Alargamento da distribuição de massa molar de polímeros sintetizados com catalisadores metalocênicos dual-site

The main topics related to the use of dual-site catalysts in the production of polymers with broad molecular weight distribution are reviewed. The polymerization using dual-site catalysts is more economical and allows to produce a higher quality product than other processes, such as polymer blend and multistage reactors. However, the formulation of these catalysts is quite complicated since the same catalyst must produce distinct polymer grades. In addition, the release of patents concerning the combination of metallocenes and new technologies for polymerization shows that polymerization processes using dual-site catalysts are of current industrial interest.

Stability-indicating RP-HPLC method for simultaneous determination of gatifloxacin and flurbiprofen in binary combination

A stability-indicating RP-HPLC method is presented for determination of gatifloxacin and flurbiprofen in binary combination. Gatifloxacin, flurbiprofen and their degradation products were detected at 254 nm using a BDS Hypersil C8 (250 X 4.6 mm, 5 µm) column and mixture of 20 mM phosphate buffer (pH 3.0) and methanol 30:70 v/v as mobile phase. Response was linear over the range of 15-105 mg mL-1 for gatifloxacin (r² > 0.998) and of 1.5-10.5 mg mL-1 for flurbiprofen (r² > 0.999). The developed method efficiently separated the analytical peaks from degradation products (peak purity index > 0.9999). The method developed can be applied successfully for determination of gatifloxacin and flurbiprofen in human serum, urine, pharmaceutical formulations, and their stability studies.

MÉTODOS DE EXTRAÇÃO DE POLI-HIDROXIALCANOATOS A PARTIR DE BIOMASSA BACTERIANA

Polyhydroxyalkanoates (PHAs) are biodegradable and biocompatible polyesters intracellularly accumulated by many bacteria as an energy reserve material and carbon source. These biopolymers may be extracted from cells after their production phase, and the extraction process involves various individual operations to ensure adequate removal of the biopolymer from the cells. During this process, the following aspects should be considered: reduction of product losses during different stages of the process to obtain a highly pure product, preservation of physical and thermal characteristics, and use of low toxicity chemicals to achieve sustainable production and avoid harming the environment. The impact of the costs of PHA extraction on the total cost of the production process may account for over 50% of the end-value of the product. Within this context, several methods of PHA extraction have been reported in the literature. These methods include the use of solvents, chemical digestion, enzymatic digestion, mechanical extraction with high-pressure homogenization and ultrasound, extraction using supercritical fluids, or a combination of these methods. The present review of the literature shows strategies for extraction processes of PHAs produced by bacteria involving cell destabilization and/or breakage, recovery, and purification of the biopolymer.

Development of Collaborative Product Structure Management

The purpose of this thesis is to develop an environment or network that enables effective collaborative product structure management among stakeholders in each unit, throughout the entire product lifecycle and product data management. This thesis uses framework models as an approach to the problem. Framework model methods for development of collaborative product structure management are proposed in this study, there are three unique models depicted to support collaborative product structure management: organization model, process model and product model. In the organization model, the formation of product data management system (eDSTAT) key user network is specified. In the process model, development is based on the case company’s product development matrix. In the product model framework, product model management, product knowledge management and design knowledge management are defined as development tools and collaboration is based on web-based product structure management. Collaborative management is executed using all these approaches. A case study from an actual project at the case company is presented as an implementation; this is to verify the models’ applicability. A computer assisted design tool and the web-based product structure manager, have been used as tools of this collaboration with the support of the key user. The current PDM system, eDSTAT, is used as a piloting case for key user role. The result of this development is that the role of key user as a collaboration channel is defined and established. The key user is able to provide one on one support for the elevator projects. Also the management activities are improved through the application of process workflow by following criteria for each project milestone. The development shows effectiveness of product structure management in product lifecycle, improved production process by eliminating barriers (e.g. improvement of two-way communication) during design phase and production phase. The key user role is applicable on a global scale in the company.

