Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

The proposed human intestinal absorption prediction model is applied to over 900 pharmaceuticals and has about 82.5% true prediction power. This study will provide a screening tool that can differentiate well absorbed and poorly absorbed drugs in the early stage of drug discovery and development. This model is based on fundamental physicochemical properties and can be applied to virtual compounds. The maximum well-absorbed dose (i.e., the maximum dose that will be more than 50 percent absorbed) calculated using this model can be utilized as a guideline for drug design, synthesis, and pre-clinical studies.

With the increasing research on advanced reactors, molten salt reactors have been recognized for their potential. As with any advanced reactor concept, each component and material must be thoroughly investigated before any reactors of that type are created. One of the most pressing issues in MSR research is that of the salts themselves. Though there are a multitude of salts to choose from when designing such a reactor, many of these salts lack the extensive research required to fully understand them. Across the decades there have been many studies that have investigated select molten salts, but there are a few problems with many of those studies. Those problems are the following: prior papers use obsolete and less reliable methods for their measurements, the papers don't investigate the salts across a wide enough range of temperatures nor at varying compositions, and finally many of the salts that are seen as candidates today were not given as much attention when molten salt reactors were first conceptualized which has resulted in a lack of research on them. Indeed, the research into these salts is lacking in many ways. This study seeks to investigate a collection of promising coolant salts in depth with acknowledgment to those past studies. LiF-NaF-KF (46.5-11.5-42.0 mol%) will be used as a calibration standard and for the purpose of verifying our methodology. Specifically, FLiNaK was used in the development of volume-height curves as calibration for density measurements. NaOH-KOH of four different compositions ( 0.5-0.5mol%, 0.55-0.45mol%, 0.6-0.4mol%, and 0.65-0.35 mol%) will be evaluated for their densities and heat capacities. And finally, BeF2-NaF(43-57mol%) will be evaluated within the question of if the properties are desirable enough that the dangers posed by beryllium are an acceptable risk. BeF2-NaF will have melting point, heat capacity, density, and vapor pressure measurements performed. Additionally, extensive impurity analysis and removal (via an HF gas system) was done to our BeF2-NaF samples. The melting point and heat capacity were evaluated using dynamic scanning calorimetry (DSC), the vapor pressure was evaluated using thermogravimetric analysis (TGA), and the density was measured using a system similar to the Arrhenius method that measures height. / Master of Science / Decades have passed since the discussion of nuclear energy began. Although great progress has been made in the field, the nuclear reactors in use today consist mainly of boiling water reactors (BWRs) or pressurized water reactors (PWRs). As reliable as these reactors have become, one can no longer ignore the fact that there is a multitude of other options for how a reactor can be built and operated. Options that provide greater safety and more energy output. Many reactor concepts of the past were discounted for the extensive research that would be required to make use of them. However, as time has passed and technology has improved, that research has become more and more possible. Many advanced reactors are the result of that attention to the reactor concepts and materials of the past that couldn't be given the attention that they deserve until now. Molten salt reactors (MSRs) are one of those promising concepts. However, before they can be built every part of the reactor, from the structure to the materials, must be entirely understood. One of the most pressing issues in MSR research is the properties of the salts in consideration for use. Though there are a multitude of salts to choose from when designing such a reactor, many of these salts lack the extensive research required to fully understand them. Across the decades there have been many studies that have investigated select molten salts, but there are a few problems with many of those studies. Those problems are the following: the papers are so old that the methods that were used are now obsolete, the papers don't investigate the salts across a wide enough range of temperatures nor at varying compositions, and finally many of the salts that are seen as candidates today were not given as much attention when molten salt reactors were first conceptualized which has resulted in a lack of research on them. Indeed, the research into these salts is lacking in many ways. This study seeks to investigate a collection of promising coolant salts in depth with acknowledgment to those past studies. LiF-NaF-KF will be used as a calibration standard and for the purpose of verifying our methodology. A multitude of different compositions of NaOH-KOH will be evaluated for their densities and heat capacities. And finally, BeF2-NaF will be evaluated within the question of if the properties are desirable enough that the dangers posed by beryllium are an acceptable risk. BeF2-NaF will have melting point, heat capacity, density, and vapor pressure measurements performed. Additionally, extensive impurity analysis and removal was done to our BeF2-NaF samples.

