Denna licensiatavhandling behandlar oxidativ upplösning av UO2. Upplösning av UO2 studeras huvudsakligen då UO2-matrisen hos använt kärnbränsle förväntas fungera som en barriär mot frigörande av radionuklider i ett framtida djupförvar. Lösligheten av U(IV) är mycket låg under i djupförvaret rådande förhållanden emedan U(VI) har betydligt högre löslighet. Oxidation av UO2-matrisen kommer därför att påverka dess löslighet och därmed dess funktion som barriär. I denna avhandling studeras den relativa effektiviteten av en- och två-elektronoxidanter för upplösning av UO2. Vid låga oxidantkoncentrationer är utbytet för upplösningen för en-elektronoxidanter signifikant lägre än för två-elektronoxidanter. För en-elektronoxidanter ökar dock utbytet med ökande oxidanthalt, vilket kan förklaras av den ökade sannolikheten för två konsekutiva en-elektronoxidationer av samma reaktionssite och den ökade möjligheten till disproportionering. Radikaler och molekylära radiolysprodukters relativa inverkan på oxidativ upplösning av UO2 studeras också i denna avhandling genom mätning av mängden upplöst U(VI) i γ-bestrålade system som dominerades av olika oxidanter. Dessa studier visade att upplösningshastigheten av UO2 kan uppskattas från oxidantkoncentrationer framtagna genom simuleringar av radiolys i motsvarande homogena system och hastighetskonstanterna för ytreaktionerna. Simuleringarna visar att de molekylära oxidanterna kommer vara de viktigaste oxidanterna i alla system i denna studie vid långa bestrålningstider (>10 timmar). Vid liknande simuleringar av α-bestrålade system fanns att vid förhållanden relevanta för ett djupförvar för använt kärnbränsle, är det endast de molekylära oxidanterna (i huvudsak H2O2) som är av betydelse för upplösningen av bränslematrisen. Då använt kärnbränsle innehåller en mängd radionuklider som utsätter UO2-matrisen för kontinuerlig bestrålning, är det av vikt att undersöka hur bestrålning påverkar reaktiviteten av UO2. Bestrålningseffekten på reaktionen mellan UO2 och MnO4- studerades. Dessa försök visade att bestrålning av UO2 vid doser >40 kGy leder till att reaktiviteten ökar upp till 1.3 gånger reaktiviteten av obestrålad UO2. Den ökade reaktiviteten kvarstår efter bestrålningen och effekten kan därför möjligen tillskrivas permanenta förändringar i materialet. Vid uppskattning av reaktiviteten hos använt kärnbränsle måste hänsyn tas till denna effekt då bränslet redan efter ett par dagar i reaktor blivit utsatt för doser >40 kGy. Det har tidigare föreslagits att hastigheten för en heterogen västka/fast-fas reaktion är beroende av partikelstorleken hos det fasta materialet, vilket har studerats för UO2-partiklar i denna avhandling. Experimentellt bestämda kinetiska parametrar jämförs med de föreslagna ekvationerna för fyra storleksfraktioner av UO2-pulver och en UO2-pellet. Studien visade partikelstorleksberoendet av andra ordningens hastighetskonstant och aktiveringsenergin för oxidation av UO2 med MnO4- beskrivs relativt väl av de föreslagna ekvationerna. / The general subject of this thesis is oxidative dissolution of UO2. The dissolution of UO2 is mainly investigated because of the importance of the UO2 matrix of spent nuclear fuel as a barrier against radionuclide release in a future deep repository. U(IV) is extremely insoluble under the reducing conditions prevalent in a deep repository, whereas U(VI) is more soluble. Hence, oxidation of the UO2-matrix will affect its solubility and thereby its function as a barrier. In this thesis the relative efficiency of one- and two electron oxidants in dissolving UO2 is studied. The oxidative dissolution yield of UO2 was found to differ between one- and two-electron oxidants. At low oxidant concentrations the dissolution yields for one-electron oxidants are significantly lower than for two-electron oxidants. However, the dissolution yield for one-electron oxidants increases with increasing oxidant concentration, which could be rationalized by the increased probability for two consecutive one-electron oxidations at the same site and the increased possibility for disproportionation. Furthermore, the relative impact of radical and molecular radiolysis products on oxidative dissolution of UO2 is investigated. Experiments were performed where the amount of dissolved U(VI) was measured in γ-irradiated systems dominated by different oxidants. We have found that the UO2 dissolution rate in systems exposed to γ-irradiation can be estimated from oxidant concentrations derived from simulations of radiolysis in the corresponding homogeneous systems and rate constants for the surface reactions. These simulations show that for all systems studied in this work, the molecular oxidants will be the most important oxidants for long irradiation times (>10 hours). Similar simulations of α-irradiated systems show that in systems relevant for a deep repository for spent nuclear fuel, only the molecular oxidants (mainly H2O2) are of importance for the dissolution of the fuel matrix. The effect on UO2 reactivity by irradiation of the material is of importance when predicting the spent fuel dissolution rate since the fuel, due to its content of radionuclides, is exposed to continuous self-irradiation. The effect of irradiation on the reaction between solid UO2 and MnO4- in aqueous solutions was studied. It was found that irradiation of UO2 at doses >40 kGy increases the reactivity of the material up to ~1.3 times the reactivity of unirradiated UO2. The increased reactivity remains after the irradiation and can possibly be attributed to permanent changes in the material. This issue must be taken into account when predicting the reactivity of spent nuclear fuel since the fuel is exposed to doses >40 kGy after only a few days in the reactor. It has earlier been suggested that the rate of a heterogeneous liquid-solid reaction depends on the size of the solid particles. This was investigated for UO2 particles in this thesis. Experimental kinetic parameters are compared to the previously proposed equations for UO2 powder of four size fractions and a UO2 pellet. We have found that the particle size dependence of the second order rate constant and activation energy for oxidation of UO2 by MnO4- is described quite well by the proposed equations. / QC 20101123

