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

Negotiating and Renegotiating Conversational Ground Rules : Formation of an Artifact Designed to Mediate Exploratory Collaboration

This study highlights the formation of an artifact designed to mediate exploratory collaboration. The data for this study was collected during a Finnish adaptation of the thinking together approach. The aim of the approach is to teach pulps how to engage in educationally beneficial form of joint discussion, namely exploratory talk. At the heart of the approach lies a set of conversational ground rules aimed to promote the use of exploratory talk. The theoretical framework of the study is based on a sociocultural perspective on learning. A central argument in the framework is that physical and psychological tools play a crucial role in human action and learning. With the help of tools humans can escape the direct stimulus of the outside world and learn to control ourselves by using tools. During the implementation of the approach, the classroom community negotiates a set of six rules, which this study conceptualizes as an artifact that mediates exploratory collaboration. Prior research done about the thinking together approach has not extensively researched the formation of the rules, which give ample reason to conduct this study. The specific research questions asked were: What kind of negotiation trajectories did the ground rules form during the intervention? What meanings were negotiated for the ground rules during the intervention The methodological framework of the study is based on discourse analysis, which has been specified by adapting the social construction of intertextuality to analyze the meanings negotiated for the created rules. The study has town units of analysis: thematic episode and negotiation trajectory. A thematic episode is a stretch of talk-in-interaction where the participants talk about a certain ground rule or a theme relating to it. A negotiation trajectory is a chronological representation of the negotiation process of a certain ground rule during the intervention and is constructed of thematic episodes. Thematic episodes were analyzed with the adapted intertextuality analysis. A contrastive analysis was done on the trajectories. Lastly, the meanings negotiated for the created rules were compared to the guidelines provided by the approach. The main result of the study is the observation, that the meanings of the created rules were more aligned with the ground rules of cumulative talk, rather than exploratory talk. Although meanings relating also to exploratory talk were negotiated, they clearly were not the dominant form. In addition, the study observed that the trajectories of the rules were non identical. Despite connecting dimensions (symmetry, composition, continuity and explicitness) none of the trajectories shared exactly the same features as the others.

Studies on metal complex formation of environmentally friendly aminopolycarboxylate chelating agents

Aminopolykarboksyylaatteja, kuten etyleenidiamiinitetraetikkahappoa (EDTA), on käytetty useiden vuosikymmenien ajan erinomaisen metalli-ionien sitomiskyvyn vuoksi kelatointiaineena lukuisissa sovelluksissa sekä analytiikassa että monilla teollisisuuden aloilla. Näiden yhdisteiden biohajoamattomuus on kuitenkin herättänyt huolta viime aikoina, sillä niiden on havaittu olevan hyvin pysyviä luonnossa. Tämä työ on osa laajempaa tutkimushanketta, jossa on tavoitteena löytää korvaavia kelatointiaineita EDTA:lle. Tutkimuksen aiheena on kuuden kelatointiaineen metalli-ionien sitomiskyvyn kartoitus. EDTA:a paremmin luonnossa hajoavina nämä ovat ympäristöystävällisiä ehdokkaita korvaaviksi kelatointiaineiksi useisiin sovelluksiin. Työssä tutkittiin niiden kompleksinmuodostusta useiden metalli-ionien kanssa potentiometrisella titrauksella. Metalli-ionivalikoima vaihteli hieman kelatointiaineesta riippuen sisältäen magnesium-, kalsium-, mangaani-, rauta-, kupari-, sinkki-, kadmium-, elohopea-, lyijy- ja lantaani-ionit. Tutkittavat metallit oli valittu tähtäimessä olevien sovellusten, synteesissä ilmenneiden ongelmien tai ympäristönäkökohtien perusteella. Tulokset osoittavat näiden yhdisteiden metallinsitomiskyvyn olevan jonkin verran heikompi kuin EDTA:lla, mutta kuitenkin riittävän useisiin sovelluksiin kuten sellunvalkaisuprosessiin. Myrkyllisten raskasmetallien, kadmiumin, elohopen ja lyijyn kohdalla EDTA:a heikompi sitoutuminen on eduksikin, koska se yhdistettynä parempaan biohajoavuuteen saattaa alentaa tutkittujen yhdisteiden kykyä mobilisoida kyseisiä metalleja sedimenteistä. Useimmilla tutkituista yhdisteistä on ympäristönäkökulmasta etuna myös EDTA:a pienempi typpipitoisuus.