No / We report a numerical calculation of the melting point of NaCl. The solid-liquid transition was located by determining the point where the chemical potentials of the solid and liquid phases intersect. To compute these chemical potentials, we made use of free energy calculations. For the solid phase the free energy was determined by thermodynamic integration from the Einstein crystal. For the liquid phase two distinct approaches were employed: one based on particle insertion and growth using the Kirkwood coupling parameter, and the other involving thermodynamic integration of the NaCl liquid to a Lennard-Jones fluid. The latter approach was found to be significantly more accurate. The coexistence point at 1074 K was characterized by a pressure of -30+/-40 MPa and a chemical potential of -97.9+/-0.2kßT. This result is remarkably good as the error bounds on the pressure enclose the expected coexistence pressure of about 0.1 MPa (ambient). Using the Clausius-Clapyron relation, we estimate that dP/dT~3 MPa/K. This yields a melting point of 1064+/-14 K at ambient pressure, which encompasses the quoted range for the experimental melting point (1072.45-1074.4 K). The good agreement with the experimental melting-point data provides additional evidence that the Tosi-Fumi model for NaCl is quite accurate. Our study illustrates that the melting point of an ionic system can be calculated accurately by employing a judicious combination of free energy techniques. The techniques used in this work can be directly extended to more complex, charged systems.

Yes / In this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility. / The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.).

This thesis covers a range of methodologies to provide an account of the current (2010-2014) state of the art and to develop new methods for solubility prediction. We focus on predictions of intrinsic aqueous solubility, as this is a measure commonly used in many important industries including the pharmaceutical and agrochemical industries. These industries require fast and accurate methods, two objectives which are rarely complementary. We apply machine learning in chapters 4 and 5 suggesting methodologies to meet these objectives. In chapter 4 we look to combine machine learning, cheminformatics and chemical theory. Whilst in chapter 5 we look to predict related properties to solubility and apply them to a previously derived empirical equation. We also look at ab initio (from first principles) methods of solubility prediction. This is shown in chapter 3. In this chapter we present a proof of concept work that shows intrinsic aqueous solubility predictions, of sufficient accuracy to be used in industry, are now possible from theoretical chemistry using a small but diverse dataset. Chapter 6 provides a summary of our most recent research. We have begun to investigate predictions of sublimation thermodynamics. We apply quantum chemical, lattice minimisation and machine learning techniques in this chapter. In summary, this body of work concludes that currently, QSPR/QSAR methods remain the current state of the art for solubility prediction, although it is becoming possible for purely theoretical methods to achieve useful predictions of solubility. Theoretical chemistry can offer little useful additional input to informatics models for solubility predictions. However, theoretical chemistry will be crucial for enriching our understanding of the solvation process, and can have a beneficial impact when applied to informatics predictions of properties related to solubility.

Não consta resumo na publicação. / Abstract not available.

