Yes / Literature data on solubilities of adamantane in organic solvents have been used to obtain properties, or descriptors, of adamantane. There is much less data on substituted adamantanes but we have been able to obtain descriptors for some 40 substituted adamantanes. These descriptors can then be used to estimate a wide range of physicochemical, environmental and other properties of the adamantanes. For the first time, the water-solvent partition coefficient and the gas-solvent partition coefficient into a large range of solvents, can be estimated, the latter being equivalent to Henry's Law constants. A variety of other important properties can also be estimated. These include vapor pressures, enthalpies of vaporization and sublimation, partitions from air and from blood into biological tissues, and skin permeability from water. The descriptors themselves are not exceptional. Adamantane itself has a rather low dipolarity, zero hydrogen bond acidity and a very low hydrogen bond basicity, in common with other multicyclic aliphatic compounds. These lead to adamantane being a very hydrophobic compound, as is evident from our estimated water-octanol partition coefficient.

Many methods exist in the literature for the prediction of pharmacokinetic parameters which describe drug distribution in rat and human, such as tissue-to-plasma partition coefficients (Kps) and volume of distribution (Vss). However, none of these methods make use of the in vivo information obtained at the early stages of the drug development process in the form of plasma concentration vs. time profiles. The overall aim of the presented study was to improve upon an existing Kp prediction method by making use of the distribution information contained within this experimental data. Chapter 2 shows that Kp values can be successfully obtained experimentally, but that this process is expensive and time-consuming. Chapter 3 compares six Kp prediction methods taken from the literature for their ability to predict the Kp values of 80 drugs. The Rodgers et al. model was found to be the most accurate, with over 77% of predictions within 3-fold of experimental values. This Chapter also discusses the Vss prediction ability of some of these methods, with the Poulin & Theil and Rodgers et al. models shown to be the most accurate predictors for rat Vss and human Vss respectively. Chapter 4 investigates the relationship between muscle Kp and the Kps of all other tissues, to show that experimental muscle Kp can be used as a surrogate from which all other non-adipose Kp values can be predicted. However, the predictions made using this method were shown to be less accurate than predictions made by the Rodgers et al. model for the same dataset of drugs. A relationship was identified between muscle Kp and tumour Kp in rat, suggesting a potential way to predict tumour Kp in the future. In Chapter 5, a novel method is developed whereby Kp predictions made by the Rodgers et al. model are updated using prior information obtained from the in vivo concentration-time profile. These updated values are then used within a physiologically-based pharmacokinetic (PBPK) model and are shown in Chapter 6 to generate improved predictions for other pharmacokinetic parameters such as Vss and clearance in both rat and human. 100% of human Vss predictions made by the most accurate of the novel methods presented here were within 3-fold of experimental values, compared to 68.8% of predictions made by the Rodgers et al. model. The work presented here has highlighted the need for a more accurate method for the prediction of Kp values, and has addressed this need by generating a model which improves upon the most accurate Kp prediction method currently found in the literature. This will lead to an increase in confidence in the use of predicted pharmacokinetic parameters within PBPK modelling.

The purpose of this thesis is to analyze the thermochemical properties of solutes in nonelectrolyte pure solvents and to develop mathematical expressions with the ability to describe and predict solution behavior using mobile order theory. Solubilities of pesticides (monuron, diuron, and hexachlorobenzene), polycyclic aromatic hydrocarbons (biphenyl, acenaphthene, and phenanthrene), and the organometallic ferrocene were studied in a wide array of solvents. Mobile order theory predictive equations were derived and percent average absolute deviations between experimental and calculated mole fraction solubilities for each solute were as follows: monuron in 21 non-alcoholic solvents (48.4%), diuron in 28 non-alcoholic solvents (60.1%), hexachlorobenzene (210%), biphenyl (13.0%), acenaphthene (37.8%), phenanthrene (41.3%), and ferrocene (107.8%). Solute descriptors using the Abraham solvation model were also calculated for monuron and diuron. Coefficients in the general solvation equation were known for all the solvents and solute descriptors calculated using multilinear regression techniques.

