From Polymorph Screening to Dissolution Testing - Solid Phase Analysis during Pharmaceutical Development and Manufacturing

Solid materials can exist in different physical structures without a change in chemical composition. This phenomenon, known as polymorphism, has several implications on pharmaceutical development and manufacturing. Various solid forms of a drug can possess different physical and chemical properties, which may affect processing characteristics and stability, as well as the performance of a drug in the human body. Therefore, knowledge and control of the solid forms is fundamental to maintain safety and high quality of pharmaceuticals. During manufacture, harsh conditions can give rise to unexpected solid phase transformations and therefore change the behavior of the drug. Traditionally, pharmaceutical production has relied on time-consuming off-line analysis of production batches and finished products. This has led to poor understanding of processes and drug products. Therefore, new powerful methods that enable real time monitoring of pharmaceuticals during manufacturing processes are greatly needed. The aim of this thesis was to apply spectroscopic techniques to solid phase analysis within different stages of drug development and manufacturing, and thus, provide a molecular level insight into the behavior of active pharmaceutical ingredients (APIs) during processing. Applications to polymorph screening and different unit operations were developed and studied. A new approach to dissolution testing, which involves simultaneous measurement of drug concentration in the dissolution medium and in-situ solid phase analysis of the dissolving sample, was introduced and studied. Solid phase analysis was successfully performed during different stages, enabling a molecular level insight into the occurring phenomena. Near-infrared (NIR) spectroscopy was utilized in screening of polymorphs and processing-induced transformations (PITs). Polymorph screening was also studied with NIR and Raman spectroscopy in tandem. Quantitative solid phase analysis during fluidized bed drying was performed with in-line NIR and Raman spectroscopy and partial least squares (PLS) regression, and different dehydration mechanisms were studied using in-situ spectroscopy and partial least squares discriminant analysis (PLS-DA). In-situ solid phase analysis with Raman spectroscopy during dissolution testing enabled analysis of dissolution as a whole, and provided a scientific explanation for changes in the dissolution rate. It was concluded that the methods applied and studied provide better process understanding and knowledge of the drug products, and therefore, a way to achieve better quality.

Strike Hard, Strike Sure - Operation Musketeer : British Military Planning during the Suez Crisis, 1956

This study analyses British military planning and actions during the Suez Crisis in 1956. It seeks to find military reasons for the change of concepts during the planning and compares these reasons with the tactical doctrines of the time. The thesis takes extensive advantage of military documents preserved in the National Archives, London. In order to expand the understanding of the exchange of views during the planning process, the private papers of high ranking military officials have also been consulted. French military documents preserved in the Service Historique de la Defence, Paris, have provided an important point of comparison. The Suez Crisis caught the British armed forces in the middle of a transition phase. The main objective of the armed forces was to establish a credible deterrence against the Soviet Union. However, due to overseas commitments the Middle East playing a paramount role because of its economic importance the armed forces were compelled to also prepare for Limited War and the Cold War. The armed forces were not fully prepared to meet this demand. The Middle Eastern garrison was being re-organised after the withdrawal from the Canal Base and the concept for a strategic reserve was unimplemented. The tactical doctrines of the time were based on experiences from the Second World War. As a result, the British view of amphibious operations and the subsequent campaigns emphasised careful planning, mastery of the sea and the air, sufficient superiority in numbers and firepower, centralised command and extensive administrative preparations. The British military had realized that Nasser could nationalise the Suez Canal and prepared an outline plan to meet this contingency. Although the plan was nothing more than a concept, it was accepted as a basis for further planning when the Canal was nationalised at the end of July. This plan was short-lived. The nominated Task Force Commanders shifted the landing site from Port Said to Alexandria because it enabled faster expansion of the bridgehead. In addition, further operations towards Cairo the hub of Nasser s power would be easier to conduct. The operational concept can be described as being traditional and was in accordance with the amphibious warfare doctrine. This plan was completely changed at the beginning of September. Apparently, General Charles Keightley, the Commander-in-Chief, and the Chairman of the Chiefs of Staff Committee developed the idea of prolonged aerial operations. The essence of the concept was to break the Egyptian will to resist by attacking the oil facilities, the transportation system and the armed forces. This victory through air concept would be supported by carefully planned psychological operations. This concept was in accordance with the Royal Air Force doctrine, which promoted a bomber offensive against selected target categories. General Keightley s plan was accepted despite suspicions at every planning level. The Joint Planning Staff and the Task Force Commanders opposed the concept from the beginning to the end because of its unpredictability. There was no information that suggested the bombing would persuade the Egyptians to submit. This problem was worsened by the fact that British intelligence was unable to provide reliable strategic information. The Task Force Commanders, who were responsible for the tactical plans, were not able to change Keightley s mind, but the concept was expanded to include a traditional amphibious assault on Port Said due to their resistance. The bombing campaign was never tested as the Royal Air Force was denied authorisation to destroy the transportation and oil targets. The Chiefs of Staff and General Keightley were too slow to realise that the execution of the plan depended on the determination of the Prime Minister. However, poor health, a lack of American and domestic support and the indecisiveness of the military had ruined Eden s resolve. In the end, a very traditional amphibious assault, which was bound to succeed at the tactical level but fail at the strategic level, was launched against Port Said.

