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.

Characterization of Ion-Exchange Fibers for Controlled Drug Delivery

Increasing attention has been focused on methods that deliver pharmacologically active compounds (e.g. drugs, peptides and proteins) in a controlled fashion, so that constant, sustained, site-specific or pulsatile action can be attained. Ion-exchange resins have been widely studied in medical and pharmaceutical applications, including controlled drug delivery, leading to commercialisation of some resin based formulations. Ion-exchangers provide an efficient means to adjust and control drug delivery, as the electrostatic interactions enable precise control of the ion-exchange process and, thus, a more uniform and accurate control of drug release compared to systems that are based only on physical interactions. Unlike the resins, only few studies have been reported on ion-exchange fibers in drug delivery. However, the ion-exchange fibers have many advantageous properties compared to the conventional ion-exchange resins, such as more efficient compound loading into and release from the ion-exchanger, easier incorporation of drug-sized compounds, enhanced control of the ion-exchange process, better mechanical, chemical and thermal stability, and good formulation properties, which make the fibers attractive materials for controlled drug delivery systems. In this study, the factors affecting the nature and strength of the binding/loading of drug-sized model compounds into the ion-exchange fibers was evaluated comprehensively and, moreover, the controllability of subsequent drug release/delivery from the fibers was assessed by modifying the conditions of external solutions. Also the feasibility of ion-exchange fibers for simultaneous delivery of two drugs in combination was studied by dual loading. Donnan theory and theoretical modelling were applied to gain mechanistic understanding on these factors. The experimental results imply that incorporation of model compounds into the ion-exchange fibers was attained mainly as a result of ionic bonding, with additional contribution of non-specific interactions. Increasing the ion-exchange capacity of the fiber or decreasing the valence of loaded compounds increased the molar loading, while more efficient release of the compounds was observed consistently at conditions where the valence or concentration of the extracting counter-ion was increased. Donnan theory was capable of fully interpreting the ion-exchange equilibria and the theoretical modelling supported precisely the experimental observations. The physico-chemical characteristics (lipophilicity, hydrogen bonding ability) of the model compounds and the framework of the fibrous ion-exchanger influenced the affinity of the drugs towards the fibers and may, thus, affect both drug loading and release. It was concluded that precisely controlled drug delivery may be tailored for each compound, in particularly, by choosing a suitable ion-exchange fiber and optimizing the delivery system to take into account the external conditions, also when delivering two drugs simultaneously.

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.

Thin-Layer Chromatography with Ultraviolet and Mass Spectrometric Detection: From Preparative-Layer to Miniaturized Ultra-Thin-Layer Technique

The present challenge in drug discovery is to synthesize new compounds efficiently in minimal time. The trend is towards carefully designed and well-characterized compound libraries because fast and effective synthesis methods easily produce thousands of new compounds. The need for rapid and reliable analysis methods is increased at the same time. Quality assessment, including the identification and purity tests, is highly important since false (negative or positive) results, for instance in tests of biological activity or determination of early-ADME parameters in vitro (the pharmacokinetic study of drug absorption, distribution, metabolism, and excretion), must be avoided. This thesis summarizes the principles of classical planar chromatographic separation combined with ultraviolet (UV) and mass spectrometric (MS) detection, and introduces powerful, rapid, easy, low-cost, and alternative tools and techniques for qualitative and quantitative analysis of small drug or drug-like molecules. High performance thin-layer chromatography (HPTLC) was introduced and evaluated for fast semi-quantitative assessment of the purity of synthesis target compounds. HPTLC methods were compared with the liquid chromatography (LC) methods. Electrospray ionization mass spectrometry (ESI MS) and atmospheric pressure matrix-assisted laser desorption/ionization MS (AP MALDI MS) were used to identify and confirm the product zones on the plate. AP MALDI MS was rapid, and easy to carry out directly on the plate without scraping. The PLC method was used to isolate target compounds from crude synthesized products and purify them for bioactivity and preliminary ADME tests. Ultra-thin-layer chromatography (UTLC) with AP MALDI MS and desorption electrospray ionization mass spectrometry (DESI MS) was introduced and studied for the first time. Because of the thinner adsorbent layer, the monolithic UTLC plate provided 10 100 times better sensitivity in MALDI analysis than did HPTLC plates. The limits of detection (LODs) down to low picomole range were demonstrated for UTLC AP MALDI and UTLC DESI MS. In a comparison of AP and vacuum MALDI MS detection for UTLC plates, desorption from the irregular surface of the plates with the combination of an external AP MALDI ion source and an ion trap instrument provided clearly less variation in mass accuracy than the vacuum MALDI time-of-flight (TOF) instrument. The performance of the two-dimensional (2D) UTLC separation with AP MALDI MS method was studied for the first time. The influence of the urine matrix on the separation and the repeatability was evaluated with benzodiazepines as model substances in human urine. The applicability of 2D UTLC AP MALDI MS was demonstrated in the detection of metabolites in an authentic urine sample.