Fluorinated systems are defined by unique properties that offer advantages in drug delivery, material synthesis and industrial applications. In comparison to their hydrocarbon counterparts, the design of fluorinated solutes for tailored applications is limited by the inability to predict the effect of fluorination on phase behavior. This work examines and interprets the influence of fluorination on the phase behavior of fluorinated solutes and surfactants, with emphasis on their impact on vesicle bilayers. Thermodynamic partitioning of functionalized series of fluorinated and hydrocarbon nicotinate prodrugs fashioned to promote solubility in a fluorocarbon solvent (perfluorooctyl bromide; PFOB) is measured. Predictive approaches are also employed to describe partitioning of these nicotinates between immiscible phases relevant to drug delivery. The findings reveal no strong correlation of the partitioning trends with biological markers of cytotoxicity and prodrug uptake for PFOB mediated delivery. However, partitioning in model membranes (liposomes), which, increases with the hydrophobicity of the perhydrocarbon nicotinates, suggests incorporation in a cellular matrix is chain length dependent. The impact of incorporating fluorinated surfactants in catanionic vesicles, which form spontaneously in dilute aqueous solutions and serve as potential substitutes to conventional meta-stable liposome-based vesicles, is studied. Much larger isotropic vesicle regions are observed in the phase map of the partially fluorinated catanionic surfactant pair, cetylpyridinium bromide/ sodium perfluorooctanoate (CPB/SPFO) than in fully fluorinated HFDPC (1,1,2,2,-tetrahydroperfluorododecyl pyridinium chloride )/SPFO. Fluorescence probing of the vesicle bilayers suggest more fluid bilayers in CPB/SPFO than in HFDPC/SPFO due to better chain packing in the fully fluorinated bilayer. However, the vesicle region is expanded in more asymmetric fluorinated bilayers of HFDPC/SPFH (sodium perfluorohexanoate). The increased chain asymmetry in HFDPC/SPFH results in reduced packing density and more fluid bilayers than in HFDPC/SPFO. The robustness of CPB/SPFO and HFDPC/SPFO vesicles is demonstrated in the synthesis of silica hollow spheres by templating and the retention of encapsulated solutes. Higher colloidal stability of the silica spheres is achieved in HFDPC/SPFO relative to CPB/SPFO due to the barrier effect of the fluorinated bilayer. Similarly, higher solute retention in HFDPC/SPFO is observed. The modulation of phase behavior with fluorination offers opportunities in tunable applications of fluorinated bilayers.

O grande magmatismo intracontinental ocorrido a 133 Ma na Bacia do Paraná foi desenvolvido por um sistema fissural no qual a interação da Pluma Tristão da Cunha na base da litosfera (com ou sem contaminação crustal) gerou derrames, diques e sills no Brasil, nos Estados do RS, SC, PR, SP, MT, MS e GO, e em parte do Paraguai, Argentina e Uruguai. Na Formação Serra Geral, representativa deste intenso magmatismo, foram coletadas amostras de sills (RS, PR, SP e GO) cristalizados entre os sedimentos Paleozóicos pré-vulcânicos da Bacia do Paraná. Já haviam sido realizados diversos estudos geoquímicos a partir da década de 80 com objetivo de identificar as variações químicas de diques, derrames e sills da Formação Serra Geral. No entanto, a utilização de novas técnicas analíticas (EPMA e LA-ICP-MS), utilizadas no presente estudo, proporcionaram o entendimento das variações químicas de forma pontual em minerais ígneos. A geoquímica dos sills estudados caracteriza-os como sub-alcalinos toleíticos continentais que variam de basaltos a andesitos basáltico. Assim, podendo ser divididos em dois grupos químicos: sills do Rio Grande do Sul (baixo TiO2 < 2 wt.%, com concentrações inferiores de P2O5, Nb, Sr, Zr, Zn, Y e Pb e concentrações superiores de Rb, Th, U, e Cs) e sills do Paraná, São Paulo e Goiás (alto TiO2 >2 wt.%, de geoquímica oposta). Petrograficamente, os sills do RS possuem granulação mais fina, ocorrência restrita de cobre nativo e distribuição modal elevada para plagioclásios cálcicos, quando comparados ao sills do PR, SP e GO. A determinação geoquímica por micro-análise em plagioclásios e clinopiroxênios demonstra que as variações químicas identificadas em rocha total são relatas as modificações químicas ocorridas nestes minerais. Variações do coeficiente de partição (KD) de elementos traços compatíveis em diversas zonas de cristais de plagioclásio e clinopiroxênio possuem correlação na substituição dos elementos Ca, Na, Al, Fe e Mg nos sistemas NaAlSi3O8-CaAl2Si2O8 e Mg2Si2O6-CaMgSi2O6-CaFeSi2O6- Fe2Si2O6, respectivamente. Coeficientes de partição de cristais de plagioclásio e clinopiroxênio agora são determinados em diferentes porções de núcleo, intermédio e borda aprimorando o conhecimento da variação do KD até então determinado como um único valor apenas para o cristal. / The large intracontinental