Ultrasound-assisted surface engineering of pharmaceutical powders

Effective processing of powdered particles can facilitate powder handling and result in better drug product performance, which is of great importance in the pharmaceutical industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted method for particle surface modification and thin-coating of pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent. By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge transfer and improved the flowability of highly cohesive powder. To determine the coating efficiency of the technique, the bioactive molecule β-galactosidase was layered onto the surface of powdered lactose particles. Enzyme-treated materials were analysed by assaying the quantity of the reaction product generated during enzymatic cleavage of the milk sugar. A near-linear increase in the thickness of the drug layer was obtained during progressive treatment. Using the enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar could be used to improve utilization of lactose-containing formulations for populations suffering from severe lactose intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid dosage forms was shown. The carrier particles coated with API gave rise to uniform distribution of the drug within the powder. The mixture remained homogeneous during further tabletting, whereas the reference physical powder mixture was subject to segregation. In conclusion, ultrasound-assisted surface engineering of pharmaceutical powders can be effective technology for improving formulation and performance of solid dosage forms such as dry powder inhalers (DPI) and direct compression products.

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

The Art of Sympathy : Forms of Moral and Emotional Persuasion in Fiction

"The Art of Sympathy: Forms of Moral and Emotional Persuasion" in Fiction is an interdisciplinary study that looks closely at the ways that stories evoke sympathy, and the significance of this emotion for the development of moral attitudes and awareness. By linking readers' emotional responses to fiction with the potential impact of such responses on "the moral imagination," the study builds on empirical research conducted by literary scholars and psychologists into the emotional effects of reading fiction, as well as social psychological research into the connections between empathy/sympathy and moral development. I first investigate the dynamics of readers beliefs regarding characters in fictional narratives, and the nature of the emotions that they may experience as a result of those beliefs. The analysis demonstrates that there are important similarities between real emotions and emotions generated by fiction. Recognizing these similarities, I claim, can help us to conceptualize the nature of sympathetic responses to fictional characters. Building on these assertions, I then draw on research from social psychology and philosophy to develop a comprehensive definition of sympathy and to clarify the ways in which sympathy operates, both in people s daily lives and in readers sympathetic responses to fictional characters. Having established this definition and delineated its practical implications, I then examine how particular stories, through a variety of narrative techniques, persuade readers to feel sympathy for characters who are unsympathetic in certain ways. In order to verify my claims about the impact of these stories on readers emotions, I also review the results of tests that I conducted with nearly 200 adolescent readers. Through these tests, which were constructed and scored according to methods prevalent in social psychological research, it was determined that a majority of readers felt sympathy for the protagonists in two of the stories included in the study. These results were combined with data from an additional test, a standard measure of empathy and sympathy in the field of social psychology. The cross-tabulation of these results suggests that there was not a strong connection between readers responses and their general tendencies to feel sympathy for others. This finding would appear to support my hypotheses regarding the sympathetic persuasiveness of the stories in question. In light of these results, finally, I consider the potential contribution that fiction can make to adolescent emotional and moral development and the implications of that potential for future language arts curricula in the schools. In particular, I suggest the pedagogical importance of providing adolescents with opportunities to engage with the lives of fictional characters, and especially to experience feelings of sympathy for individuals towards whom they ordinarily might feel aversion.

Vikuroivia vilkaisuja : Ruumis, sukupuoli, seksuaalisuus ja visuaalisen kulttuurin tutkimus