Raloxifene is a highly insoluble, highly metabolized serum estrogen receptor modulator approved for use in the treatment of osteoporosis. Hydroxybutenyl-beta-cyclodextrin (HBenBCD) is a novel solubility enhancer previously demonstrated to increase the oral bioavailability of tamoxifen, letrozole, and itraconazole. The current study evaluated the pharmacokinetics of raloxifene in oral and intravenous formulations with HBenBCD in male Wistar-Hannover rats. Analytical methodology to measure raloxifene and its metabolites was developed by measuring raloxifene metabolism in vitro. Formulation with HBenBCD significantly increased raloxifene oral bioavailability. Mean ± S.D. oral bioavailabilities were 2.6 ± 0.4% for raloxifene formulated with microcrystalline cellulose, 7.7 ± 2.1% for a solid capsule formulation of raloxifene:HBenBCD complex, and 5.7 ± 1.3% for a liquid-filled capsule formulation containing raloxifene:HBenBCD/PEG400/H2O. Relative to raloxifene/microcrystalline filled capsules, the presence of HBenBCD in the solid capsule formulation afforded: (i) a decrease in raloxifene Tmax (2.5 ± 0.5 h versus 4.0 ± 0.5 h); (ii) a two-fold increase in raloxifene Cmax and a three-fold increase in raloxifene AUC; and (iii) a 12-fold increase in raloxifene glucuronide Cmax and a 6.5-fold increase in raloxifene glucuronide AUC. Hence, these studies demonstrate that raloxifene formulations containing HBenBCD significantly increased the oral bioavailability in rats relative to formulations that did not contain HBenBCD.