magmatism occurred at 133 Ma in the Paraná Basin was developed by a fissure system in which the interaction of Tristan da Cunha plume at the base of the lithosphere (with or without crustal contamination) caused lava flows, dikes and sills in the RS, SC, PR, SP, MT, MS and GO and part of Paraguay, Argentina and Uruguay. In the Serra Geral Formation, representative of intense magmatism, sills crystallized samples were collected (RS, PR, SP and GO) between the Paleozoic prevolcanic sediments of Paraná basin. Several geochemical studies have been carried out since the 80's in order to identify the chemical variations of dikes, sills and lava flows of the Serra Geral Formation. However, the use of new analytical techniques (EPMA and LA-ICP-MS) provided the study of chemical variations in a timely manner in igneous minerals. The geochemistry of the sills studied characterized them as sub-alkaline continental tholeiitic basalts ranging from the basalt to basaltic andesites. Divided into two chemical groups: sills of Rio Grande do Sul (low TiO2 <2 wt.%, With lower concentrations of P2O5, Nb, Sr, Zr, Zn, Y and Pb and higher concentrations of Rb, Th, U, and Cs) and sills of Parana, Sao Paulo and Goiás (high TiO2> 2 wt.%, geochemical opposite). Petrographically the sills of the RS have finer grain, restricted occurrence of native copper and modal higher to calcic plagioclase, compared to the sills of the PR, SP and GO. Geochemical determination by micro-analysis in plagioclases and clinopyroxenes show that the chemical variations identified in whole rock we describe the chemical changes occurring in these minerals. Variations of the partition coefficient (KD) of compatible trace elements in various parts of crystals of plagioclase and clinopyroxene were correlated in the replacement of Ca, Na, Al, Fe and Mg systems NaAlSi3O8-CaAl2Si2O8 and Mg2Si2O6-CaMgSi2O6-CaFeSi2O6-Fe2Si2O6, respectively. Partition coefficients of crystals of plagioclase and clinopyroxene are now determined in different portions of core, intermediate and rim enhance knowledge of the variation of KD previously determined as a single value only to the crystal.

The Miocene rhyolites of the Spor Mountain Formation hosts the world's largest beryllium deposit which produced 85% of the world's beryllium in 2010. The fresh lava is extremely enriched in Be (up to 75 ppm in matrix glass). We have examined the rhyolite to understand the Be enrichment. The Spor Mountain rhyolite contains ~40% quartz, ~40% sanidine, ~10% biotite, and ~10% plagioclase, along with accessory fluorite, columbite, euxenite, fergusonite, monazite, thorite, and zircon. Two types of rhyolite erupted within the Spor Mountain Formation, a less evolved magma (1150 ppm Rb, 42 ppm Be, 0.68 wt% F in matrix glass) and an evolved magma (1710 ppm Rb, 75 ppm Be, 1.56 wt% F in matrix glass). Eruption temperatures estimated using zircon saturation, feldspar-liquid, two feldspar, and Ti-in-quartz geothermometers converge on 718 °C for the less evolved magma and 682 °C for the evolved magma. Using the Ti-in-Qz equation of Huang and Audetat (2012), the pressure of the Spor Mountain rhyolite system is estimated to be around 2 kbar at 700°C. Water content of the rhyolite melt was less than <5 wt%, based on the presence of all four major mineral phases at 700°C and the magma was water undersaturated (Webster et al., 1987). Viscosity of the rhyolite was about 6.2 log Pa·s for the less evolved rhyolite and 5.8 log Pa·s for the evolved rhyolite. Magma viscosities calculated using the Einstein-Roscoe question suggest the evolved magma has a slightly higher viscosity than the less evolved magma (7.0 log Pa·s in the evolved magma vs 6.7 log Pa·s in the less evolved magma) because of higher phenocryst content. Fluorine lowered the melt viscosity, though not by a significant amount (less than 0.5 log units at 1.7 wt% F). Partition coefficients for 32 elements have been calculated for biotite, for 21 elements for sanidine and plagioclase, and for 6 elements for quartz, using data acquired by laser ablation inductively coupled plasma mass spectrometry. Partition coefficients for feldspars in the Spor Mountain rhyolite are generally higher than other silicic magmas, and lower for biotite. Beryllium is one of the most incompatible trace elements in the Spor Mountain rhyolite, with a bulk partition coefficient <0.1. Volatile content of the melt (specifically F), melt composition, and the low temperature of crystallization act as the major controls of trace element partitioning. Trace element models using these partition coefficients suggests that crystal fractionation is the dominant magmatic enrichment process within the rhyolite, requiring ~45% crystallization (f = 55%) of the observed phenocrysts to get compositions from the less evolved to evolved rhyolite. Accumulation of batches of melt formed by different degrees of partial melting cannot explain the great depletion of compatible elements.