The PhD dissertation "Bucking Glances: On Body, Gender, Sexuality and Visual Culture Research" consists of theoretical introduction and five articles published between 2002-2005. The articles analyze the position of visual representations in the processes of knowledge production on acceptable genders, bodies, and sexualities in contemporary Wes¬tern societies. The research material is heterogeneous, consisting of representations of contemporary art, advertisements, and fashion images. The ideological starting point of the PhD dissertation is the politics of the gaze and the methods used to expose this are the concepts of oppositional gaze, close reading, and resisting reading. The study situates visual representations in dialogue with the concepts of the grotesque and androgyny, as well as with queer-theory and theories of the gaze. The research challenges normative meanings of visual representations and opens up space for more non-conventional readings attached to femininity and masculinity. The visual material is read as troubling the prevailing heteronormative gender system. The dissertation also indicates how visual culture research utilizing the approach of queer theory can be fruitful in opposing and re-visioning changes in the repressive gender system. The article "A Heroic Male and A Beautiful Woman. Teemu Mäki, Orlan and the Ambivalence of the Grotesque Body" problematizes the concept of heroic masculinity through the analysis of the Finnish artist Teemu Mäki's masochistic performance The Good Friday (1989). It also analyzes cosmetic surgery, undertaken by the French artist Orlan, as a cultural tool in constructing and visualizing the contemporary, com¬mercial ideals of female beauty. The article "Boys Will Be Girls Will Be Boys Will Be Girls. The Ambivalence of Androgyny in Calvin Klein' Advertisements" is a close reading of the Calvin Klein perfume advertisement One (1998) in reference to the concept of androgyny. The critical point of the article is that androgynous male bodies allow the extension of the categorical boundaries of masculinity and homosexuality, whereas representations of androgynous women feed into the prevailing stereotypes of femininity, namely the fear of fat. The article "See-through Closet: Female Androgyny in the 1990s Fashion Images, New Woman and Lesbian Chic" analyzes the late 1990s fashion advertisements through the concept of female androgyny. The article argues that the figures of the masculine female androgynes in the late 1990s fashion magazines do not problematize the dichotomous gender binary. The women do not pass as men but produce a variation of heterosexual desirability. At the same time, the representations open up space for lesbian gazing and desiring. The article "Why are there no lesbian advertisements?" addresses the issue of femme gaze and desire in relation to heterosexual fashion advertisements from the British edition of the mainstream fashion magazine Vogue. The article considers possibilities for resistant femme visibility, identification, and desire. The article "Woman, Food, Home. Pirjetta Brander's and Heidi Romo's Works as Bucking Representations of Femininity" analyses the production and queering of heteronormative femininity and family through the analysis of art works. The article discusses how the term queer has been translated into Finnish. The article also introduces a new translation for the term queer: the noun vikuuri, i.e. faulty form and the verb vikuroida, i.e. to buck. In Finnish, the term vikuuri is the vernacular or broken form of the term figure, i.e. figuuri. Vikuuri represents all forms situated outside the norm and the normative.

Post-industrial Intervention : An Activity-Theoretical Expedition Tracing the Proximal Development of Forms of Conducting Interventions

Ei saatavilla

Preparation of Industrially Important Hydroxy Acids and Diacids from 2,2-Disubstituted Propane-1,3-Diols and Linear Primary Diols by Green Chemistry Methods

