Due to the wide application of silica based systems ranging from microelectronics to nuclear waste disposal, detailed knowledge of water-silica interactions plays an important role in understanding fundamental processes, such as glass corrosion and the long term reliability of devices. In this dissertation, atomistic computer simulation methods have been used to explore and identify the mechanisms of water-silica reactions and the detailed processes that control the properties of the water-silica interfaces due to their ability to provide atomic level details of the structure and reaction pathways. The main challenges of the amorphous nature of the silica based systems and nano-porosity of the structures were overcome by a combination of simulation methodologies based on classical molecular dynamics (MD) simulations with Reactive Force Field (ReaxFF) and density functional theory (DFT) based ab initio MD simulations. Through the development of nanoporous amorphous silica structure models, the interactions between water and the complex unhydroxylated internal surfaces identified the unusual stability of strained siloxane bonds in high energy ring structure defects, as well as the hydroxylation reaction kinetics, which suggests the difficulty in using DFT methods to simulate Si-O bond breakage with reasonable efficiency. Another important problem addressed is the development of silica gel structures and their interfaces, which is considered to control the long term residual dissolution rate in borosilicate glasses. Through application of the ReaxFF classical MD potential, silica gel structures which mimic the development of interfacial layers during silica dissolution were created A structural model, consisting of dense silica, silica gel, and bulk water, and the related interfaces was generated, to represent the dissolution gel structure. High temperature evolution of the silica-gel-water (SGW) structure was performed through classical MD simulation of the system, and growth of the gel into the water region occurred, as well as the formation of intermediate range structural features of dense silica. Additionally, hydroxylated silica monomers (SiO4H4) and longer polymerized silica chains were formed in the water region, indicating that glass dissolution is occurring, even at short time frames. The creation of the SGW model provides a framework for a method of identifying how interfacial structures which develop at glass-water interfaces can be incorporated into atomistic models for additional analysis of the dissolution of silicates in water.