O grande magmatismo intracontinental ocorrido a 133 Ma na Bacia do Paraná foi desenvolvido por um sistema fissural no qual a interação da Pluma Tristão da Cunha na base da litosfera (com ou sem contaminação crustal) gerou derrames, diques e sills no Brasil, nos Estados do RS, SC, PR, SP, MT, MS e GO, e em parte do Paraguai, Argentina e Uruguai. Na Formação Serra Geral, representativa deste intenso magmatismo, foram coletadas amostras de sills (RS, PR, SP e GO) cristalizados entre os sedimentos Paleozóicos pré-vulcânicos da Bacia do Paraná. Já haviam sido realizados diversos estudos geoquímicos a partir da década de 80 com objetivo de identificar as variações químicas de diques, derrames e sills da Formação Serra Geral. No entanto, a utilização de novas técnicas analíticas (EPMA e LA-ICP-MS), utilizadas no presente estudo, proporcionaram o entendimento das variações químicas de forma pontual em minerais ígneos. A geoquímica dos sills estudados caracteriza-os como sub-alcalinos toleíticos continentais que variam de basaltos a andesitos basáltico. Assim, podendo ser divididos em dois grupos químicos: sills do Rio Grande do Sul (baixo TiO2 < 2 wt.%, com concentrações inferiores de P2O5, Nb, Sr, Zr, Zn, Y e Pb e concentrações superiores de Rb, Th, U, e Cs) e sills do Paraná, São Paulo e Goiás (alto TiO2 >2 wt.%, de geoquímica oposta). Petrograficamente, os sills do RS possuem granulação mais fina, ocorrência restrita de cobre nativo e distribuição modal elevada para plagioclásios cálcicos, quando comparados ao sills do PR, SP e GO. A determinação geoquímica por micro-análise em plagioclásios e clinopiroxênios demonstra que as variações químicas identificadas em rocha total são relatas as modificações químicas ocorridas nestes minerais. Variações do coeficiente de partição (KD) de elementos traços compatíveis em diversas zonas de cristais de plagioclásio e clinopiroxênio possuem correlação na substituição dos elementos Ca, Na, Al, Fe e Mg nos sistemas NaAlSi3O8-CaAl2Si2O8 e Mg2Si2O6-CaMgSi2O6-CaFeSi2O6- Fe2Si2O6, respectivamente. Coeficientes de partição de cristais de plagioclásio e clinopiroxênio agora são determinados em diferentes porções de núcleo, intermédio e borda aprimorando o conhecimento da variação do KD até então determinado como um único valor apenas para o cristal. / The large intracontinental magmatism occurred at 133 Ma in the Paraná Basin was developed by a fissure system in which the interaction of Tristan da Cunha plume at the base of the lithosphere (with or without crustal contamination) caused lava flows, dikes and sills in the RS, SC, PR, SP, MT, MS and GO and part of Paraguay, Argentina and Uruguay. In the Serra Geral Formation, representative of intense magmatism, sills crystallized samples were collected (RS, PR, SP and GO) between the Paleozoic prevolcanic sediments of Paraná basin. Several geochemical studies have been carried out since the 80's in order to identify the chemical variations of dikes, sills and lava flows of the Serra Geral Formation. However, the use of new analytical techniques (EPMA and LA-ICP-MS) provided the study of chemical variations in a timely manner in igneous minerals. The geochemistry of the sills studied characterized them as sub-alkaline continental tholeiitic basalts ranging from the basalt to basaltic andesites. Divided into two chemical groups: sills of Rio Grande do Sul (low TiO2 <2 wt.%, With lower concentrations of P2O5, Nb, Sr, Zr, Zn, Y and Pb and higher concentrations of Rb, Th, U, and Cs) and sills of Parana, Sao Paulo and Goiás (high TiO2> 2 wt.%, geochemical opposite). Petrographically the sills of the RS have finer grain, restricted occurrence of native copper and modal higher to calcic plagioclase, compared to the sills of the PR, SP and GO. Geochemical determination by micro-analysis in plagioclases and clinopyroxenes show that the chemical variations identified in whole rock we describe the chemical changes occurring in these minerals. Variations of the partition coefficient (KD) of compatible trace elements in various parts of crystals of plagioclase and clinopyroxene were correlated in the replacement of Ca, Na, Al, Fe and Mg systems NaAlSi3O8-CaAl2Si2O8 and Mg2Si2O6-CaMgSi2O6-CaFeSi2O6-Fe2Si2O6, respectively. Partition coefficients of crystals of plagioclase and clinopyroxene are now determined in different portions of core, intermediate and rim enhance knowledge of the variation of KD previously determined as a single value only to the crystal.