The problem of inadequate measurement techniques for quantifying the isothermal solidification process during transient liquid phase sintering (TLPS) in binary isomorphous systems such as Ni-Cu, and the resulting uncertainty regarding the solidification mechanism and its sensitivity to important process parameters, has been investigated. A unique combination of differential scanning calorimetry (DSC), neutron diffraction (ND), and metallographic techniques has enabled the quantitative characterization of important TLPS stages (i.e., solid-state sintering, melting and dissolution, isothermal solidification, and homogenization) as well as verifying the re-melt behaviour of post-sintered specimens and measuring variable melting point (VMP) properties. This has resulted in the advancement of the fundamental understanding of liquid formation and its removal mechanism during isothermal, or diffusional, solidification. The Ni-Cu system was chosen for experimentation due to its commercial relevance as a braze filler material and also because it is an ideal model system (due to its isomorphous character) that is not well understood on a quantitative or phenomenological basis. Samples consisted of elemental Ni and Cu powder mixtures of varying particle size and composition. In DSC experiments, the progress of isothermal solidification was determined by measuring the enthalpy of melting and solidification after isothermal hold periods of varying length and comparing these to the measured enthalpy of pure Cu. The low melting enthalpies measured for all Ni/Cu mixtures heated just past the Cu melting point (1090°C) indicate that solid-state sintering and interdiffusion during heat-up significantly suppress initial liquid formation and densification from the wetting liquid. For samples heated well past the Cu melting point (1140°C), Ni dissolution causes increased initial liquid fractions and densification. It was found that significantly more time was required for complete liquid removal at 1140°C vs. 1090°C. This is attributed to the observed increase in initial liquid fractions formed at higher processing temperatures due to the dissolution of Ni. This effectively counteracts the increased diffusivities at these temperatures, and thus more time is required to completely remove the increased liquid content. TLP mixtures sintered at 1140°C using three different particle sizes revealed that fine base metal Ni particles cause high degrees of solid-state interdiffusion during heat-up, small initial liquid fractions, and accelerated liquid removal rates due to high surface area/volume ratios. A diffusion-based analytical model was developed to account for these effects (i.e., particle size, temperature, solid-state sintering, and dissolution). Comparison with experimental DSC results reveals that this model can accurately predict liquid removal given accurate diffusivities. Metallographic analysis of post-sintered DSC specimens via SEM and EDS indicates that isothermal liquid solidification leaves behind Ni-rich cores surrounded by Cu-rich matrix regions having compositions given by the Ni-Cu phase diagram solidus (CS) at a selected isothermal processing temperature (TP). ND experiments were used to investigate the melting event and interdiffusion during the isothermal hold segment by analyzing the evolution of the {200} FCC peaks of Ni and Cu. ND patterns were collected in situ at 1 minute intervals during prolonged sintering cycles for larger powder specimens. The Cu melting event was characterized by an abrupt decrease in Cu peak intensity at 1085°C as well as a shift towards higher 2 angles corresponding to lower Cu contents. This shifted residual peak (hereafter referred to as the CS peak) originates from regions of the specimen having compositions near solidus at TP. Immediately following the melting event, the evolution of ND patterns shows that these CS peaks grow rapidly, indicating the isothermal growth of a Cu-rich phase. These in situ findings confirmed the metallographic and DSC data and indicated that isothermal solidification of the liquid phase proceeds via the growth of a solute-rich solid solution layer surrounding the Ni particles. This occurs by the transient progression of the solid/liquid interface at compositions given by the liquidus and solidus (CS/CL). During sintering, diffraction intensities gradually increased at intermediate 2 angles between previous Ni and Cu peaks. ND patterns gradually evolved from initially having a broad double-peak profile to a sharper single-peak profile due to increased Ni-Cu interdiffusion. The 2position and width of the post-sintered peaks indicated very homogeneous sintered alloys. Metallographic analysis of post-sintered specimens having undergone prolonged sintering and homogenization revealed extensive Kirkendall pore formation from unequal diffusivities (DCu > DNi). In this study, the unique combination of diffusion-based modelling as well as DSC, ND, and supporting metallographic analysis has enabled the identification of characteristic sintering behaviour, important process parameters, and processing windows for TLPS in Ni-Cu systems. Quantitative and in situ information of this nature is absent in the previous TLPS literature.