Shooting from the Wild Zone : A Study of the Chicana Art Photographers Laura Aguilar, Celia Álvarez Muñoz, Delilah Montoya, and Kathy Vargas

The dissertation analyzes and elaborates upon the changing map of U.S. ethno-racial formation from the vantage point of North American Studies, multi-disciplinary cultural studies, and the criticism of visual culture. The focus is on four contemporary Mexican American (Chicana) women photographers, whose art production is discussed, on the one hand, in the context of the Euro-American history of photographic genres and, on the other hand, in the context of so-called decolonizing cultural and academic discourses produced by Mexican Americans themselves. The manuscript consists of two parts. Part I outlines the theoretical and methodological domain of the study, positioning it in the interstices of American studies, European postmodern criticism, postcolonial feminist theory, and the theories of visual culture, particularly of art photography. In addition, the main issues and paradigms of Chicano Studies (Mexican American ethnic studies) are introduced. Part II consists of seven essays, each of which discusses rather independently a particular photographic work or a series of photographs, formulating and defending arguments about their meaning, position in the history of photographic genres, and their cultural and socio-political significance. The study closes with a discussion about ethno-racial identity formation and the role of Chicana photography therein - in embodying and reproducing new subjectivities, alternative categories of knowledge, and open ended historical narratives. It is argued that, symbolically, the "Wild Zone" of gendered and race-specific knowledge becomes associated with the body of the mother, a recurrent image in Chicana art works under discussion. Embedded in this image, the construction of an alternative notion of a family thus articulates the parameters of a matrifocal ethno-racial community unified by the proliferation of differences rather than by conformities typical of nationalistic ideologies. While focusing on art photography, the study as a whole simultaneously constructs, from a European vantage point, a "thick" description of Mexican American history, identities, communities, cultural practices, and self-representations about which very little is known in Finland.

Disabled Revolutionary War Veterans and the Construction of Disability in the Early United States, c. 1776-1840

This thesis addresses the following broad research question: what did it mean to be a disabled Revolutionary War veteran in the early United States during the period from 1776 to roughly 1840? The study approaches the question from two angles: a state-centred one and an experiential one. In both cases, the theoretical framework employed comes from disability studies. Consequently, disability is regarded as a sociocultural phenomenon rather than a medical condition. The state-centred dimension of the study explores the meaning of disability and disabled veterans to the early American state through an examination of the major military pension laws of the period. An analysis of this legislation, particularly the invalid pension acts of 1793 and 1806, indicates that the early United States represents a key period in the development of the modern disability category. The experiential approach, in contrast, shifts the focus of attention away from the state towards the lived experiences of disabled veterans. It seeks to address the issue of whether or not the disabilities of disabled veterans had any significant material impact on their everyday lives. It does this through a comparison of the situation of 153 disabled veterans with that of an equivalent number of nondisabled veterans. The former group received invalid pensions while the latter did not. In comparing the material conditions of disabled and nondisabled veterans, a wide range of primary sources from military records to memoirs and letters are used. The most important sources in this regard are the pension application papers submitted by veterans in the early nineteenth century. These provide us with a unique insight into the everyday lives of veterans. Looking at the issue of experience through the window of the pension files reveals that there was not much difference in the broad contours of disabled and nondisabled veteran life. This finding has implications for the theorisation of disability that are highlighted and discussed in the thesis. The main themes covered in this study are: the wartime experiences of injured American soldiers, the military pension establishment of the early United States and the legal construction of disability, and the post-war working and family lives of disabled veterans. Keywords: disability, early America, veterans, military pensions, disabled people, Revolutionary War, United States, disability theory.

Governance Matters : China's Developing Western Region with a Focus on Qinghai Province

This study is about governance in contemporary China. The focus is on Qinghai Province, one of the twelve provincial-level units included in the western region development strategy launched in 2000 by the government of China. Qinghai, the subject of the case study, is not a very well-known province. Hence, this study is significant, because it provides new knowledge about the province of Qinghai, its governance and diverse challenges, and deepens one s overall knowledge regarding China. Qinghai province is one of the slowest developing regions of China. My research problem is to analyze to what extent provincial development correlates with the quality of governance. The central concept of this research is good governance. This dissertation employs a grounded theory approach while the theoretical framework of this study is built on the Three World s approach of analyzing the three main themes, namely, the environment, economic development, and cultural diversity, and to support the empirical work. Philosophical issues in the humanities and contemporary theories of governance are brought in to provide deeper understanding of governance, and to understand to what extent and how characteristics of good governance (derived from the Western canon) are combined with Chinese tradition. A qualitative research method is chosen to provide a deeper understanding of the contemporary challenges of Qinghai (and China) and to provide some insight into the role and impact of governance on provincial development. It also focuses on the Tibetan ethnic group in order to develop as full an understanding as possible about the province. The challenges faced by Qinghai concern in particular its environment, economic development, and cultural diversity, all of which are closely interrelated. The findings demonstrate that Qinghai Province is not a powerful actor, because it has weak communications with the central government and weak collaboration with its stakeholders and civil society. How Qinghai s provincial government conducts provincial development remains a key question in terms of shaping the province s future. The question is how is Qinghai s government best able to govern in a way that is beneficial for the people. This study demonstrates that this is a significant question that challenges governance everywhere, and particularly in China given the absence of democracy. This study provides the ingredients for reflection as to how provincial government can be motivated to choose to govern in a sustainable way, instead of leaning on growth factors with too little consideration about the impact on the environment and the people.