When considering oral administration, drug release from its pharmaceutical form and its dissolution into gastrointestinal fluids generally precedes absorption and systemic availability. The solubility-dissolution behaviour of a drug is frequently the rate-limiting step to absorption of drugs from the gastrointestinal tract (BCS class II drugs). Poor aqueous solubility has always been a very challenging obstacle as it is, together with membrane permeability, an essential factor in the limitation of a drug’s bioavailability following oral administration. Since an increasing number of newly developed drug candidates in pre-clinical development phases present poor water-solubility characteristics, there is a great need for formulation approaches to overcome this factor.<p><p>Out of the many ways to increase a product’s solubility/dissolution rate characteristics with the aim of enhancing its oral bioavailability, drug formulation as nanoparticles has received much-increased interest over the last decade. The hypothesis behind dissolution rate enhancement, considering drug particle size reduction to nanometer range, lies primarily in a much-increased effective surface area (Noyes-Whitney) presented by the resulting drug nanoparticles. Out of the various technologies available for drug particle size reduction to nanometer range, milling using high pressure homogenization is regarded as one of the simplest and most effective techniques. High pressure homogenization is a solvent-free process and is relatively rapid (time-saving). Furthermore, and most importantly, the scaling up of this technique is already established; processing capacities ranging from 3 l/h (e.g. EmulsiFlex C3®: minimum sample volume - 10 ml) to 1000 l/h (e.g. EmulsiFlex C1000®: minimum sample volume - 2 l).<p><p>Four model drugs were studied in this work. Nifedipine (NIF), an extensively studied poorly water-soluble drug in the literature, was used as the main model on which most of the development was done. In parallel to the work carried out on NIF, three UCB S.A. molecules currently under development were also studied as poorly water-soluble drugs: these being ucb-35440-3, UCB-A and UCB-B (salt of UCB-A). These three UCB S.A. model drugs are, contrarily to NIF, predicted highly dosed drugs and are weak bases, and thus present pH-dependent solubility profiles, which allowed us to investigate model drugs with different profiles.<p><p>Firstly, investigations regarding appropriate formulation development (stabilizer (surfactant) selection) and appropriate high pressure homogenization operating conditions (pre-milling cycles, influence of the number of high pressure homogenizing cycles, influence of homogenizing pressure, influence of sample temperature) were made. It has been shown, through this development, for the four studied model drugs, that high pressure homogenization is an appropriate technique for reducing drug particle size to nanometer range (NIF &61566; 290 nm, ucb-35440-3 &61566; 180 nm, UCB-A &61566; 350 nm and UCB-B &61566; 250 nm). Investigations regarding water-removal from the nanosuspensions obtained and most importantly regarding the redispersion characteristics of the retrieved powders (i.e. nanoparticles) were then carried out. In that regard, it has been shown that the presence of carriers in the formulation is essential for limiting nanoparticles agglomeration during the water-removal operation.<p><p>Drug crystalline state characterizations before and following particle size reduction were then carried out on the three studied model drugs, mainly through DSC and PXRD studies. In fact, one of the advantages of this particle size reduction approach (using high pressure homogenization), versus other frequently studied solubility/dissolution rate enhancement technologies (e.g. such as solid dispersions), is that original crystalline state shall not be altered in such a way that the achieved increased solubility and dissolution rate characteristics do not rely on the presence of the amorphous form of the drug; this furthermore implying a greater time-stability of the developed formulations. Through the data obtained, it has been shown that original drug crystalline state seems to be unaltered following particle size reduction.<p><p>In vitro solubility and dissolution characteristics were then evaluated on the formulations developed in order to verify the posed hypothesis regarding effective surface area increase. It has been shown through these studies that drug solubility and most importantly drug dissolution rate can be significantly enhanced for nanoparticulate systems (verified for NIF, ucb-35440-3, UCB-A and UCB-B). For example, solubility was enhanced from 26 µg/ml vs. 19.5 µg/ml for NIF nanoparticles and the dissolution characteristics showed that 100% of the tested dose (equivalent to 10 mg NIF) was already dissolved following 10 min vs. less than 5% for un-milled NIF. Following these very interesting and promising results, and preliminary to the in vivo pharmacokinetic studies carried out, in vitro permeation studies (apical to basolateral transfer studies) across intestinal cell models (Caco-2 and HT29-5M21 cultures and co-cultures) were carried out. This evaluation was only carried out using NIF as a model drug and showed a 6-fold increase in the permeation rate for NIF nanoparticles. The influence of chitosan (permeability enhancer/bioadhesive polymer) in the NIF nanoparticle formulation with regard to in vitro NIF permeation rate was also evaluated.<p><p>In vivo pharmacokinetic studies in rats were conducted using NIF and ucb-35440-3 as model drugs. The very different profiles of these two model drugs allowed us to retrieve interesting information regarding the in vivo behaviour of the developed formulations. As expected from the in vitro (i.e. solubility/dissolution/permeation) studies and results obtained for NIF, an increased extent of exposure could be observed for NIF nanoparticles versus un-milled NIF; the difference being more pronounced when the formulations were orally administered into capsules (2.5-fold increase in extent of exposure and 6-fold increase in Cmax). For ucb-35440-3, a poorly water-soluble weak base with a reported significant food effect considering oral bioavailability, an increased extent of exposure for nanoparticles, versus the un-milled drug, could only be observed in fasted state (4-fold increase in extent of exposure and 2.7-fold increase in Cmax). These different, diet-relative observations allowed us to put forward some limitations and precautions (considering poorly water-soluble weak bases) relative to the possibility of drug reprecipitation following stomach’s exiting, particularly if dissolution in the stomach is quite fast (e.g. nanoparticulate systems).<p><p>In parallel to the in vivo pharmacokinetic evaluation of NIF nanoparticles, evaluation of the antihypertensive effect of the systems developed following oral administration, using spontaneously hypertensive rats, was also carried out and compared to un-millled NIF. The results obtained showed a significant drop in systolic blood pressure for NIF nanoparticles (32% reduction of initial SBP following 30 min vs. 1% for un-milled NIF) and nicely complemented the in vitro and in vivo results obtained for NIF nanoparticles.<p><p>Finally, a stability study of the optimized NIF nanoparticle formulation was carried out with respect to reported ICH conditions (25°C/60% RH; 30°C/65% RH; 40°C/75% RH). The results showed that the studied NIF nanoparticle formulation retains all its original characteristics (dissolution, crystalline state, redispersion characteristics); this being verified over time (12 months) and for each of the three storage conditions studied.<p> / Doctorat en sciences pharmaceutiques / info:eu-repo/semantics/nonPublished

The master thesis "Latvia's transition to democracy and the challenges of democratic consolidation in Latvia" deals with the analysis of Latvian transition to democracy and the processes of democratic consolidation after regaining the independence in Latvia. The thesis focuses on the development of transformation processes in the late nineteen eighties and at the beginning of the nineteen nineties in this Baltic republic as well as it analyses the most significant problematic aspects of the development of Latvian democracy after regaining the independence till now.