O grande magmatismo intracontinental ocorrido a 133 Ma na Bacia do Paraná foi desenvolvido por um sistema fissural no qual a interação da Pluma Tristão da Cunha na base da litosfera (com ou sem contaminação crustal) gerou derrames, diques e sills no Brasil, nos Estados do RS, SC, PR, SP, MT, MS e GO, e em parte do Paraguai, Argentina e Uruguai. Na Formação Serra Geral, representativa deste intenso magmatismo, foram coletadas amostras de sills (RS, PR, SP e GO) cristalizados entre os sedimentos Paleozóicos pré-vulcânicos da Bacia do Paraná. Já haviam sido realizados diversos estudos geoquímicos a partir da década de 80 com objetivo de identificar as variações químicas de diques, derrames e sills da Formação Serra Geral. No entanto, a utilização de novas técnicas analíticas (EPMA e LA-ICP-MS), utilizadas no presente estudo, proporcionaram o entendimento das variações químicas de forma pontual em minerais ígneos. A geoquímica dos sills estudados caracteriza-os como sub-alcalinos toleíticos continentais que variam de basaltos a andesitos basáltico. Assim, podendo ser divididos em dois grupos químicos: sills do Rio Grande do Sul (baixo TiO2 < 2 wt.%, com concentrações inferiores de P2O5, Nb, Sr, Zr, Zn, Y e Pb e concentrações superiores de Rb, Th, U, e Cs) e sills do Paraná, São Paulo e Goiás (alto TiO2 >2 wt.%, de geoquímica oposta). Petrograficamente, os sills do RS possuem granulação mais fina, ocorrência restrita de cobre nativo e distribuição modal elevada para plagioclásios cálcicos, quando comparados ao sills do PR, SP e GO. A determinação geoquímica por micro-análise em plagioclásios e clinopiroxênios demonstra que as variações químicas identificadas em rocha total são relatas as modificações químicas ocorridas nestes minerais. Variações do coeficiente de partição (KD) de elementos traços compatíveis em diversas zonas de cristais de plagioclásio e clinopiroxênio possuem correlação na substituição dos elementos Ca, Na, Al, Fe e Mg nos sistemas NaAlSi3O8-CaAl2Si2O8 e Mg2Si2O6-CaMgSi2O6-CaFeSi2O6- Fe2Si2O6, respectivamente. Coeficientes de partição de cristais de plagioclásio e clinopiroxênio agora são determinados em diferentes porções de núcleo, intermédio e borda aprimorando o conhecimento da variação do KD até então determinado como um único valor apenas para o cristal. / The large intracontinental magmatism occurred at 133 Ma in the Paraná Basin was developed by a fissure system in which the interaction of Tristan da Cunha plume at the base of the lithosphere (with or without crustal contamination) caused lava flows, dikes and sills in the RS, SC, PR, SP, MT, MS and GO and part of Paraguay, Argentina and Uruguay. In the Serra Geral Formation, representative of intense magmatism, sills crystallized samples were collected (RS, PR, SP and GO) between the Paleozoic prevolcanic sediments of Paraná basin. Several geochemical studies have been carried out since the 80's in order to identify the chemical variations of dikes, sills and lava flows of the Serra Geral Formation. However, the use of new analytical techniques (EPMA and LA-ICP-MS) provided the study of chemical variations in a timely manner in igneous minerals. The geochemistry of the sills studied characterized them as sub-alkaline continental tholeiitic basalts ranging from the basalt to basaltic andesites. Divided into two chemical groups: sills of Rio Grande do Sul (low TiO2 <2 wt.