A risk infection simulation model for fusarium head blight of wheat

Fusarium Head Blight (FHB) is a disease of great concern in wheat (Triticum aestivum). Due to its relatively narrow susceptible phase and environmental dependence, the pathosystem is suitable for modeling. In the present work, a mechanistic model for estimating an infection index of FHB was developed. The model is process-based driven by rates, rules and coefficients for estimating the dynamics of flowering, airborne inoculum density and infection frequency. The latter is a function of temperature during an infection event (IE), which is defined based on a combination of daily records of precipitation and mean relative humidity. The daily infection index is the product of the daily proportion of susceptible tissue available, infection frequency and spore cloud density. The model was evaluated with an independent dataset of epidemics recorded in experimental plots (five years and three planting dates) at Passo Fundo, Brazil. Four models that use different factors were tested, and results showed all were able to explain variation for disease incidence and severity. A model that uses a correction factor for extending host susceptibility and daily spore cloud density to account for post-flowering infections was the most accurate explaining 93% of the variation in disease severity and 69% of disease incidence according to regression analysis.

Engineering of Business Critical Web Applications

Research focus of this thesis is to explore options for building systems for business critical web applications. Business criticality here includes requirements for data protection and system availability. The focus is on open source software. Goals are to identify robust technologies and engineering practices to implement such systems. Research methods include experiments made with sample systems built around chosen software packages that represent certain technologies. The main research focused on finding a good method for database data replication, a key functionality for high-availability, database-driven web applications. Research included also finding engineering best practices from books written by administrators of high traffic web applications. Experiment with database replication showed, that block level synchronous replication offered by DRBD replication software offered considerably more robust data protection and high-availability functionality compared to leading open source database product MySQL, and its built-in asynchronous replication. For master-master database setups, block level replication is more recommended way to build high-availability into the system. Based on thesis research, building high-availability web applications is possible using a combination of open source software and engineering best practices for data protection, availability planning and scaling.

Outsourcing process in pharmaceutical product development

The aim of this study was to create an outsourcing process for pharmaceutical product development. This study focuses on two main questions. The first question is “What is the outsourcing process model?” In the second phase key success factors of the outsourcing process are identified. As a result of the literature reviews, a general outsourcing process was created. Transaction cost economics and resource based view were used to derived a theoretical framework to the process by combining the existing processes presented in the literature. The model of process is considered used to the outsourcing broadly. The general outsourcing process was then developed further with the key factors that affect the success of pharmaceutical product development and the interviews of pharmaceutical outsourcing experts. The result of the research was the process consists of seven phases with key activities and expected outputs for each of the phases. In addition, the strategic decision-making framework for outsourcing decision in pharmaceutical product development is giving as well as the tools for selecting supplier and preparing structured contract. This study also gives some recommendations for managing the outsourcing process.

Product costing model for laser welded hollow core steel panels

The aim of the study was to create an easily upgradable product costing model for laser welded hollow core steel panels to help in pricing decisions. The theory section includes a literature review to identify traditional and modern cost accounting methodologies, which are used by manufacturing companies. The theory section also presents the basics of steel panel structures and their manufacturing methods and manufacturing costs based on previous research. Activity-Based costing turned out to be the most appropriate methodology for the costing model because of wide product variations. Activity analysis and the determination of cost drivers based on observations and interviews were the key steps in the creation of the model. The created model was used to test how panel parameters affect the costs caused by the main manufacturing stages and materials. By comparing cost structures, it was possible to find the panel types that are the most economic and uneconomic to manufacture. A sensitivity analysis proved that the model gives sufficiently reliable cost information to support pricing decisions. More reliable cost information could be achieved by determining the cost drivers more accurately. Alternative methods for manufacturing the cores were compared with the model. The comparison proved that roll forming can be more advantageous and flexible than press brake bending. However, more extensive research showed that roll forming is possible only when the cores are designed to be manufactured by roll forming. Due to that fact, when new panels are designed consideration should be given to the possibility of using roll forming.