Environmentally benign and economical methods for the preparation of industrially important hydroxy acids and diacids were developed. The carboxylic acids, used in polyesters, alkyd resins, and polyamides, were obtained by the oxidation of the corresponding alcohols with hydrogen peroxide or air catalyzed by sodium tungstate or supported noble metals. These oxidations were carried out using water as a solvent. The alcohols are also a useful alternative to the conventional reactants, hydroxyaldehydes and cycloalkanes. The oxidation of 2,2-disubstituted propane-1,3-diols with hydrogen peroxide catalyzed by sodium tungstate afforded 2,2-disubstituted 3-hydroxypropanoic acids and 1,1-disubstituted ethane-1,2-diols as products. A computational study of the Baeyer-Villiger rearrangement of the intermediate 2,2-disubstituted 3-hydroxypropanals gave in-depth data of the mechanism of the reaction. Linear primary diols having chain length of at least six carbons were easily oxidized with hydrogen peroxide to linear dicarboxylic acids catalyzed by sodium tungstate. The Pt/C catalyzed air oxidation of 2,2-disubstituted propane-1,3-diols and linear primary diols afforded the highest yield of the corresponding hydroxy acids, while the Pt, Bi/C catalyzed oxidation of the diols afforded the highest yield of the corresponding diacids. The mechanism of the promoted oxidation was best described by the ensemble effect, and by the formation of a complex of the hydroxy and the carboxy groups of the hydroxy acids with bismuth atoms. The Pt, Bi/C catalyzed air oxidation of 2-substituted 2-hydroxymethylpropane-1,3-diols gave 2-substituted malonic acids by the decarboxylation of the corresponding triacids. Activated carbon was the best support and bismuth the most efficient promoter in the air oxidation of 2,2-dialkylpropane-1,3-diols to diacids. In oxidations carried out in organic solvents barium sulfate could be a valuable alternative to activated carbon as a non-flammable support. In the Pt/C catalyzed air oxidation of 2,2-disubstituted propane-1,3-diols to 2,2-disubstituted 3-hydroxypropanoic acids the small size of the 2-substituents enhanced the rate of the oxidation. When the potential of platinum of the catalyst was not controlled, the highest yield of the diacids in the Pt, Bi/C catalyzed air oxidation of 2,2-dialkylpropane-1,3-diols was obtained in the regime of mass transfer. The most favorable pH of the reaction mixture of the promoted oxidation was 10. The reaction temperature of 40°C prevented the decarboxylation of the diacids.

Composition operators on vector-valued BMOA and related function spaces

A composition operator is a linear operator between spaces of analytic or harmonic functions on the unit disk, which precomposes a function with a fixed self-map of the disk. A fundamental problem is to relate properties of a composition operator to the function-theoretic properties of the self-map. During the recent decades these operators have been very actively studied in connection with various function spaces. The study of composition operators lies in the intersection of two central fields of mathematical analysis; function theory and operator theory. This thesis consists of four research articles and an overview. In the first three articles the weak compactness of composition operators is studied on certain vector-valued function spaces. A vector-valued function takes its values in some complex Banach space. In the first and third article sufficient conditions are given for a composition operator to be weakly compact on different versions of vector-valued BMOA spaces. In the second article characterizations are given for the weak compactness of a composition operator on harmonic Hardy spaces and spaces of Cauchy transforms, provided the functions take values in a reflexive Banach space. Composition operators are also considered on certain weak versions of the above function spaces. In addition, the relationship of different vector-valued function spaces is analyzed. In the fourth article weighted composition operators are studied on the scalar-valued BMOA space and its subspace VMOA. A weighted composition operator is obtained by first applying a composition operator and then a pointwise multiplier. A complete characterization is given for the boundedness and compactness of a weighted composition operator on BMOA and VMOA. Moreover, the essential norm of a weighted composition operator on VMOA is estimated. These results generalize many previously known results about composition operators and pointwise multipliers on these spaces.

On linear order and computation : The expressiveness of interactive computations on linear orders and computations indexed by ordinals

We solve the Dynamic Ehrenfeucht-Fra\"iss\'e Game on linear orders for both players, yielding a normal form for quantifier-rank equivalence classes of linear orders in first-order logic, infinitary logic, and generalized-infinitary logics with linearly ordered clocks. We show that Scott Sentences can be manipulated quickly, classified into local information, and consistency can be decided effectively in the length of the Scott Sentence. We describe a finite set of linked automata moving continuously on a linear order. Running them on ordinals, we compute the ordinal truth predicate and compute truth in the constructible universe of set-theory. Among the corollaries are a study of semi-models as efficient database of both model-theoretic and formulaic information, and a new proof of the atomicity of the Boolean algebra of sentences consistent with the theory of linear order -- i.e., that the finitely axiomatized theories of linear order are dense.