Understanding the chemistry of atmospheric aerosol particle formation via observations of physical properties

It is widely accepted that the global climate is heating up due to human activities, such as burning of fossil fuels. Therefore we find ourselves forced to make decisions on what measures, if any, need to be taken to decrease our warming effect on the planet before any irrevocable damage occurs. Research is being conducted in a variety of fields to better understand all relevant processes governing Earth s climate, and to assess the relative roles of anthropogenic and biogenic emissions into the atmosphere. One of the least well quantified problems is the impact of small aerosol particles (both of anthropogenic and biogenic origin) on climate, through reflecting solar radiation and their ability to act as condensation nuclei for cloud droplets. In this thesis, the compounds driving the biogenic formation of new particles in the atmosphere have been examined through detailed measurements. As directly measuring the composition of these newly formed particles is extremely difficult, the approach was to indirectly study their different characteristics by measuring the hygroscopicity (water uptake) and volatility (evaporation) of particles between 10 and 50 nm. To study the first steps of the formation process in the sub-3 nm range, the nucleation of gaseous precursors to small clusters, the chemical composition of ambient naturally charged ions were measured. The ion measurements were performed with a newly developed mass spectrometer, which was first characterized in the laboratory before being deployed at a boreal forest measurement site. It was also successfully compared to similar, low-resolution instruments. The ambient measurements showed that sulfuric acid clusters dominate the negative ion spectrum during new particle formation events. Sulfuric acid/ammonia clusters were detected in ambient air for the first time in this work. Even though sulfuric acid is believed to be the most important gas phase precursor driving the initial cluster formation, measurements of the hygroscopicity and volatility of growing 10-50 nm particles in Hyytiälä showed an increasing role of organic vapors of a variety of oxidation levels. This work has provided additional insights into the compounds participating both in the initial formation and subsequent growth of atmospheric new aerosol particles. It will hopefully prove an important step in understanding atmospheric gas-to-particle conversion, which, by influencing cloud properties, can have important climate impacts. All available knowledge needs to be constantly updated, summarized, and brought to the attention of our decision-makers. Only by increasing our understanding of all the relevant processes can we build reliable models to predict the long-term effects of decisions made today.

Experiments on homogeneous nucleation and physicochemical properties related to atmospheric new particle formation

Aerosol particles play a role in the earth ecosystem and affect human health. A significant pathway of producing aerosol particles in the atmosphere is new particle formation, where condensable vapours nucleate and these newly formed clusters grow by condensation and coagulation. However, this phenomenon is still not fully understood. This thesis brings an insight to new particle formation from an experimental point of view. Laboratory experiments were conducted both on the nucleation process and physicochemical properties related to new particle formation. Nucleation rate measurements are used to test nucleation theories. These theories, in turn, are used to predict nucleation rates in atmospheric conditions. However, the nucleation rate measurements have proven quite difficult to conduct, as different devices can yield nucleation rates with differences of several orders of magnitude for the same substances. In this thesis, work has been done to have a greater understanding in nucleation measurements, especially those conducted in a laminar flow diffusion chamber. Systematic studies of nucleation were also made for future verification of nucleation theories. Surface tensions and densities of substances related to atmospheric new particle formation were measured. Ternary sulphuric acid + ammonia + water is a proposed candidate to participate in atmospheric nucleation. Surface tensions of an alternative candidate to nucleate in boreal forest areas, sulphuric acid + dimethylamine + water, were also measured. Binary compounds, consisting of organic acids + water are possible candidates to participate in the early growth of freshly nucleated particles. All the measured surface tensions and densities were fitted with equations, thermodynamically consistent if possible, to be easily applied to atmospheric model calculations of nucleation and subsequent evolution of particle size.