Estimation of local forest attributes, utilizing two-phase sampling and auxiliary data

This thesis examines the feasibility of a forest inventory method based on two-phase sampling in estimating forest attributes at the stand or substand levels for forest management purposes. The method is based on multi-source forest inventory combining auxiliary data consisting of remote sensing imagery or other geographic information and field measurements. Auxiliary data are utilized as first-phase data for covering all inventory units. Various methods were examined for improving the accuracy of the forest estimates. Pre-processing of auxiliary data in the form of correcting the spectral properties of aerial imagery was examined (I), as was the selection of aerial image features for estimating forest attributes (II). Various spatial units were compared for extracting image features in a remote sensing aided forest inventory utilizing very high resolution imagery (III). A number of data sources were combined and different weighting procedures were tested in estimating forest attributes (IV, V). Correction of the spectral properties of aerial images proved to be a straightforward and advantageous method for improving the correlation between the image features and the measured forest attributes. Testing different image features that can be extracted from aerial photographs (and other very high resolution images) showed that the images contain a wealth of relevant information that can be extracted only by utilizing the spatial organization of the image pixel values. Furthermore, careful selection of image features for the inventory task generally gives better results than inputting all extractable features to the estimation procedure. When the spatial units for extracting very high resolution image features were examined, an approach based on image segmentation generally showed advantages compared with a traditional sample plot-based approach. Combining several data sources resulted in more accurate estimates than any of the individual data sources alone. The best combined estimate can be derived by weighting the estimates produced by the individual data sources by the inverse values of their mean square errors. Despite the fact that the plot-level estimation accuracy in two-phase sampling inventory can be improved in many ways, the accuracy of forest estimates based mainly on single-view satellite and aerial imagery is a relatively poor basis for making stand-level management decisions.

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.

From the river to the open sea - a critical life phase of young Atlantic salmon migrating from the Simojoki river