Examining the Role of Rebranding in Perceived Image of a Product Line

The main objective for this study was to explore certain organization’s product line rebranding process and its impact on product line’s perceived image. The case company is a global paper, packaging and forest products company, business segment paper board. The audience explored is one of the company’s major customers, merchant in Germany. The research was performed as a descriptive case study with a purpose to provide longitudinal insight into the product line image and its eventual alteration as a result of the case company’s rebranding process. Mainly qualitative methods were used for conducting the research. The data for the empirical part was collected with a web-based survey at two different points of time; before the rebranded products entered the market and after they had been available approximately six months. The results of this study reveal that the case company has performed well in its attempt to improve product line’s brand image through rebranding. It was found that between the two brand image measurements the product brand image seems to have improved in all of the areas which according to theoretical framework of this study contribute to formation of brand image; brand associations, marketing communications and interpersonal relationships, not forgetting the original platform that initiated the change; technical quality modifications. In other words it may be concluded that as technical quality was brought to a new level, also assessments about the brand image improved respectively.

Kemikaalien ja aineiden käyttöön liittyvä lainsäädäntö tuotteiden elinkaaren eri vaiheissa ja sen vaikutukset suomalaisten teknologiateollisuusyritysten liiketoiminnan kehittämiseen

Työn tavoitteena oli tuottaa tietoa ja esimerkkejä siitä, miten suomalaisten teknologiateollisuusyritysten tulisi suhtautua kemikaalilainsäädännön vaatimuksiin. Aihetta tarkasteltiin elinkaari- ja toimitusketjunäkökulmasta ja mallinnettiin erilaisia toimitusketjuja. Lisäksi tarkasteltiin yritysten lainsäädäntöosaamiseen vaikuttavia tekijöitä uuden nk. tietoisuuskolmiomallin avulla. Käytännössä aihetta havainnollistettiin kolmen esimerkkisäädöksen, REACH- ja CLP-asetuksen ja RoHS-direktiivin, sekä neljän esimerkkiyrityksen ja -tuotteen avulla. Yritysten tehtäviä esimerkkituotteen toimitusketjussa ja yritysten tietoisuutta esimerkkisäädösten vaatimuksista tarkasteltiin kyselyn avulla. Tulokseksi saatiin, että yritysten lainsäädäntöosaamisen ja -tietoisuuden tasoon vaikuttavat erityisesti lainsäädännön seurantaan käytetyt resurssit ja verkostoituminen. Kemikaalilainsäädäntö edellyttää yrityksiltä tuotteen elinkaaren hallintaa sekä siihen liittyvien ainevirtojen ja toimitusketjun hallintaa. Tuotteet on kyettävä pilkkomaan raaka-aineisiinsa ja yritysten on tunnistettava toimitusketjurooleihinsa liittyvät velvoitteet. On tiedostettava paitsi esimerkkisäädösten, myös muun, alati lisääntyvän kemikaali- ja ympäristösääntelyn vaatimukset, joihin on yrityksissä syytä varautua riittävin resurssein.