Locality and order-invariant logics

Malli on logiikassa käytetty abstraktio monille matemaattisille objekteille. Esimerkiksi verkot, ryhmät ja metriset avaruudet ovat malleja. Äärellisten mallien teoria on logiikan osa-alue, jossa tarkastellaan logiikkojen, formaalien kielten, ilmaisuvoimaa malleissa, joiden alkioiden lukumäärä on äärellinen. Rajoittuminen äärellisiin malleihin mahdollistaa tulosten soveltamisen teoreettisessa tietojenkäsittelytieteessä, jonka näkökulmasta logiikan kaavoja voidaan ajatella ohjelmina ja äärellisiä malleja niiden syötteinä. Lokaalisuus tarkoittaa logiikan kyvyttömyyttä erottaa toisistaan malleja, joiden paikalliset piirteet vastaavat toisiaan. Väitöskirjassa tarkastellaan useita lokaalisuuden muotoja ja niiden säilymistä logiikkoja yhdistellessä. Kehitettyjä työkaluja apuna käyttäen osoitetaan, että Gaifman- ja Hanf-lokaalisuudeksi kutsuttujen varianttien välissä on lokaalisuuskäsitteiden hierarkia, jonka eri tasot voidaan erottaa toisistaan kasvavaa dimensiota olevissa hiloissa. Toisaalta osoitetaan, että lokaalisuuskäsitteet eivät eroa toisistaan, kun rajoitutaan tarkastelemaan äärellisiä puita. Järjestysinvariantit logiikat ovat kieliä, joissa on käytössä sisäänrakennettu järjestysrelaatio, mutta sitä on käytettävä siten, etteivät kaavojen ilmaisemat asiat riipu valitusta järjestyksestä. Määritelmää voi motivoida tietojenkäsittelyn näkökulmasta: vaikka ohjelman syötteen tietojen järjestyksellä ei olisi odotetun tuloksen kannalta merkitystä, on syöte tietokoneen muistissa aina jossakin järjestyksessä, jota ohjelma voi laskennassaan hyödyntää. Väitöskirjassa tutkitaan minkälaisia lokaalisuuden muotoja järjestysinvariantit ensimmäisen kertaluvun predikaattilogiikan laajennukset yksipaikkaisilla kvanttoreilla voivat toteuttaa. Tuloksia sovelletaan tarkastelemalla, milloin sisäänrakennettu järjestys lisää logiikan ilmaisuvoimaa äärellisissä puissa.

On the Geometry of Infinite-Dimensional Grassmannian Manifolds and Gauge Theory

This PhD Thesis is about certain infinite-dimensional Grassmannian manifolds that arise naturally in geometry, representation theory and mathematical physics. From the physics point of view one encounters these infinite-dimensional manifolds when trying to understand the second quantization of fermions. The many particle Hilbert space of the second quantized fermions is called the fermionic Fock space. A typical element of the fermionic Fock space can be thought to be a linear combination of the configurations m particles and n anti-particles . Geometrically the fermionic Fock space can be constructed as holomorphic sections of a certain (dual)determinant line bundle lying over the so called restricted Grassmannian manifold, which is a typical example of an infinite-dimensional Grassmannian manifold one encounters in QFT. The construction should be compared with its well-known finite-dimensional analogue, where one realizes an exterior power of a finite-dimensional vector space as the space of holomorphic sections of a determinant line bundle lying over a finite-dimensional Grassmannian manifold. The connection with infinite-dimensional representation theory stems from the fact that the restricted Grassmannian manifold is an infinite-dimensional homogeneous (Kähler) manifold, i.e. it is of the form G/H where G is a certain infinite-dimensional Lie group and H its subgroup. A central extension of G acts on the total space of the dual determinant line bundle and also on the space its holomorphic sections; thus G admits a (projective) representation on the fermionic Fock space. This construction also induces the so called basic representation for loop groups (of compact groups), which in turn are vitally important in string theory / conformal field theory. The Thesis consists of three chapters: the first chapter is an introduction to the backround material and the other two chapters are individually written research articles. The first article deals in a new way with the well-known question in Yang-Mills theory, when can one lift the action of the gauge transformation group on the space of connection one forms to the total space of the Fock bundle in a compatible way with the second quantized Dirac operator. In general there is an obstruction to this (called the Mickelsson-Faddeev anomaly) and various geometric interpretations for this anomaly, using such things as group extensions and bundle gerbes, have been given earlier. In this work we give a new geometric interpretation for the Faddeev-Mickelsson anomaly in terms of differentiable gerbes (certain sheaves of categories) and central extensions of Lie groupoids. The second research article deals with the question how to define a Dirac-like operator on the restricted Grassmannian manifold, which is an infinite-dimensional space and hence not in the landscape of standard Dirac operator theory. The construction relies heavily on infinite-dimensional representation theory and one of the most technically demanding challenges is to be able to introduce proper normal orderings for certain infinite sums of operators in such a way that all divergences will disappear and the infinite sum will make sense as a well-defined operator acting on a suitable Hilbert space of spinors. This research article was motivated by a more extensive ongoing project to construct twisted K-theory classes in Yang-Mills theory via a Dirac-like operator on the restricted Grassmannian manifold.