Numerical approaches to new particle formation and growth in the atmosphere

Aerosols impact the planet and our daily lives through various effects, perhaps most notably those related to their climatic and health-related consequences. While there are several primary particle sources, secondary new particle formation from precursor vapors is also known to be a frequent, global phenomenon. Nevertheless, the formation mechanism of new particles, as well as the vapors participating in the process, remain a mystery. This thesis consists of studies on new particle formation specifically from the point of view of numerical modeling. A dependence of formation rate of 3 nm particles on the sulphuric acid concentration to the power of 1-2 has been observed. This suggests nucleation mechanism to be of first or second order with respect to the sulphuric acid concentration, in other words the mechanisms based on activation or kinetic collision of clusters. However, model studies have had difficulties in replicating the small exponents observed in nature. The work done in this thesis indicates that the exponents may be lowered by the participation of a co-condensing (and potentially nucleating) low-volatility organic vapor, or by increasing the assumed size of the critical clusters. On the other hand, the presented new and more accurate method for determining the exponent indicates high diurnal variability. Additionally, these studies included several semi-empirical nucleation rate parameterizations as well as a detailed investigation of the analysis used to determine the apparent particle formation rate. Due to their high proportion of the earth's surface area, oceans could potentially prove to be climatically significant sources of secondary particles. In the lack of marine observation data, new particle formation events in a coastal region were parameterized and studied. Since the formation mechanism is believed to be similar, the new parameterization was applied in a marine scenario. The work showed that marine CCN production is feasible in the presence of additional vapors contributing to particle growth. Finally, a new method to estimate concentrations of condensing organics was developed. The algorithm utilizes a Markov chain Monte Carlo method to determine the required combination of vapor concentrations by comparing a measured particle size distribution with one from an aerosol dynamics process model. The evaluation indicated excellent agreement against model data, and initial results with field data appear sound as well.

Experimental studies on new particle formation and ions

Atmospheric aerosol particles have significant climatic effects. Secondary new particle formation is a globally important source of these particles. Currently, the mechanisms of particle formation and the vapours participating in this process are, however, not truly understood. The recently developed Neutral cluster and Air Ion Spectrometer (NAIS) was widely used in field studies of atmospheric particle formation. The NAIS was calibrated and found to be in adequate agreement with the reference instruments. It was concluded that NAIS can be reliably used to measure ions and particles near the sizes where the atmospheric particle formation begins. The main focus of this thesis was to study new particle formation and participation of ions in this process. To attain this objective, particle and ion formation and growth rates were studied in various environments - at several field sites in Europe, in previously rarely studied sites in Antarctica and Siberia and also in an indoor environment. New particle formation was observed at all sites were studied and the observations were used as indicatives of the particle formation mechanisms. Particle size-dependent growth rates and nucleation mode hygroscopic growth factors were examined to obtain information on the particle growth. It was found that the atmospheric ions participate in the initial steps of new particle formation, although their contribution was minor in the boundary layer. The highest atmospheric particle formation rates were observed at the most polluted sites where the role of ions was the least pronounced. Furthermore, the increase of particle growth rate with size suggested that enhancement of the growth by ions was negligible. Participation of organic vapours in the particle growth was supported by laboratory and field observations. It was addressed that secondary new particle formation can also be a significant source of indoor air particles. These results, extending over a wide variety of environments, give support to previous observations and increase understanding on new particle formation on a global scale.

Observations on the first steps of atmospheric particle formation and growth

Atmospheric aerosol particles have a significant impact on air quality, human health and global climate. The climatic effects of secondary aerosol are currently among the largest uncertainties limiting the scientific understanding of future and past climate changes. To better estimate the climatic importance of secondary aerosol particles, detailed information on atmospheric particle formation mechanisms and the vapours forming the aerosol is required. In this thesis we studied these issues by applying novel instrumentation in a boreal forest to obtain direct information on the very first steps of atmospheric nucleation and particle growth. Additionally, we used detailed laboratory experiments and process modelling to determine condensational growth properties, such as saturation vapour pressures, of dicarboxylic acids, which are organic acids often found in atmospheric samples. Based on our studies, we came to four main conclusions: 1) In the boreal forest region, both sulphurous compounds and organics are needed for secondary particle formation, the previous contributing mainly to particle formation and latter to growth; 2) A persistent pool of molecular clusters, both neutral and charged, is present and participates in atmospheric nucleation processes in boreal forests; 3) Neutral particle formation seems to dominate over ion-mediated mechanisms, at least in the boreal forest boundary layer; 4) The subcooled liquid phase saturation vapour pressures of C3-C9 dicarboxylic acids are of the order of 1e-5 1e-3 Pa at atmospheric temperatures, indicating that a mixed pre-existing particulate phase is required for their condensation in atmospheric conditions. The work presented in this thesis gives tools to better quantify the aerosol source provided by secondary aerosol formation. The results are particularly useful when estimating, for instance, anthropogenic versus biogenic influences and the fractions of secondary aerosol formation explained by neutral or ion-mediated nucleation mechanisms, at least in environments where the average particle formation rates are of the order of some tens of particles per cubic centimeter or lower. However, as the factors driving secondary particle formation are likely to vary depending on the environment, measurements on atmospheric nucleation and particle growth are needed from around the world to be able to better describe the secondary particle formation, and assess its climatic effects on a global scale.