The Council for Scientific and Industrial Research (CSIR) in South Africa is developing a process to produce titanium tetrachloride from a low-grade material such as ilmenite. Titanium tetrachloride can then be used as feed material for titanium metal or pigment-grade titanium dioxide production. Titanium tetrachloride is commercially produced by chlorinating synthetic rutile (<92% TiO2) or titanium dioxide slag (<85% TiO2) at ~900 ˚C. A drawback of chlorination at this temperature is that any constituents other than TiO2 will end up as hazardous waste material. A characteristic step in the CSIR’s proposed process is to nitride titanium dioxide contained in the feed material before it is sent for chlorination. The chlorination of the resulting titanium nitride is achieved at a much lower temperature (~200 ˚C) than that of the existing titanium dioxide chlorination reaction. An added advantage of the low-temperature chlorination reaction is that chlorine is selective mostly towards titanium nitride and metallic iron, which means that any other constituents present are not likely to react with the chlorine. The result is reduced chlorine consumption and less hazardous waste produced. The nitrided ilmenite must, however, be upgraded by removing all iron before it can be sent for chlorination. Commercial ilmenite upgrading processes, called synthetic rutile production, also require the removal of iron and other transition metals before chlorination. A literature review of existing ilmenite upgrading processes revealed four possible process options that could remove iron from nitrided ilmenite. Two of these process options, the Becher and Austpac ERMS SR processes, are proven process routes. The other two are novel ideas – one to passivate iron contained in the nitrided ilmenite against chlorination and the other to use ammonium chloride (as used in the Becher process) as a stoichiometric reactant to produce a ferrous chloride solution. A preliminary experimental evaluation of these process options indicated that the Austpac ERMS SR process is the most viable option for removing iron from nitrided ilmenite. The Austpac ERMS SR process was therefore selected as a template for further process development. A detailed Austpac ERMS SR process review found that two process units in the Austpac ERMS SR process could be used in a process that separates iron from nitrided ilmenite. These are the Enhanced Acid Regeneration System and the Direct Reduced Iron process units. The review also concluded that another leach unit would have to be developed. It was therefore necessary to further investigate the dissolution of nitrided ilmenite in hydrochloric acid. A detailed experimental evaluation of nitrided ilmenite dissolution in hydrochloric acid found that hydrochloric acid could be used as the lixiviant to selectively remove iron from nitrided ilmenite. The dissolution of metallic iron in 90 ˚C hydrochloric acid reached levels of at least 96% after only 60 minutes. An average “combined resistance” rate law was found that could be used to describe this dissolution reaction. The observed activation energy and Arrhenius pre-exponential factor were found to be equal to 9.45 kJ.mol-1 and 30.8 s-1 respectively. The Austpac ERMS SR process review and experimental results described above were then combined and used to propose a process that could be employed to remove iron from nitrided ilmenite. The proposed process was modelled using the Flowsheet Simulation module in HSC Chemistry 7.0 / Dissertation (MEng (Chemical Engineering))--University of Pretoria, 2010. / Chemical Engineering / MEng (Chemical Engineering) / unrestricted

The carbonate saturometer method developed by Weyl (1961) was studied in respect to the effect of several variables on the solubility of carbonates. The solubility of three solid carbonate materials was measured in four different salt solutions, at four ionic strengths, and at two different temperatures . The solids studied included: calcite, dolomite, and a calcareous soil. It was found that the three solid carbonate materials varied in solubility from a low in the soil carbonates to a high in dolomite. Increasing the ionic strength of the solution increased the solubility of most of the solid carbonate materials. By decreasing the temperature, the solubility was increased. When S04- was present in solution, the solubility of both calcium carbonate and dolomite increased. When Mg++ was present in solution the solubility of calcium carbonate was increased more than was the solubility of dolomite.

In October of 1972, the Dissolution of Marriage Act (hereinafter referred to as the Act) became a part of the law and judicial practice of the state of Oregon. The Act represents a significant change in Oregon's law. It also represents a significant evolutionary development in the 'attitude of the legal community toward the process of divorce or as it is now termed, dissolution of marriage. The Act was a response to extensive criticism from professionals and from the public. The problem is the legislators were not sure of the effects of the Act and now that it is in effect there is still little or no objective data regarding its effectiveness. This study is an exploratory attempt to evaluate the consequences of the Act, the accomplishment of its stated purposes and its impact upon the process of dissolution and the people involved.

CHARLES UNIVERSITY Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Technology Name: Vendula Longinová Title of diploma thesis: Rheological and adhesive properties of matrix for freeze-dryied oral vaccines Supervisor: PharmDr. Eva Snejdrova, Ph.D. The aim of the diploma thesis was to evaluate the rheological and adhesive properties of formulations for lyophilized oral vaccines and lyophilized tablets formulated on the basis of dextran, iota-carrageenan or trehalose. The theoretical part characterizes dosage forms for application to the oral cavity, lyophilized preparations and excipients for mucoadhesive preparations. In the experimental part, rheological and mucoadhesive properties on a rotary rheometer were evaluated. Formulations containing iota-carrageenan showed higher viscosity, higher gel stiffness, lower degree of relaxation and higher yield stress than trehalose formulations. All lyophilized tablets showed sufficient adhesion to a standardized mucin support in vitro. The performed experiments represent pilot tests of flow, viscoelastic and mucoadhesive properties of lyophilized tablets for oral administration of pertussis vaccine. The contribution of the work is the design of a testing methodology for the final formulations during stability tests. Key words: lyophilized...