Thesis (M. Pharmacy ((Pharmaceutics)) -- University of Limpopo, 2022 / According to the biopharmaceutical classification system, Clarithromycin is considered a class II molecule with low solubility. Poorly soluble drugs result in low bioavailability. Various techniques have been studied to improve the solubility of drugs and subsequently bioavailability. Of these techniques, preparation of amorphous form is the preferred method because it is a more effortless and convenient way to improve the aqueous solubility and dissolution of poorly water soluble drugs. The only disadvantage of amorphous materials is that they are less thermodynamically stable and can recrystallize during processing and storage. Aim: The aim of this study is to prepare amorphous form of clarithromycin to improve its solubility, dissolution rate, and, subsequently, bioavailability. Methods: In this study, preparation of amorphous form of clarithromycin was conducted using the quench cooling method in which the purchased anhydrous crystalline clarithromycin was spread on an aluminum foil and heated to a melting point (217˚C - 220˚C) and then rapidly cooled. Various techniques were conducted to characterize the prepared amorphous clarithromycin, and these include Differential Scanning Calorimetry (DSC), Fourier-Transform Infrared Spectroscopy (FTIR), and X-Ray Powder Diffraction (XRPD). In addition, tablets were formulated using the amorphous clarithromycin mixed with selected excipients from compatibility studies, and in vitro dissolution and stability studies were conducted over a period of 6 months. Results: The DSC thermogram results confirmed that the material prepared using the quench cooling process is an amorphous solid-state. Furthermore, the XRPD confirmed an amorphous solid-state with scattering halo peaks. The FTIR also depicted some broader and lower intensity peaks that indicated a formation of an amorphous material. The dissolution rate of amorphous clarithromycin tablets improved by more than 30% when compared to commercial crystalline clarithromycin tablets. The study revealed a drop in dissolution rate at months 3 to 6 under accelerated conditions due to recrystallization. The 6 monthly stability study at long term conditions showed no change in the integrity of the tablets and their contents. Conclusion: As indicated by the study, it can be concluded that the amorphous clarithromycin remained stable during processing and storage under long-term stability for 6 months. Furthermore, based on dissolution results, it can be concluded that amorphous solids have an improved dissolution rate. / Medical Research Council CHIETA