Effect of hydrodynamics on modelling, monitoring and control of crystallization

Crystallization is a purification method used to obtain crystalline product of a certain crystal size. It is one of the oldest industrial unit processes and commonly used in modern industry due to its good purification capability from rather impure solutions with reasonably low energy consumption. However, the process is extremely challenging to model and control because it involves inhomogeneous mixing and many simultaneous phenomena such as nucleation, crystal growth and agglomeration. All these phenomena are dependent on supersaturation, i.e. the difference between actual liquid phase concentration and solubility. Homogeneous mass and heat transfer in the crystallizer would greatly simplify modelling and control of crystallization processes, such conditions are, however, not the reality, especially in industrial scale processes. Consequently, the hydrodynamics of crystallizers, i.e. the combination of mixing, feed and product removal flows, and recycling of the suspension, needs to be thoroughly investigated. Understanding of hydrodynamics is important in crystallization, especially inlargerscale equipment where uniform flow conditions are difficult to attain. It is also important to understand different size scales of mixing; micro-, meso- and macromixing. Fast processes, like nucleation and chemical reactions, are typically highly dependent on micro- and mesomixing but macromixing, which equalizes the concentrations of all the species within the entire crystallizer, cannot be disregarded. This study investigates the influence of hydrodynamics on crystallization processes. Modelling of crystallizers with the mixed suspension mixed product removal (MSMPR) theory (ideal mixing), computational fluid dynamics (CFD), and a compartmental multiblock model is compared. The importance of proper verification of CFD and multiblock models is demonstrated. In addition, the influence of different hydrodynamic conditions on reactive crystallization process control is studied. Finally, the effect of extreme local supersaturation is studied using power ultrasound to initiate nucleation. The present work shows that mixing and chemical feeding conditions clearly affect induction time and cluster formation, nucleation, growth kinetics, and agglomeration. Consequently, the properties of crystalline end products, e.g. crystal size and crystal habit, can be influenced by management of mixing and feeding conditions. Impurities may have varying impacts on crystallization processes. As an example, manganese ions were shown to replace magnesium ions in the crystal lattice of magnesium sulphate heptahydrate, increasing the crystal growth rate significantly, whereas sodium ions showed no interaction at all. Modelling of continuous crystallization based on MSMPR theory showed that the model is feasible in a small laboratoryscale crystallizer, whereas in larger pilot- and industrial-scale crystallizers hydrodynamic effects should be taken into account. For that reason, CFD and multiblock modelling are shown to be effective tools for modelling crystallization with inhomogeneous mixing. The present work shows also that selection of the measurement point, or points in the case of multiprobe systems, is crucial when process analytical technology (PAT) is used to control larger scale crystallization. The thesis concludes by describing how control of local supersaturation by highly localized ultrasound was successfully applied to induce nucleation and to control polymorphism in reactive crystallization of L-glutamic acid.

Biokaasu-, bioetanoli- ja yhdistelmäprosessin energia- ja hiilidioksiditase vertailu

Biojäte soveltuu erinomaisesti biokaasuprosessin raaka-aineeksi sisältämänsä runsaan or-gaanisen aineksen vuoksi. Bioetanoliprosessin raaka-aineeksi se soveltuu, koska biojäte sisäl-tää runsaasti tärkkelystä sekä selluloosaa. Tässä työssä tutkittiin laskennallisesti bioetanoli-, biokaasu- sekä näiden yhdistelmäprosessin energia- ja hiilidioksiditaseita kirjallisuuden tietoihin pohjautuen. Biokaasuprosessista lopputuotteena saatavan biometaanin käyttäminen bensiiniä korvaavana liikennepolttoaineena tuottaa jo pelkästään palamistuotteena syntyvän hiilidioksidin säästöinä 62 kg/tbiojätettä. Energian suhteen biokaasuprosessi on selvästi yliomavaraisin kaikista kolmesta prosessista, vaikka energiankulutukseen huomioidaan myös jalostuksen tarvitsema sähkönku-lutus. Biokaasuprosessissa oma käyttö on alle 20 % lopputuotteen lämpöarvosta, yhdistelmä-prosessin osalta luku on 4 %-yks alhaisempi.

Identifying and Characterizing New Ingredients in vitro for Prebiotic and Synbiotic use