The problem of inadequate measurement techniques for quantifying the isothermal solidification process during transient liquid phase sintering (TLPS) in binary isomorphous systems such as Ni-Cu, and the resulting uncertainty regarding the solidification mechanism and its sensitivity to important process parameters, has been investigated. A unique combination of differential scanning calorimetry (DSC), neutron diffraction (ND), and metallographic techniques has enabled the quantitative characterization of important TLPS stages (i.e., solid-state sintering, melting and dissolution, isothermal solidification, and homogenization) as well as verifying the re-melt behaviour of post-sintered specimens and measuring variable melting point (VMP) properties. This has resulted in the advancement of the fundamental understanding of liquid formation and its removal mechanism during isothermal, or diffusional, solidification. The Ni-Cu system was chosen for experimentation due to its commercial relevance as a braze filler material and also because it is an ideal model system (due to its isomorphous character) that is not well understood on a quantitative or phenomenological basis. Samples consisted of elemental Ni and Cu powder mixtures of varying particle size and composition. In DSC experiments, the progress of isothermal solidification was determined by measuring the enthalpy of melting and solidification after isothermal hold periods of varying length and comparing these to the measured enthalpy of pure Cu. The low melting enthalpies measured for all Ni/Cu mixtures heated just past the Cu melting point (1090°C) indicate that solid-state sintering and interdiffusion during heat-up significantly suppress initial liquid formation and densification from the wetting liquid. For samples heated well past the Cu melting point (1140°C), Ni dissolution causes increased initial liquid fractions and densification. It was found that significantly more time was required for complete liquid removal at 1140°C vs. 1090°C. This is attributed to the observed increase in initial liquid fractions formed at higher processing temperatures due to the dissolution of Ni. This effectively counteracts the increased diffusivities at these temperatures, and thus more time is required to completely remove the increased liquid content. TLP mixtures sintered at 1140°C using three different particle sizes revealed that fine base metal Ni particles cause high degrees of solid-state interdiffusion during heat-up, small initial liquid fractions, and accelerated liquid removal rates due to high surface area/volume ratios. A diffusion-based analytical model was developed to account for these effects (i.e., particle size, temperature, solid-state sintering, and dissolution). Comparison with experimental DSC results reveals that this model can accurately predict liquid removal given accurate diffusivities. Metallographic analysis of post-sintered DSC specimens via SEM and EDS indicates that isothermal liquid solidification leaves behind Ni-rich cores surrounded by Cu-rich matrix regions having compositions given by the Ni-Cu phase diagram solidus (CS) at a selected isothermal processing temperature (TP). ND experiments were used to investigate the melting event and interdiffusion during the isothermal hold segment by analyzing the evolution of the {200} FCC peaks of Ni and Cu. ND patterns were collected in situ at 1 minute intervals during prolonged sintering cycles for larger powder specimens. The Cu melting event was characterized by an abrupt decrease in Cu peak intensity at 1085°C as well as a shift towards higher 2 angles corresponding to lower Cu contents. This shifted residual peak (hereafter referred to as the CS peak) originates from regions of the specimen having compositions near solidus at TP. Immediately following the melting event, the evolution of ND patterns shows that these CS peaks grow rapidly, indicating the isothermal growth of a Cu-rich phase. These in situ findings confirmed the metallographic and DSC data and indicated that isothermal solidification of the liquid phase proceeds via the growth of a solute-rich solid solution layer surrounding the Ni particles. This occurs by the transient progression of the solid/liquid interface at compositions given by the liquidus and solidus (CS/CL). During sintering, diffraction intensities gradually increased at intermediate 2 angles between previous Ni and Cu peaks. ND patterns gradually evolved from initially having a broad double-peak profile to a sharper single-peak profile due to increased Ni-Cu interdiffusion. The 2position and width of the post-sintered peaks indicated very homogeneous sintered alloys. Metallographic analysis of post-sintered specimens having undergone prolonged sintering and homogenization revealed extensive Kirkendall pore formation from unequal diffusivities (DCu > DNi). In this study, the unique combination of diffusion-based modelling as well as DSC, ND, and supporting metallographic analysis has enabled the identification of characteristic sintering behaviour, important process parameters, and processing windows for TLPS in Ni-Cu systems. Quantitative and in situ information of this nature is absent in the previous TLPS literature.

Homogenous acid catalysts are prevalent throughout the chemical industry but all have the drawback of requiring post reaction neutralization and subsequent downstream removal of the product salt. The use of a base to neutralize the acid and the processing of the salt are ancillary to the process and the disposal of the salt is an environmental concern. The work presented here shows the use of alkylcarbonic acids, which form in situ with CO₂ pressure and neutralize on loss of CO₂ pressure rather than requiring a base. Thus CO₂ can be used to "switch" the acid on and off. The properties of alkylcarbonic acids are explored to gain understanding of the mechanisms by which they act. The acids are also used to catalyze the synthesis of α-pinene, methyl yellow, and benzyl iodide. These reactions are examples of common acid catalyzed reactions where this technology could be implemented. The second half of the work explores two other "switches". The first is using temperature to break an emulsion with a novel thermally cleavable surfactant. This technology has potential applications in a wide range of fields where surfactants are used including polymerization, oil recovery, and biosynthesis. The second is using CO₂ to liquefy a solid ionic compound to allow its use as a solvent. This would greatly increase the number of ionic species available for use in ionic liquid-CO₂ biphasic systems.