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

Valuation of reduced eutrophication in the Gulf of Finland : Choice experiment with attention to heterogeneous and discontinuous preferences and respondent uncertainty

Eutrophication of the Baltic Sea is a serious problem. This thesis estimates the benefit to Finns from reduced eutrophication in the Gulf of Finland, the most eutrophied part of the Baltic Sea, by applying the choice experiment method, which belongs to the family of stated preference methods. Because stated preference methods have been subject to criticism, e.g., due to their hypothetical survey context, this thesis contributes to the discussion by studying two anomalies that may lead to biased welfare estimates: respondent uncertainty and preference discontinuity. The former refers to the difficulty of stating one s preferences for an environmental good in a hypothetical context. The latter implies a departure from the continuity assumption of conventional consumer theory, which forms the basis for the method and the analysis. In the three essays of the thesis, discrete choice data are analyzed with the multinomial logit and mixed logit models. On average, Finns are willing to contribute to the water quality improvement. The probability for willingness increases with residential or recreational contact with the gulf, higher than average income, younger than average age, and the absence of dependent children in the household. On average, for Finns the relatively most important characteristic of water quality is water clarity followed by the desire for fewer occurrences of blue-green algae. For future nutrient reduction scenarios, the annual mean household willingness to pay estimates range from 271 to 448 and the aggregate welfare estimates for Finns range from 28 billion to 54 billion euros, depending on the model and the intensity of the reduction. Out of the respondents (N=726), 72.1% state in a follow-up question that they are either Certain or Quite certain about their answer when choosing the preferred alternative in the experiment. Based on the analysis of other follow-up questions and another sample (N=307), 10.4% of the respondents are identified as potentially having discontinuous preferences. In relation to both anomalies, the respondent- and questionnaire-specific variables are found among the underlying causes and a departure from standard analysis may improve the model fit and the efficiency of estimates, depending on the chosen modeling approach. The introduction of uncertainty about the future state of the Gulf increases the acceptance of the valuation scenario which may indicate an increased credibility of a proposed scenario. In conclusion, modeling preference heterogeneity is an essential part of the analysis of discrete choice data. The results regarding uncertainty in stating one s preferences and non-standard choice behavior are promising: accounting for these anomalies in the analysis may improve the precision of the estimates of benefit from reduced eutrophication in the Gulf of Finland.

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.

Tannakian Formalism Applied to the Category of Mixed Hodge Structures

Many problems in analysis have been solved using the theory of Hodge structures. P. Deligne started to treat these structures in a categorical way. Following him, we introduce the categories of mixed real and complex Hodge structures. Category of mixed Hodge structures over the field of real or complex numbers is a rigid abelian tensor category, and in fact, a neutral Tannakian category. Therefore it is equivalent to the category of representations of an affine group scheme. The direct sums of pure Hodge structures of different weights over real or complex numbers can be realized as a representation of the torus group, whose complex points is the Cartesian product of two punctured complex planes. Mixed Hodge structures turn out to consist of information of a direct sum of pure Hodge structures of different weights and a nilpotent automorphism. Therefore mixed Hodge structures correspond to the representations of certain semidirect product of a nilpotent group and the torus group acting on it.

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.