Growth curves with time-dependent explanatory variables

A class of growth models incorporating time-dependent factors and stochastic perturbations are introduced. The proposed model includes the existing growth models used in fisheries as special cases. Particular attention is given to growth of a population (in average weight or length) from which observations are taken randomly each time and the analysis of tag-recapture data. Two real data sets are used for illustration: (a) to estimate the seasonal effect and population density effect on growth of farmed prawn (Penaeus monodon) from weight data and (b) to assess the effect of tagging on growth of barramundi (Lates calcarifer)

Les formes d’adresse dans un corpus de films français et leur traduction en finnois

The use of forms of address in French films and their Finnish translations The use of forms of address constitutes an integral part of speakers’ communicative competence. In fact, they are not only used to assign to whom the speech is addressed, but also to construct the relationship between speakers. However, the choice of a suitable form is not necessarily evident in modern, pluralistic society. By the notion form of address, I refer to pronouns of address (tu vs. vous) and different nouns of address like names, titles (Monsieur, Madame, Mademoiselle), kinship terms, occupational terms, terms of endearment and insults. The purpose of the present thesis is, first, to study the semantic and pragmatic values of forms of address in dialogues of modern French films, and, second, their translation in Finnish subtitles. It is evident that film language is not spontaneous, but only a representation of authentic speech, and that subtitles are a written version of the original spoken language. Consequently, this thesis studies spoken fictive dialogues and their written translations. The methods applied in the study are the Interactional and Pragmatic Approach as well as Translatology. The role of forms of address in an interpersonal relationship is studied with dimensions of distance and power (Brown and Gilman 1960, Kerbrat-Orecchioni 1992), whereas the pragmatic dimension permits studying in particular the use of forms of address in speech acts (Kerbrat-Orecchioni 2001). The translation strategies are studied with the help of Venuti’s (1995) notions of foreignizing and domesticating strategies. The results of the thesis suggest that the pronoun use in the studied films is usually reciprocal. However, the relations of power have not disappeared, but are expressed in a more discrete manner with nouns of address (for instance vous + Docteur vs. vous + Anita). The use of the pronoun of address vous seems still to be common, but increased intimacy is expressed by accompanying familiar nouns of address like first names. The nominal forms of address accompany different speech acts, but not in a systematic manner. In a dialogue they appear usually in the first speech act, and more rarely in the response, but not in both. In addition, they have an important role in the mechanics of conversation. The translators here face multiple demands, and their translations seem mostly to be a compromise between foreignizing and domesticating strategies.

La coordination et les phrases juxtaposées en français

Coordination and juxtaposed sentences The object of this study is the examination of the relations between juxtaposed clauses in contemporary French. The matter in question is sentences which are composed of several clauses adjoined without a conjunction or other connector, as in: Je détournai les yeux, mon c ur se mit à battre. The aim of the study is to determine, which quality is the relation in these sentences and, on the other hand, what is the part of the coordination there. Furthermore, what is this relation of coordination, which, according to some grammars, manifests through a conjunction of coordination, but which, according to some others is marked in juxtaposed sentences through different features. The study is based on a corpus of written French from literary and journalistic text sources. Syntactic, semantic and textual properties in the clauses are discussed. The analysis points to differences so, it has been noted, in each case, if one of the clauses is affirmative and the other negative and if in the second clause, the subject has not been repeated. Also, an analysis has been made on the ground of the tense, mode, phrase structure type, and thematic structure, taking into account, in each case, if the clauses are identical or different. Punctuation has been one of the properties considered. The final aim has been to eliminate gradually, based on the partition of properties, subordinate sentences, so that only the hard core of coordinate sentences remains. In this way, the coordination could be defined similarly as the phoneme is defined as a group of distinctive features. The quantitative analyses have led to the conclusion that the sentences which, from a semantic point of view, are interpreted as coordinating, contain the least of these differences, while the sentences which can be considered as subordinating present the most of these differences. The conditions of coordination are, in that sense, hierarchical, so that the syntactic constraints have to make room for semantic, textual and cognitive factors. It is interesting to notice that everyone has the ability to produce correct coordinating structures and recognize incorrect coordinating structures. This can be explained by the human ability to categorize which has been widely researched in the semantic of prototype. The study suggests that coordination and subordination could be considered as prototypical cognitive categories based on different linguistic and pragmatic features.

