-sceptic role identity and corporate Poland from its narrated borders of Otherness towards Russia and Germany, but even then one cannot be sure whether any other perspective than the Polish one on a common stand towards Russia would satisfy the Poles themselves.