The growing development of nanotechnology has resulted in an increased use of nanoparticles (NPs) in various applications ranging from medicine, military, to daily consumer products. There is a concern that NPs can be dispersed into the environment in various ways, for example to air and water during manufacture, use, incineration or recycling of products and thus pose a risk to health and the environment. Risk assessments of NPs are hence necessary. One property of NPs, which may make them very useful and at the same time potentially harmful, is their small size (in nanometer range) and hence high surface area per NP mass.This study forms part of the National Mistra Environmental Nanosafety Research Program. The program provides an interdisciplinary platform for researchers from e.g. nanoscience, medicine, chemistry, material science, life cycle analysis, and social science. Specific aspects of this program involve characterization of NPs in different environmental settings, toxicity studies of aquatic organisms, integrated risk assessment of NPs, and societal dimensions of nanosafety. The contribution of this thesis within the program includes studies of stability and mobility of metal NPs and their extent of transformation/dissolution upon environmental interaction. Environmental risk assessments of NPs require a detailed understanding of how they change in terms of physical and chemical properties (charge, size, and surface oxide composition), important aspects for their stability, mobility, and reactivity in the environment. Generated data is highly relevant for the other activities of the Mistra Environmental Nanosafety program, e.g. to gain an improved understanding and design of particle dispersions and ecotoxicity studies, as any environmental interaction will result in the transformation/dissolution of the NPs and change the surface chemistry (e.g. adsorption of natural organic matter, changes in surface oxide properties), aspects that largely influence their speciation and potential toxicity.Common sonication protocols exist to prepare particle dispersions for different in vitro studies. The influence of key parameters stipulated by these protocols on the particle size, transformation/dissolution, and extent of sedimentation was investigated for bare metal NPs. Improved knowledge on these aspects is crucial for design and interpretation of results of NP-related investigations. Reactive metal NPs such as Cu and Mn NPs started to dissolve and release metals already during the probe sonication step of the stock solution, and that the presence of bovine serum albumin (often added as a stabilizing agent) enhanced this process. Even though prolonged sonication time i.e. increased delivered acoustic energy, reduced the size of formed agglomerates, sedimentation was still significant. As a consequence, administered doses from pipetted stock solutions were significantly lower (30-70%) than the nominal doses. The main reason behind the significant extent of agglomeration, with concomitant sedimentation, is related to the strong van der Waals forces prevailing between metal NPs. It is hence essential to determine the administrated dose of metallic NPs in e. g. nanotoxicological testing.Interactions between metallic NPs and natural organic matter (NOM) were studied in terms of stability, mobility and metal dissolution in order to mimic a potential exposure scenario. NOM was represented by humic acid (HA), a main component of organic matter in the environment, and by dihydroxybenzoic acid (DHBA), a small degradation product of NOM. Sedimentation of the Cu, and the Al NPs were slower in the presence of NOM in freshwater compared with freshwater only, whereas the effect of NOM was small for the Mn NPs. Stabilization was related to surface adsorption of NOM, which increased the steric repulsion between the particles, and in the case of HA also increased the magnitude of the zeta potential (resulting in increased electrostatic repulsion). Slight initial increase in particle stability wasobserved in freshwater containing DHBA, but after 24 h, sedimentation of the NPs was comparable to the conditions in freshwater only. The presence of HA (at a concentration of 20 mg/L) was found to stabilize the NPs in freshwater for more than 24 h. However, both the lower and higher HA concentration (2 and 40 mg/L) resulted in agglomeration of the Cu and Al NPs already within a few hours. Mn NPs were more stable in terms of sedimentation in freshwater at all three humic acid concentrations. This concludes that the concentration and type of NOM largely influence the stability of the studied metal NPs in solution. In contrast, SiO2 NPs were not influenced by the presence of NOM in terms of stability, most probably predominantly related to smaller attractive van der Waals forces and larger electrostatic repulsion (due to higher surface charge) compared with the metal NPs.Metal release from the Cu and Al NPs was enhanced in the presence of NOM, whereas no significant influence was observed for the Mn NPs. All metal NPs were dissolved relatively fast; 10% or more of the particle mass was dissolved within 24 h. Speciation predictions revealed rapid complexation between released Cu and Al in solution and NOM, reducing the bioavailability, whereas less complexation was evident for released Mn (as ions). In all, rapid agglomeration and sedimentation imply that any risks associated with the environmental dispersion of these metal NPs will be limited to the vicinity of their source. Mn NPs, having lower sedimentation rates than the Cu and Al NPs, and lack of solution complexation of released ions will likely have a relatively higher probability to be mobile and transported to other aquatic settings.

[pt] Neste trabalho aplicamos o método Lattice Boltzmann (LBM) para simular os processos de reações químicas que ocorrem na interação entre o fluido e a fase sólida, modificando o meio poroso. Para isso apresentaremos como o método LBM aborda a simulação do escoamento de fluido em um meio poroso irregular para os casos de um ou mais fluidos incluindo o processo de dissolução química. A partir dos processos anteriores, propomos uma modificação onde a dissolução possa ocorrer como uma característica do fluido que interage com a fase sólida. Ao abordar a dissolução como característica da interação do fluido com a fase sólida, é possível ter uma maior compreensão de como o fluido pode modificar a geometria do meio poroso e impactar nas mudanças de fluxo. A proposta de modificação foi avaliada em alguns casos em que o fluxo no meio poroso é bem definido: o canal aberto, canal com cilindros e em um meio poroso de geometria complexa. A proposta foi estendida para a simulação em um meio poroso 3D, onde analisamos como a dissolução foi impactada pela presença de forças externas como a gravidade. / [en] In this work, we apply the Lattice Boltzmann (LBM) method to simulate the chemical reaction processes that occur in the interaction between the fluid and the solid phase, modifying the porous medium. For this, we will present how the LBM method approaches fluid flow simulation in an irregular porous medium for cases of one or more fluids, including the chemical dissolution process. Based on the previous processes, we propose a modification where dissolution can occur as a characteristic of the fluid that interacts with the solid phase. By approaching dissolution as a characteristic of the interaction of the fluid with the solid phase, it is possible to better understand how the fluid can modify the geometry of the porous medium and impact the flow changes. The modification proposal was evaluated in some cases where the flow in the porous medium is well defined: the open channel, a channel with cylinders, and a porous medium with complex geometry. The proposal was extended to the simulation in a 3D porous medium, where we analyzed how the dissolution was impacted by external forces such as gravity.