Problems of Proto-Slavic Historical Nominal Morphology : On the Basis of Old Church Slavic

In this study I offer a diachronic solution for a number of difficult inflectional endings in Old Church Slavic nominal declensions. In this context I address the perhaps most disputed and the most important question of the Slavic nominal inflectional morphology: whether there was in Proto-Slavic an Auslautgesetz (ALG), a law of final syllables, that narrowed the Proto-Indo-European vowel */o/ to */u/ in closed word-final syllables. In addition, the work contains an exhaustive morphological classification of the nouns and adjectives that occur in canonical Old Church Slavic. I argue that Proto-Indo-European */o/ became Proto-Slavic */u/ before word-final */s/ and */N/. This conclusion is based on the impossibility of finding credible analogical (as opposed to phonological) explanations for the forms supporting the ALG hypothesis, and on the survival of the neuter gender in Slavic. It is not likely that the */o/-stem nominative singular ending */-u/ was borrowed from the accusative singular, because the latter would have been the only paradigmatic form with the stem vowel */-u-/. It is equally unlikely that the ending */-u/ was borrowed from the */u/-stems, because the latter constituted a moribund class. The usually stated motivation for such an analogical borrowing, i.e. a need to prevent the merger of */o/-stem masculines with neuters of the same class, is not tenable. Extra-Slavic, as well as intra-Slavic evidence suggests that phonologically-triggered mergers between two semantically opaque genders do not tend to be prevented, but rather that such mergers lead to the loss of the gender opposition in question. On the other hand, if */-os/ had not become */-us/, most nouns and, most importantly, all adjectives and pronouns would have lost the formal distinction between masculines and neuters. This would have necessarily resulted in the loss of the neuter gender. A new explanation is given for the most apparent piece of evidence against the ALG hypothesis, the nominative-accusative singular of the */es/-stem neuters, e.g. nebo 'sky'. I argue that it arose in late Proto-Slavic dialects, replacing regular nebe, under the influence of the */o/- and */yo/-stems where a correlation had emerged between a hard root-final consonant and the termination -o, on the one hand, and a soft root-final consonant and the termination -e, on the other.

Vyra enie obob čёnno-ličnogo značenija v russkom jazyke

Expressing generalized-personal meaning in Russian Based on data from Russian, this doctoral dissertation examines generalized-personal meaning that is, generic expressions referring to all human beings, people in general, each or any person (e.g. S vozrastom načinae cenit prostye ve či With age you start to appreciate simple things ). The study shares its basic theoretical orientation with functional approaches going from meaning to form . The objective of the thesis is to determine and describe the various linguistic means which can be used by the speaker to express generalized-personal meaning. The main material of the study consists of 2,000 examples collected from modern Russian literature, newspapers, and magazines. The linguistic means of expressing generalized-personal meaning are divided into three main classes. Morphological and lexico-grammatical means (22% of the material) include the use of personal pronouns and personal verbal endings. In Russian, all personal forms except the 3rd person singular can be used in a generalized-personal meaning. Lexical means (14% of the material) involve, above all, pronouns like vse all , ka dyj everyone , nikto no one , as well as the nouns čelovek man and ljudi people . In emotional speech, generalized-personal meaning can also be conveyed lexically by using utterances like da e idiot znaet even an idiot knows . In rhetorical questions the pronoun kto who can appear in this meaning (cf. Kto ne ljubit moro enoe?! Who doesn t like ice cream?! ). The third main class, syntactic means (64% of the material), consists of constructions in which the generic person is not expressed at the surface level. This class mainly includes two-component structures in which the infinitive relates to a modal predicative adverb (e.g. mo no can, be allowed to , nado must ), modal verb (e.g. stoit be worth(while) , sleduet must, be obliged to ), or predicative adverb ending in -о (e.g. trudno it is hard to , neprilično is not appropriate ). Other syntactic means are: one-component infinitive structures, so-called embedded structures, structures with a processual noun, passive constructions, and gerund constructions. The different forms of expression available in Russian are not interchangeable in all contexts. Even if a given context tolerates the substitution of one construction for another, the two expressions are never entirely synonymous. In addition to determining the range of forms which can express generalized-personal meaning, the study aims to compare these forms and to specify the conditions and possible restrictions (contextual, semantic, syntactic, stylistic, etc.) associated with the use of each construction. In Russian linguistics, the generalized-personal meaning has not been extensively studied from a functional perspective. The advantage of a meaning-based functional approach is that it gives a comprehensive picture of the diversity and distribution of the phenomenon.