Current dissolution apparatuses require several hundred milligrams of sample per trial, measure dissolution rate indirectly via concentration sampling, and cannot maintain sink conditions throughout the duration of a test. This work describes a novel dissolution testing methodology developed using a commercial quartz crystal microbalance (QCM) system to measure dissolution rates of drugs while overcoming the limitations of current dissolution methods. The apparatus was characterized for a sample drug system of benzoic acid dissolved using a dissolution medium of deionized water at flow rates of 1000, 100, 50, and 10 &mgr;L/min. Using an analysis method that combines the responses of resonance frequency and resistance of the quartz crystal during dissolution, the dissolution rate of benzoic acid was found to be 4.029 ± 0.743, 2.026 ± 0.913, 1.565 ± 0.349, and 1.060 ± 0.103 % mass/s, for each flow rate, respectively. The QCM dissolution apparatus method can be used to measure drug dissolution directly by quantifying mass loss (rather than indirectly via concentration changes as with current methods), reduce sample sizes compared with current methods by three orders of magnitude onto the microgram scale, and maintain sink conditions throughout the duration of the test.

No description available.

The kinetics for radiation induced dissolution of spent nuclear fuel is a key issue in the safety assessment of a future deep repository. Spent nuclear fuel mainly consists of UO2 and therefore the release of radionuclides (fission products and actinides) is assumed to be governed by the oxidation and subsequent dissolution of the UO2 matrix. The process is influenced by the dose rate in the surrounding groundwater (a function of fuel age and burn up) and on the groundwater composition. In this licentiate thesis the effects of HCO3- (a strong complexing agent for UO22+) and ionic strength on the kinetics of UO2 oxidation and dissolution of oxidized UO2 have been studied experimentally. The experiments were performed using aqueous UO2 particle suspensions where the oxidant concentration was monitored as a function of reaction time. These reaction systems frequently display first order kinetics. Second order rate constants were obtained by varying the solid UO2 surface area to solution volume ratio and plotting the resulting pseudo first order rate constants against the surface area to solution volume ratio. The oxidants used were H2O2 (the most important oxidant under deep repository conditions), MnO4- and IrCl62-. The kinetics was studied as a function of HCO3- concentration and ionic strength (using NaCl and Na2SO4 as electrolytes). The rate constant for the reaction between H2O2 and UO2 was found to increase linearly with the HCO3- concentration in the range 0-1 mM. Above 1 mM the rate constant is independent of the HCO3- concentration. The HCO3- concentration independent rate constant is interpreted as being the true rate constant for oxidation of UO2 by H2O2 [(4.4 ± 0.3) x 10-6 m min-1] while the HCO3- concentration dependent rate constant is used to estimate the rate constant for HCO3- facilitated dissolution of UO22+ (oxidized UO2) [(8.8 ± 0.5) x 10-3 m min-1]. From experiments performed in suspensions free from HCO3- the rate constant for dissolution of UO22+ was also determined [(7 ± 1) x 10-8 mol m-2 s-1]. These rate constants are of significant importance for simulation of spent nuclear fuel dissolution. The rate constant for the oxidation of UO2 by H2O2 (the HCO3- concentration independent rate constant) was found to be independent of ionic strength. However, the rate constant for dissolution of oxidized UO2 displayed ionic strength dependence, namely it increases with increasing ionic strength. The HCO3- concentration and ionic strength dependence for the anionic oxidants is more complex since also the electron transfer process is expected to be ionic strength dependent. Furthermore, the kinetics for the anionic oxidants is more pH sensitive. For both MnO4- and IrCl62- the rate constant for the reaction with UO2 was found to be diffusion controlled at higher HCO3- concentrations (~0.2 M). Both oxidants also displayed ionic strength dependence even though the HCO3- independent reaction could not be studied exclusively. Based on changes in reaction order from first to zeroth order kinetics (which occurs when the UO2 surface is completely oxidized) in HCO3- deficient systems the oxidation site density of the UO2 powder was determined. H2O2 and IrCl62- were used in these experiments giving similar results [(2.1 ± 0.1) x 10-4 and (2.7 ± 0.5) x 10-4 mol m-2, respectively]. / QC 20101116