%, With lower concentrations of P2O5, Nb, Sr, Zr, Zn, Y and Pb and higher concentrations of Rb, Th, U, and Cs) and sills of Parana, Sao Paulo and Goiás (high TiO2> 2 wt.%, geochemical opposite). Petrographically the sills of the RS have finer grain, restricted occurrence of native copper and modal higher to calcic plagioclase, compared to the sills of the PR, SP and GO. Geochemical determination by micro-analysis in plagioclases and clinopyroxenes show that the chemical variations identified in whole rock we describe the chemical changes occurring in these minerals. Variations of the partition coefficient (KD) of compatible trace elements in various parts of crystals of plagioclase and clinopyroxene were correlated in the replacement of Ca, Na, Al, Fe and Mg systems NaAlSi3O8-CaAl2Si2O8 and Mg2Si2O6-CaMgSi2O6-CaFeSi2O6-Fe2Si2O6, respectively. Partition coefficients of crystals of plagioclase and clinopyroxene are now determined in different portions of core, intermediate and rim enhance knowledge of the variation of KD previously determined as a single value only to the crystal.

The Abraham Solvation Parameter Model (ASPM) is a linear, free-energy relationship that can be used to predict various solute properties based on solute-solvent interactions. The ASPM has been used to predict log (K or Cs,organic/Cs,gas) values, as well as log (P or Cs,organic/Cs,water) values for solute transfer into the following organic solvents: 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 2-isopropoxyethanol and 2-butoxyethanol. The derived log (K or Cs,organic/Cs,gas) correlations describe the experimental data to within 0.14 log units (or less). The derived log (P or Cs,organic/Cs,water) correlations describe the experimental data to within 0.16 log units (or less). The ASPM has also been used to predict the enthalpies of solvation of organic solutes dissolved in the following solvents: acetic acid, dimethyl carbonate, diethyl carbonate, 1-butanol, 1-pentanol, 1-hexanol. The derived enthalpy of solvation correlations, using the L solute descriptor, describe the experimental data to within 2.50 log units (or less). The derived enthalpy of solvation correlations, using the V solute descriptor, describe the experimental data to within 3.10 log units (or less). Validation analyses have been performed on several of the correlations; and, as long as the solute descriptors fall within the given ranges as reported, the original correlations show good predictive ability for determining 1) solute transfer into, and 2) enthalpy of solvation for the aforementioned solvents.

The thermotropic behavior of multilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC), or of DPPC in admixture with cardiolipin or cholesterol, in the presence of various N-alkyl derivatives of both adriamycin-14-valerate has been investigated by high sensitivity differential scanning calorimetry. The analogues, particularly the 14-valerate derivatives, which were most lipophilic as judged by their lipid/buffer, and to a lesser extent by their octanol/buffer, partition coefficients, were the most effective in depressing the tm of the investigated lipids; correlations, however, were not absolute. Other factors, such as the distribution of the drugs between the solid and liquid-crystalline phases of the bilayer, were also important to the observed membrane perturbations. With all anthracyclines, however, no major changes in the transition enthalpy were observed. In the case of vesicles prepared from pure DPPC, curve fitting analysis based on ideal solution theory (J.M. Sturtevant (1984) Proc. Natl. Acad. Sci. USA 81, 1398-1400) applied at relatively low drug concentrations where single peak transitions were produced, adequately described the differential scanning calorimetric results. At high drug concentrations, however, the presence of multipeak transitions were indicative of non-ideality.