Thesis title: Formulation and characterization of oxime loaded PLGA nanoparticles Author: Ramin Hafezi Supervisor: PharmDr. Eva Šnejdrová, Ph.D. Advisor: PharmDr. Juraj Martiška, Ph.D. Department: Department of Pharmaceutical Technology The diploma thesis was focused on PLGA nanoparticles (NPs) which could be loaded with oximes, prepared by a double emulsion technique, and characterised by size, polydispersity and zeta potential. The theoretical part deals with the most common methods of the NPs preparation, the polymers and stabilizers employed, and drug delivery to brain. In the experimental part the effect of various formulation factors on NP characteristics were studied: linear or branched PLGA derivative, the concentrations of polymer, the volumes of primary emulsion. Dichloromethane (DCM) or Dimethyl sulfoxide (DMSO) as solvent for polymers were used and Poloxamer 407 or Didodecyldimethylammonium bromide (DDAB) as an outer phase stabilizer were employed. By comparison among the collected results, it seemed 1% A2 in DMSO and stabilization with poloxamer 407 could be best candidate for the oxime loaded drug delivery systems as it was possible to produce nanoparticles with size from 152 to 168 nm with PDI of below 0.15. Electrostatic stability in case of using DDAB was resulted excellent and...

The present research studies marital dissolution using data from both spouses from the National Survey of Families and Households (NSFH) and uses the method of multiple imputation to handle missing data. Role theory and another four approaches (social exchange theory, stake theory, gender perspective and heterogeneity perspective) are used to make a methodological argument why using data from both spouses is necessary to study marital stability. Five data sets are imputed and there are 3,777 observations in each imputed data set. Main research findings are as followed. First, the model fits of the data from both spouses on marital dissolution are significantly better than the model fits of the data from one spouse only; therefore, gathering perceptual data from both spouses is necessary to understand marital dissolution. Second, overall, the effects of most spousal discrepancies do not support the heterogeneity perspective. Third, the model fits of the wife only model are significantly better than the model fits of the husband only model across different periods of marital duration, and the predictability of wives' variables is more stable than husbands' variables. Therefore, if only individual-level data are available to use, researchers are encouraged to use wives' data rather than husbands' data. Fourth, the predictability of factors varies with marital duration and gender in the models with data from both spouses.

No description available.

<p>  </p> <p>Due to the difficulty in physically observing the phenomena inside the actual ladle furnace in the industry, to ascertain optimized methodology for high-grade steel production, an investigation was carried out using numerical modeling to simulate the behavior of alloying elements within the liquid steel bulk using ANSYS Fluent 2020 R1 (ANSYS Inc., Pittsburgh, PA, USA). The model solves the governing equations utilized in computing the trajectories of each particle in the discrete phase. Furthermore, a user defined (UDF) code maps the mass of each parcel based on the total amount of alloy injected. The code also defines the total time it takes for the shell formed around the added materials to melt or dissolve. The study consists of a two-step procedure: ladle stirring by argon inert gas injection and mixing study by injecting micro-alloying elements to capture the flow field, turbulence, and species transport occurring during the refining process. A generic dual plug ladle metallurgy furnace, dimensions, and data obtained from Nucor Steel is used to validate the CFD simulation results. Concise parametric studies consist of ladle geometry design adjustments, variations of argon gas flow rates, and different alloying elements. Though the efficiency of the LMF process is quantified using the mixing time, which decreases as initial gas flow rates increase, results from this study show that extremely high charging of ladles is optional in obtaining shorter mixing. Also, particles behave substantially differently when their densities are below or above that of steel, and their melting points and specific heat capacities influence the time it takes for them to melt or dissolve. The overall potential outcome for this study is to improve the mixing practices due to different optimal procedures required by some materials than others.</p>