The high- and low-activity forms of human plasma phospholipid transfer protein (PLTP)

Plasma phospholipid transfer protein (PLTP) plays a crucial role in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). It mediates the generation of pre-beta-HDL particles, enhances the cholesterol efflux from peripheral cells to pre-beta-HDL, and metabolically maintains the plasma HDL levels by facilitating the transfer of post-lipolytic surface remnants of triglyceride-rich lipoproteins to HDL. In addition to the antiatherogenic properties, recent findings indicate that PLTP has also proatherogenic characteristics, and that these opposite characteristics of PLTP are dependent on the site of PLTP expression and action. In human plasma, PLTP exists in a high-activity (HA-PLTP) and a low-activity form (LA-PLTP), which are associated with macromolecular complexes of different size and composition. The aims of this thesis were to isolate the two PLTP forms from human plasma, to characterize the molecular complexes in which the HA- and LA-PLTP reside, and to study the interactions of the PLTP forms with apolipoproteins (apo) and the ability of apolipoproteins to regulate PLTP activity. In addition, we aimed to study the distribution of the two PLTP forms in a Finnish population sample as well as to find possible regulatory factors for PLTP by investigating the influence of lipid and glucose metabolism on the balance between the HA- and LA-PLTP. For these purposes, an enzyme-linked immunosorbent assay (ELISA) capable of determining the serum total PLTP concentration and quantitating the two PLTP forms separately was developed. In this thesis, it was demonstrated that the HA-PLTP isolated from human plasma copurified with apoE, whereas the LA-PLTP formed a complex with apoA-I. The separation of these two PLTP forms was carried out by a dextran sulfate (DxSO4)-CaCl2 precipitation of plasma samples before the mass determination. A similar immunoreactivity of the two PLTP forms in the ELISA could be reached after a partial sample denaturation by SDS. Among normolipidemic Finnish individuals, the mean PLTP mass was 6.6 +/- 1.5 mg/l and the mean PLTP activity 6.6 +/- 1.7 umol/ml/h. Of the serum PLTP concentration, almost 50% represented HA-PLTP. The results indicate that plasma HDL levels could regulate PLTP concentration, while PLTP activity could be regulated by plasma triglyceride-rich very low-density lipoprotein (VLDL) concentration. Furthermore, new evidence is presented that PLTP could also play a role in glucose metabolism. Finally, both PLTP forms were found to interact with apoA-I, apoA-IV, and apoE. In addition, both apoE and apoA-IV, but not apoA-I, were capable of activating the LA-PLTP. These findings suggest that the distribution of the HA- and LA-PLTP in human plasma is subject to dynamic regulation by apolipoproteins.