Molecular line and continuum studies of the early stages of star formation

New stars form in dense interstellar clouds of gas and dust called molecular clouds. The actual sites where the process of star formation takes place are the dense clumps and cores deeply embedded in molecular clouds. The details of the star formation process are complex and not completely understood. Thus, determining the physical and chemical properties of molecular cloud cores is necessary for a better understanding of how stars are formed. Some of the main features of the origin of low-mass stars, like the Sun, are already relatively well-known, though many details of the process are still under debate. The mechanism through which high-mass stars form, on the other hand, is poorly understood. Although it is likely that the formation of high-mass stars shares many properties similar to those of low-mass stars, the very first steps of the evolutionary sequence are unclear. Observational studies of star formation are carried out particularly at infrared, submillimetre, millimetre, and radio wavelengths. Much of our knowledge about the early stages of star formation in our Milky Way galaxy is obtained through molecular spectral line and dust continuum observations. The continuum emission of cold dust is one of the best tracers of the column density of molecular hydrogen, the main constituent of molecular clouds. Consequently, dust continuum observations provide a powerful tool to map large portions across molecular clouds, and to identify the dense star-forming sites within them. Molecular line observations, on the other hand, provide information on the gas kinematics and temperature. Together, these two observational tools provide an efficient way to study the dense interstellar gas and the associated dust that form new stars. The properties of highly obscured young stars can be further examined through radio continuum observations at centimetre wavelengths. For example, radio continuum emission carries useful information on conditions in the protostar+disk interaction region where protostellar jets are launched. In this PhD thesis, we study the physical and chemical properties of dense clumps and cores in both low- and high-mass star-forming regions. The sources are mainly studied in a statistical sense, but also in more detail. In this way, we are able to examine the general characteristics of the early stages of star formation, cloud properties on large scales (such as fragmentation), and some of the initial conditions of the collapse process that leads to the formation of a star. The studies presented in this thesis are mainly based on molecular line and dust continuum observations. These are combined with archival observations at infrared wavelengths in order to study the protostellar content of the cloud cores. In addition, centimetre radio continuum emission from young stellar objects (YSOs; i.e., protostars and pre-main sequence stars) is studied in this thesis to determine their evolutionary stages. The main results of this thesis are as follows: i) filamentary and sheet-like molecular cloud structures, such as infrared dark clouds (IRDCs), are likely to be caused by supersonic turbulence but their fragmentation at the scale of cores could be due to gravo-thermal instability; ii) the core evolution in the Orion B9 star-forming region appears to be dynamic and the role played by slow ambipolar diffusion in the formation and collapse of the cores may not be significant; iii) the study of the R CrA star-forming region suggests that the centimetre radio emission properties of a YSO are likely to change with its evolutionary stage; iv) the IRDC G304.74+01.32 contains candidate high-mass starless cores which may represent the very first steps of high-mass star and star cluster formation; v) SiO outflow signatures are seen in several high-mass star-forming regions which suggest that high-mass stars form in a similar way as their low-mass counterparts, i.e., via disk accretion. The results presented in this thesis provide constraints on the initial conditions and early stages of both low- and high-mass star formation. In particular, this thesis presents several observational results on the early stages of clustered star formation, which is the dominant mode of star formation in our Galaxy.