Syftet med detta examensarbete är att förkorta 20-timmars frisättningen för en tablettformulering med förlängd frisättning genom att använda maskininlärning genom multivariat prediktiv modellering, helt automatisera frisättningsmetoden och utvärdera antalet tabletter som kan representera en batch vid frisättningsanalys av en specifik provtablett. Prediktionsmodellerna byggdes i SIMCA 14, som är en programvara för multivariat dataanalys. Två PLS-prediktionsmodeller byggdes som använder sig av de första 8 timmarna av frisättningen som X-variabler för att prediktera mängden aktiv farmaceutisk ingrediens som frisatts vid timme 12 och timme 20. Y-variablerna behandlades med logit-transformation i SIMCA 14. Modellerna bedömdes med en oberoende testset med avseende på linjäritet och precision. Beräkningar visar att prediktionerna av 12 och 20 timmars värden är utmärkta. RMSEP för 12-timmars prediktionen är 0,39 och 1,12 för 20-timmars prediktionen. Detta visar att modellerna korrekt kan prediktera timme 12 och timme 20 efter en 8 timmars frisättningsanalys. En automatiserad 8-timmars frisättningsmetod med alla nödvändiga kommandon har byggts för SingBATH-roboten i SenISS-programvaran. Det är möjligt att koppla modellerna till SingBATH-metoden till SIMCA Quick Predict-modulen som finns i SenISS-programvaran. SingBATH-robotarna är placerade i produktionsanläggningarna, vilket innebär att hela analysen kan överföras från laboratoriet för kvalitetskontroll till produktionen. För att utvärdera möjligheten att använda färre än 6 tabletter vid frisättning av provtabletten för en batch, användes ett testset med data från 73 olika batcher. Flera beräkningar har utförts för att undersöka effekten av att minska antalet tabletter från 6 till 3 tabletter per batch. Det visas att risken för felaktig bedömning av batchens frisättning vid timme 1, 4, 8 och 20 med frisättning av 3 tabletter istället för 6 är mycket liten. Dessutom är den tid och resurser som sparas när antalet testade tabletter per batch minskas mycket stora. En utvärdering av prediktionsmodellerna med 6 och 3 tabletter per batch har också utförts. Resultaten visar att skillnaderna i resultat är små. Genom att flytta analyserna till produktionen, med hjälp av prediktionsmodeller för att minska analystiden till 8 timmar istället för 20 timmar och att minska antalet tabletter som representerar en batchs frisättning till 3 tabletter, från 6 tabletter, innebär en stor tidsbesparing för analys av denna provtablett. / The aim of this thesis degree is to shorten the 20-hour dissolution time of an extended release tablet formulation by using machine learning through multivariate predictive modelling, fully automate the dissolution method and assess the number of tablets needed to have correct test result for a batch of the formulation analyzed in this thesis.  The prediction models were built in SIMCA 14, which is a software for multivariate data analysis. Two PLS prediction models were built using the first 8 hours of dissolution as X-variables to predict the amount active pharmaceutical ingredient dissolved at hour 12 and hour 20. The Y variables were treated with logit transformation in SIMCA 14. The models were assessed with an independent test set with respect to linearity and precision. Calculations show that predictions of the 12 and 20 hour values are excellent. RMSEP for the 12-hour prediction is 0,39 whereas it is 1,12 for the 20-hour prediction. This shows that the models can correctly predict hour 12 and hour 20 after an 8 hours dissolution analysis.  An automated 8 hour dissolution method with all the necessary commands has been built for the SingBATH robot in the SenISS software. It is possible to couple the models to the SingBATH method to the SIMCA Quick Predict module available in the SenISS software. The SingBATH robots are placed in the production facilities, which means that the entire analysis can be transferred from the quality control laboratory to the production. To evaluate the possibility of using fewer than 6 tablets when testing the dissolution profile for a batch, a test set with data from 73 different batches was used. Several calculations have been performed to investigate the effect of reducing the number of tablets from 6 to 3 tablets per batch. It is shown that the risk of incorrectly judging the batch dissolution at hour 1, 4, 8 and 20 associated with testing 3 tablets instead of 6 is very small. Moreover, the time and resources saved when  the number of tablets tested per batch are reduced are very large.  An evaluation of the prediction models with 6 and 3 tablets per batch has also been performed. The results show that the differences in results are minor. By moving the analyses to the production, using prediction models to reduce the analysis time to 8 hours instead of 20 hours, and to reduce the number of tablets representing a batch dissolution to 3 tablets, from 6 tablets, means a great time saving for this analysis.