Long-term monitoring data collected from wild smolts of Atlantic salmon (Salmo salar) in the Simojoki river, northern Finland, were used in studying the relationships between the smolt size and age, smolt and postsmolt migration, environmental conditions and postsmolt survival. The onset of the smolt run was significantly dependent on the rising water temperature and decreasing discharge of the river in the spring. The mean length of smolts migrating early in the season was commonly higher and the mean age always older than among smolts migrating later. Many of the smolts migrating early in the season and almost all smolts migrating later had started their new growth in spring in the river before their sea entry. Among postsmolts, the time required for emigration from the estuary was dependent on the sea surface temperature (SST) off the river, being significantly shorter in years with warm than cold sea temperatures. After leaving the estuary, the postsmolts migrated southwards along the eastern coast of the northern Gulf of Bothnia, the geographical distribution of the tag recoveries coinciding with the warm thermal zone in spring in the coastal area. After arriving in the southern Gulf of Bothnia in late summer the postsmolts mostly migrated near the western coast, reaching the Baltic Main Basin in late autumn. Until the early 1990s there was only a weak positive association between smolt length and postsmolt survival. However, following a subsequent decrease in the mean smolt size, a significant positive dependence was observed between smolt size and the reported recapture rate of tagged salmon. The differences in recapture rates between smolts tagged during the first and second half of the annual migration season were insignificant, indicating that the seasonal variation in smolt size and age seem to be too small to affect survival. Among the climatic factors examined, the summer SST in the Gulf of Bothnia was most clearly related to the survival of the wild postsmolts. Postsmolt survival appeared to be highest in years when the SST in June in the Bothnian Bay varied between 9 and 12 ºC. In addition, the survival of wild postsmolts showed a significant positive dependence on the SST in July in the Bothnian Sea, but not on the abundance of the prey fish (0+ herring, Clupea harengus and sprat, Sprattus sprattus) in the Bothnian Sea and in the Baltic Main Basin. The results suggest, that if the incidence of extreme weather conditions were to increase due to climatic changes, it would probably reduce the postsmolt survival of wild salmon populations. For improving the performance of hatchery-reared smolts, it could be useful to examine opportunities to produce smolts that are in their smolt traits and abilities more similar to the wild smolts described in this thesis.

Näkökulmia eurooppalaiseen sosiaalipolitiikkaan : malli, väestö, resurssit ja kommunikaatio

The study analyses European social policy as a political project that proceeds under the guidance of the European Commission. In the name of modernisation, the project aims to build a new idea for the welfare state. To understand the project, it is necessary to distance oneself from both the juridical competence of the European Union and the traditional national welfare state models. The question is about sharing problems, as well as solutions to them: it is the creation and sharing of common views, concepts and images that play a key role in European integration. Drawing on texts and speeches produced by the European Commission, the study throws light on the development of European social policy during the first years of the 2000s. The study "freeze-frames" the welfare debate having its starting points in the nation states in the name of the entity of Europe. The first article approaches the European social model as a story in itself, a preparatory, persuasive narrative that concerns the management of change. The article shows how the audience can be motivated to work towards a set target by using discursive elements in a persuasive manner: the function of a persuasive story is to convince the target audience of the appropriateness of the chosen direction and to shape their identity so that they are favourably disposed to the desired political targets. This is a kind of "intermediate state" where the story, despite its inner contradictions and inaccuracies, succeeds in appearing as an almost self-evident path towards a modern social policy that Europe is currently seen to be in need of. The second article outlines the European social model as a question of governance. Health as a sector of social policy is detached from the old political order, which was based on the welfare state, and is closely linked to economy. At the same time the population is primarily seen as an economic resource. The Commission is working towards a "Europe of Health" that grapples with the problem of governance with the help of the "healthisation" of society, healthy citizenship and health economics. The way the Commission speaks is guided by the Union's powerful interest to act as "Europe" in the field of welfare policy. At the same time, the traditional separateness of health policy is effaced in order to be able to make health policy reforms a part of the Union's wider modernisation targets. The third article then shows the European social policy as its own area of governance. The article uses an approach based on critical discourse analysis in examining the classification systems and presentation styles adopted by Commission communications, as well as the identities that they help build. In analysing the "new start" of the Lisbon strategy from the perspective of social policy, the article shows how the emphasis has shifted from the persuasive arguments for change with necessary common European targets in the early stages of the strategy towards the implementation of reforms: from a narrative to a vision and from a diagnosis to healing. The phase of global competition represents "the modern" with which European society with its culture and ways of life now has to be matched. The Lisbon strategy is a way to direct this societal change, thus building a modern European social policy. The fourth article describes how the Commission uses its communications policy to build practices and techniques of governance and how it persuades citizens to participate in the creation of a European project of change. This also requires a new kind of agency: agents for whom accountability and responsibilities mean integration into and commitment to European society. Accountability is shaped into a decisive factor in implementing the European Union's strategy of change. As such it will displace hierarchical confrontations and emphasise common action with a view to modernising Europe. However, the Union's discourse cannot be described as being a political language that would genuinely rouse and convince the audience at the level of everyday life. Keywords: European social policy, EU policy, European social model, European Commission, modernisation of welfare, welfare state, communications, discoursiveness.