Analysis of Atmospheric Particle Formation Events

Atmospheric aerosol particle formation events can be a significant source for tropospheric aerosols and thus influence the radiative properties and cloud cover of the atmosphere. This thesis investigates the analysis of aerosol size distribution data containing particle formation events, describes the methodology of the analysis and presents time series data measured inside the Boreal forest. This thesis presents a methodology to identify regional-scale particle formation, and to derive the basic characteristics such as growth and formation rates. The methodology can also be used to estimate concentration and source rates of the vapour causing particle growth. Particle formation was found to occur frequently in the boreal forest area over areas covering up to hundreds of kilometers. Particle formation rates of boreal events were found to be of the order of 0.01-5 cm^-3 s^-1, while the nucleation rates of 1 nm particles can be a few orders of magnitude higher. The growth rates of over 3 nm sized particles were of the order of a few nanometers per hour. The vapor concentration needed to sustain such growth is of the order of 10^7--10^8 cm^-3, approximately one order of magnitude higher than sulphuric acid concentrations found in the atmosphere. Therefore, one has to assume that other vapours, such as organics, have a key role in growing newborn particles to sizes where they can become climatically active. Formation event occurrence shows a clear annual variation with peaks in summer and autumns. This variation is similar to the variation exhibited the obtained formation rates of particles. The growth rate, on the other hand, reaches its highest values during summer. This difference in the annual behavior, and the fact that no coupling between the growth and formation process could be identified, suggest that these processes might be different ones, and that both are needed for a particle formation burst to be observed.

Exploring Customer Value Formation: A Customer Dominant Logic Perspective

This paper extends current discussions about value creation and proposes a customer dominant value perspective. A customer-dominant marketing logic positions the customer in the center, rather than the service provider/producer or the interaction or the system. The focus is shifted from the company´s service processes involving the customer, to the customer´s multi-contextual value formation, involving the company. It is argued that value is not always an active process of creation; instead value is embedded and formed in the highly dynamic and multi-contextual reality and life of the customer. This leads to a need to look beyond the current line of visibility where visible customer-company interactions are focused to the invisible and mental life of the customer. From this follows a need to extend the temporal scope, from exchange and use even further to accumulated experiences in the customer´s life. The aim of this paper is to explore value formation from a customer dominant logic perspective. This is done in three steps: first, value formation is contrasted to earlier views on the company’s role in value creation by using a broad ontologically driven framework discussing what, how, when, where and who. Next, implications of the proposed characteristics of value formation compared to earlier approaches are put forward. Finally, some tentative suggestions of how this perspective would affect marketing in service companies are presented. As value formation in a CDL perspective has a different focus and scope than earlier views on value it leads to posing questions about the customer that reveals earlier hidden aspects of the role of a service for the customer. This insight might be used in service development and innovation.

Direct detection of atmospheric particle formation using the Neutral cluster and Air Ion Spectrometer

Aerosol particles play an important role in the Earth s atmosphere and in the climate system: they scatter and absorb solar radiation, facilitate chemical processes, and serve as seeds for cloud formation. Secondary new particle formation (NPF) is a globally important source of these particles. Currently, the mechanisms of particle formation and the vapors participating in this process are, however, not truly understood. In order to fully explain atmospheric NPF and subsequent growth, we need to measure directly the very initial steps of the formation processes. This thesis investigates the possibility to study atmospheric particle formation using a recently developed Neutral cluster and Air Ion Spectrometer (NAIS). First, the NAIS was calibrated and intercompared, and found to be in good agreement with the reference instruments both in the laboratory and in the field. It was concluded that NAIS can be reliably used to measure small atmospheric ions and particles directly at the sizes where NPF begins. Second, several NAIS systems were deployed simultaneously at 12 European measurement sites to quantify the spatial and temporal distribution of particle formation events. The sites represented a variety of geographical and atmospheric conditions. The NPF events were detected using NAIS systems at all of the sites during the year-long measurement period. Various particle formation characteristics, such as formation and growth rates, were used as indicators of the relevant processes and participating compounds in the initial formation. In a case of parallel ion and neutral cluster measurements, we also estimated the relative contribution of ion-induced and neutral nucleation to the total particle formation. At most sites, the particle growth rate increased with the increasing particle size indicating that different condensing vapors are participating in the growth of different-sized particles. The results suggest that, in addition to sulfuric acid, organic vapors contribute to the initial steps of NPF and to the subsequent growth, not just later steps of the particle growth. As a significant new result, we found out that the total particle formation rate varied much more between the different sites than the formation rate of charged particles. The results infer that the ion-induced nucleation has a minor contribution to particle formation in the boundary layer in most of the environments. These results give tools to better quantify the aerosol source provided by secondary NPF in various environments. The particle formation characteristics determined in this thesis can be used in global models to assess NPF s climatic effects.