The endogenous microbiota, constituting the microbes that live inside and on humans, is estimated to outnumber human cells by a factor of ten. This commensal microbial population has an important role in many physiological functions, with the densest microbiota population found in the colon. The colonic microbiota is a highly complex and diverse bacterial ecosystem, and a delicate balance exists between the gut microbiota and its host. An imbalance in the microbial ecosystem may lead to severe symptoms in and also beyond the gastrointestinal tract. Due to the important role of the gut microbiota in human health, means of its modification have been introduced in the dietary concepts of pro-, pre- and synbiotics. Prebiotics, which are usually carbohydrates, strive to selectively influence beneficial microbes resident in the colon with the aim of modifying the composition and functionality of the commensal microbial population towards a purportedly healthier one. The study of prebiotic effects on colonic micro-organisms is typically done by using human faecal material, though this provides relatively little information on bacterial populations and metabolic events in different parts of the colon. For this reason, several in vitro models have been developed to investigate the gut microbiota. The aim of this doctoral thesis was to screen through some of the promising prebiotic candidates, characterize their effects on the microbiota through the use of two in vitro methods (pure microbial cultures and a colon simulator model) and to evaluate their potential as emerging prebiotics or synbiotics when combined with the probiotic Bifidobacterium lactis . As a result of the screening work and subsequent colon simulation studies, several compounds with promising features were identified. Xylo-oligosaccharides (XOS), which have previously already shown promise as prebiotic compounds, were well fermented by several probiotic Bifidobacterium lactis strains in pure culture studies and in the following simulation studies utilizing the complex microbiota by endogenous B. lactis Another promising compound was panose, a trisaccharide belonging to isomalto-oligosaccharides (IMO) that also was also able to modify the microbiota in vitro by increasing the number of beneficial microbes investigated. Panose has not been widely studied previously and therefore, this thesis work provided the first data on panose fermentation in mixed colonic microbiota. Galacto-oligosaccharide (GOS) is an established prebiotic, and it was studied here in conjunction with another potential polygosaccharide polydextrose (PDX) and probiotic B. lactis Bi-07. In this final study, the synbiotics including GOS were more effective than the constituting pro- or prebiotics alone in modulating the microbiota composition, thus indicating a synergy resulting from the combination. The results obtained in this in vitro work can be, and have already been, utilized in product development aimed at the nutritional modification of the human colonic microbiota. Some of the compounds have entered the human clinical intervention phase to nvestigate in more detail the prebiotic and synbiotic properties seen in these in vitro studies.

First-Line Chemotherapy with Anthracycline and Taxane Combination in Metastatic Breast Cancer. Detection of bone metastases with TRACP 5b

Background: In Finland, breast cancer (BC) is the most common cancer among women, and prostate cancer (PC) that among men. At the metastatic stage both cancers remain essentially incurable. The goals of therapy include palliation of symptoms, improvement or maintenance of quality of life (QoL), delay of disease progression, and prolongation of survival. Balancing between efficacy and toxicity is the major challenge. With increasing costs of new treatments, appropriate use of resources is paramount. When new treatment regimes are introduced into clinical practice a comprehensive assessment of clinical benefit, adverse effects and cost is necessary. Both BC and PC show a predilection to metastasize to bone. Bone metastases cause significant morbidity impairing the patients´ QoL. Diagnosis of bone metastases relies mainly on radiological methods, which however lack optimal sensitivity and specificity. New tools are needed for detection and follow-up of bone metastases. Aims: Anthracyclines and taxanes are effective chemotherapeutic agents in the treatment of metastatic breast cancer (MBC) with different mechanisms of action. Therefore, evaluation of the combination of anthracyclines with taxanes was a justifiable approach in the treatment of MBC patients. We assessed the efficacy, toxicity, cost of treatment and QoL of BC patients treated with first-line chemotherapy for metastatic disease with the combination epirubicin and docetaxel. We also evaluated the diagnostic potential of tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptides of type I collagen (ICTP) in the diagnosis of bone metastases in BC and TRACP 5b in PC patients. Results: The combination of epirubicin and docetaxel was effective in this phase II study, but required individual dose adjustment to avoid neutropenic infections, and the use of growth factors to maintain a feasible dose level. The response rate was 54 % (95 % CI 37-71) and the median overall survival (OS) was 26 months. Of the patients, 87 % were treated for infections. The treatment of adverse events required additional use of health resources mainly due to neutropenic infections, thereby raising direct treatment costs by 20 %. Despite adverse events, the global QoL was not significantly compromised during the treatment. Clinically evident acute cardiac toxicity was not observed. The combination of serum TRACP 5b and ICTP was at least equally sensitive and specific in detection of of bone metastases as commonly used total alkaline phosphatise (tALP) in BC patients. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC patients. Conclusions: Treatment with epirubicin and docetaxel showed high efficacy in first-line chemotherapy of MBC. The relatively high incidence of neutropenic infections requiring hospitalization increased the treatment costs. Despite adverse events, the global QoL of the patients was not significantly compromised. The combination of TRACP 5b and ICTP showed similar activity as tALP in detecting bone metastases in MBC. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC.