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.

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.

O problema de rejeitos radioativos é uma preocupação de âmbito mundial, uma vez que não há, ainda, um local definido para a construção de um repositório para rejeitos radioativos de alto nível. Uma das etapas preliminares para a escolha do local mais apropriado é o estudo geológico associado a estudos experimentais de adsorção das espécies químicas envolvidas nos processo. Neste trabalho foi utilizado uma amostra de rocha basáltica, da região sul da Formação Serra Geral, coletada em Frederico Westphalen (RS), que servirá como candidata à rocha hospedeira para locação de rejeitos radioativos. Foram realizados dois experimentos, a saber: "Batch Test" e percolação, ambos sob pressão atmosférica, à temperatura ambiente de 25°C, com a finalidade de estudar a capacidade de sorção dos elementos terras raras - ETR. Os ETR são utilizados neste trabalho em função de sua analogia com os actinídeos, visando a investigar o comportamento geoquímico e a especiações dos mesmos em águas naturais, buscando a possibilidade de armazenamento geológico de rejeitos radioativos, uma vez que a adsorção dos ETR depende de variáveis do ambiente como pH, força iônica, temperatura e presença de ligantes, como carbonatos e constituintes de superfícies dos minerais. Foi realizado experimento de percolação dos ETR, a 100ppb, no basalto (com granulometria 80 mesh) em soluções com força iônica I= 0,025 M e I=0,5 M de NaCl. O pH foi controlado em uma faixa de 5,6 a 7,6 com adição de HNO3. As concentrações foram analisadas por ICP-MS. O "Batch Test" é uma eficiente forma de se obter isotermas de sorção/dessorção, além de valores da razão entre as distribuições sólido/solução e estimar a solubilidade. O experimento de percolação, foi realizado sob pH controlado em torno de 6, e permitiu verificar a "preferência" dos ETR pesados em relação aos ETR leves. / The problem of radioactive wastes is a concern of world-wide scope, a time that does not still have a defined local for the construction of a repository for radioactive wastes of high level. One of the preliminary stages for the choice of the place more appropriate is the geologic study associated to the experimental studies of adsorprtion of the involved chemical species in the process. In this work, a sample of basaltic rock was used, of the South Region of the Formation Serra Geral, collected in Frederico Westphalen Town (RS), that it will be probably a candidate to the rock hostess for location of radioactive wastes. Two experiments have been carried out through, namely: "Test Batch" and Percolating, both under atmospheric pressure, at the ambient temperature of 25°C, with the purpose to study the capacity of sorption of the rare earth elements - REE. The REE are used in this work in function of its analogy with the actinídes, aiming at to investigate the chemistry behavior and the speciations of the same in natural waters, searching the possibility of geologic storage of radioactive wastes, a time that the adsorption of the REE depends on variables of the environment as pH, ionic strengh, temperature and presence of ligants, as carbonates and constituent of surfaces of minerals. Experiment of percolating of the REE was carried through, 100ppb, in the basalt (with 80 mesh) in solutions with ionic strengh I= 0,025 M and I=0,5 M of NaCl. pH was controlled in a range of 5,6 the 7,6 with HNO3 addition. The concentrations were analyzed by ICP-MS. The "Batch Test" is an efficient form of studing sorption/dessorption isotherms, beyond values of the reason between the distributions solid/solution and estimation of the solubility. The percolating experiment, was carried through under pH controlled around 6, and allowed to verify the behaviour of heavy REE in comparison with the light REE.

O problema de rejeitos radioativos é uma preocupação de âmbito mundial, uma vez que não há, ainda, um local definido para a construção de um repositório para rejeitos radioativos de alto nível. Uma das etapas preliminares para a escolha do local mais apropriado é o estudo geológico associado a estudos experimentais de adsorção das espécies químicas envolvidas nos processo. Neste trabalho foi utilizado uma amostra de rocha basáltica, da região sul da Formação Serra Geral, coletada em Frederico Westphalen (RS), que servirá como candidata à rocha hospedeira para locação de rejeitos radioativos. Foram realizados dois experimentos, a saber: "Batch Test" e percolação, ambos sob pressão atmosférica, à temperatura ambiente de 25°C, com a finalidade de estudar a capacidade de sorção dos elementos terras raras - ETR. Os ETR são utilizados neste trabalho em função de sua analogia com os actinídeos, visando a investigar o comportamento geoquímico e a especiações dos mesmos em águas naturais, buscando a possibilidade de armazenamento geológico de rejeitos radioativos, uma vez que a adsorção dos ETR depende de variáveis do ambiente como pH, força iônica, temperatura e presença de ligantes, como carbonatos e constituintes de superfícies dos minerais. Foi realizado experimento de percolação dos ETR, a 100ppb, no basalto (com granulometria 80 mesh) em soluções com força iônica I= 0,025 M e I=0,5 M de NaCl. O pH foi controlado em uma faixa de 5,6 a 7,6 com adição de HNO3. As concentrações foram analisadas por ICP-MS. O "Batch Test" é uma eficiente forma de se obter isotermas de sorção/dessorção, além de valores da razão entre as distribuições sólido/solução e estimar a solubilidade. O experimento de percolação, foi realizado sob pH controlado em torno de 6, e permitiu verificar a "preferência" dos ETR pesados em relação aos ETR leves. / The problem of radioactive wastes is a concern of world-wide scope, a time that does not still have a defined local for the construction of a repository for radioactive wastes of high level. One of the preliminary stages for the choice of the place more appropriate is the geologic study associated to the experimental studies of adsorprtion of the involved chemical species in the process. In this work, a sample of basaltic rock was used, of the South Region of the Formation Serra Geral, collected in Frederico Westphalen Town (RS), that it will be probably a candidate to the rock hostess for location of radioactive wastes. Two experiments have been carried out through, namely: "Test Batch" and Percolating, both under atmospheric pressure, at the ambient temperature of 25°C, with the purpose to study the capacity of sorption of the rare earth elements - REE. The REE are used in this work in function of its analogy with the actinídes, aiming at to investigate the chemistry behavior and the speciations of the same in natural waters, searching the possibility of geologic storage of radioactive wastes, a time that the adsorption of the REE depends on variables of the environment as pH, ionic strengh, temperature and presence of ligants, as carbonates and constituent of surfaces of minerals. Experiment of percolating of the REE was carried through, 100ppb, in the basalt (with 80 mesh) in solutions with ionic strengh I= 0,025 M and I=0,5 M of NaCl. pH was controlled in a range of 5,6 the 7,6 with HNO3 addition. The concentrations were analyzed by ICP-MS. The "Batch Test" is an efficient form of studing sorption/dessorption isotherms, beyond values of the reason between the distributions solid/solution and estimation of the solubility. The percolating experiment, was carried through under pH controlled around 6, and allowed to verify the behaviour of heavy REE in comparison with the light REE.

O problema de rejeitos radioativos é uma preocupação de âmbito mundial, uma vez que não há, ainda, um local definido para a construção de um repositório para rejeitos radioativos de alto nível. Uma das etapas preliminares para a escolha do local mais apropriado é o estudo geológico associado a estudos experimentais de adsorção das espécies químicas envolvidas nos processo. Neste trabalho foi utilizado uma amostra de rocha basáltica, da região sul da Formação Serra Geral, coletada em Frederico Westphalen (RS), que servirá como candidata à rocha hospedeira para locação de rejeitos radioativos. Foram realizados dois experimentos, a saber: "Batch Test" e percolação, ambos sob pressão atmosférica, à temperatura ambiente de 25°C, com a finalidade de estudar a capacidade de sorção dos elementos terras raras - ETR. Os ETR são utilizados neste trabalho em função de sua analogia com os actinídeos, visando a investigar o comportamento geoquímico e a especiações dos mesmos em águas naturais, buscando a possibilidade de armazenamento geológico de rejeitos radioativos, uma vez que a adsorção dos ETR depende de variáveis do ambiente como pH, força iônica, temperatura e presença de ligantes, como carbonatos e constituintes de superfícies dos minerais. Foi realizado experimento de percolação dos ETR, a 100ppb, no basalto (com granulometria 80 mesh) em soluções com força iônica I= 0,025 M e I=0,5 M de NaCl. O pH foi controlado em uma faixa de 5,6 a 7,6 com adição de HNO3. As concentrações foram analisadas por ICP-MS. O "Batch Test" é uma eficiente forma de se obter isotermas de sorção/dessorção, além de valores da razão entre as distribuições sólido/solução e estimar a solubilidade. O experimento de percolação, foi realizado sob pH controlado em torno de 6, e permitiu verificar a "preferência" dos ETR pesados em relação aos ETR leves. / The problem of radioactive wastes is a concern of world-wide scope, a time that does not still have a defined local for the construction of a repository for radioactive wastes of high level. One of the preliminary stages for the choice of the place more appropriate is the geologic study associated to the experimental studies of adsorprtion of the involved chemical species in the process. In this work, a sample of basaltic rock was used, of the South Region of the Formation Serra Geral, collected in Frederico Westphalen Town (RS), that it will be probably a candidate to the rock hostess for location of radioactive wastes. Two experiments have been carried out through, namely: "Test Batch" and Percolating, both under atmospheric pressure, at the ambient temperature of 25°C, with the purpose to study the capacity of sorption of the rare earth elements - REE. The REE are used in this work in function of its analogy with the actinídes, aiming at to investigate the chemistry behavior and the speciations of the same in natural waters, searching the possibility of geologic storage of radioactive wastes, a time that the adsorption of the REE depends on variables of the environment as pH, ionic strengh, temperature and presence of ligants, as carbonates and constituent of surfaces of minerals. Experiment of percolating of the REE was carried through, 100ppb, in the basalt (with 80 mesh) in solutions with ionic strengh I= 0,025 M and I=0,5 M of NaCl. pH was controlled in a range of 5,6 the 7,6 with HNO3 addition. The concentrations were analyzed by ICP-MS. The "Batch Test" is an efficient form of studing sorption/dessorption isotherms, beyond values of the reason between the distributions solid/solution and estimation of the solubility. The percolating experiment, was carried through under pH controlled around 6, and allowed to verify the behaviour of heavy REE in comparison with the light REE.

Estudos de coeficiente de partição mostram que o valor de Kp do metal pode variar ordens de grandeza conforme as características físico-químicas do solo. Portanto, o Kp é um parâmetro sensível no modelo de avaliação de risco à saúde humana, e normalmente é um valor nominal adotado por agências ambientais que pode não representar adequadamente o solo em estudo e implicar erros no cálculo do risco. Este trabalho tem como objetivos: avaliar a contaminação do solo adjacente à usina termoelétrica de Figueira por metais tóxicos; determinar o Kp dos metais As, Cd, Co, Cr, Cu, Mo, Ni, Pb e Zn no solo pela razão entre a concentração do metal obtida por digestão com HNO3 concentrado e a concentração do metal obtida por extração com EDTA 0,05 mol L-1 (KpEDTA) ou Ca(NO3)2 0,1 mol L-1 (KpCa(NO3)2); e avaliar a influência do uso dos diferentes valores de Kp no modelo de avaliação de risco à saúde humana C-Soil no cálculo do risco. As principais conclusões foram: os metais contaminantes do solo de Figueira foram As, Cd, Mo, Pb e Zn, e o As foi o elemento mais crítico; tanto o valor de KpCa(NO3)2 quanto o de KpEDTA poderiam ser utilizados no cálculo do risco à saúde humana, no caso de Figueira, exceto para o Pb, mas o KpEDTA seria mais recomendado, por apresentar valores com menor dispersão; os valores nominais de KpCSoil dos metais poderiam ser utilizados para o cálculo de risco à saúde humana no caso de Figueira, ou seja, não teria necessidade de se determinar valores de Kp locais (KpEDTA e KpCa(NO3)2), exceto para o Pb. / Studies of partition coefficient show that Kp values of metals can vary orders of magnitude according to the soil physical-chemistry characteristics. Therefore, the Kp is a sensible parameter in human health risk assessment model. In general, a default value is adopted by environmental agencies and often it is not represent suitably the soil studied and can cause errors in the risk calculation. The objectives of this work are: evaluate the heavy metals soil contamination around the Figueira coal-fired power plant; determine the metal Kp of As, Cd, Co, Cr, Cu, Mo, Ni, Pb and Zn in soil by the ratio between the metal concentration obtained by concentrate HNO3 digestion and the metal concentration obtained by extraction with EDTA 0,05 mol L-1 (KpEDTA) or Ca(NO3)2 0,1 mol L-1 (KpCa(NO3)2); and evaluate the influence of the application of different Kp values in human health risk assessment C-Soil model in risk calculation. The main conclusions of the present study were: As, Cd, Mo, Pb e Zn were the Figueira soil metal contaminants, being As the pollunt of major human health concern; either KpCa(NO3)2 or KpEDTA values could be used for human health risk calculation, in Figueira case, except for Pb, and the KpEDTA values were preferably recommended due to the less dispersion of their values; the KpCSoil metals default values could be applied for the human health risk calculation in Figueira case, in other words, it would not have necessity to determine Kp values of region (KpEDTA and KpCa(NO3)2), except to Pb.

Submitted by Edineia Teixeira (edineia.teixeira@unioeste.br) on 2017-09-04T17:30:26Z No. of bitstreams: 2 Carlos_Olguin2017.pdf: 2821259 bytes, checksum: 4f44c019ceff1c4613be9b0b525a188e (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-09-04T17:30:26Z (GMT). No. of bitstreams: 2 Carlos_Olguin2017.pdf: 2821259 bytes, checksum: 4f44c019ceff1c4613be9b0b525a188e (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-02-17 / The soil sorption coefficient normalized for organic carbon content (Koc) is a physicochemical parameter used in environmental risk assessments to determine the final destination of chemicals released in the environment. So, in oreder to predict this parameter, several models were proposed based on the relationship between LogKoc and LogP. The difficulty and cost to obtain experimental values of LogP have drawn to the algorithms development to calculate those values. Thus, in the first paper of this thesis, several free algorithms were considered to calculate LogP, and it was concluded that the best QSPR models to predict soil sorption coefficient of organic nonionic compounds were obtained using ALOGPs, KOWWIN and XLOGP3 algorithms. This study demonstrated the importance and usefulness of the statistical equivalence test used, since it allowed us to state that the models obtained from the considered algorithms are statistically equivalent. In this study, the both importance and usefulness of the statistical equivalence test were proved. These data allowed us to state that the models that have been obtained from the algorithms are statistically equivalent. Thus, in the impossibility of obtaining LogP values based on one of the algorithms, values obtained by another one of them can be used. It was also observed that the models presented in this study presented statistical quality and predictive capacity compatible with more complex models recently published in the area. In addition, it is a well accepted practice in the area the requirement to validate the prediction of a QSPR model from a data set that was not used in the model generation. In this context, some studies have explored the impact that several sizes of training sets would have on the predictive capacity of the generated QSPR models, consequently not reaching conclusive results. Thus, the second paper has been shown that, from not so large training sets, statistically equivalent QSPR models can be developed and that these models have similar predictive capacity to those ones created from a larger training set. Therefore, models were generated considering LogP values of the total training set, calculated with the ALOGPs algorithm and also with subsets of itself (i.e., halves, quarters and eighths). This study, just like the previous one, has confirmed the importance of using the statistical equivalence test since it was ascertained that, following the adopted procedures, the models obtained with subsets of the training set are statistically equivalent / O coeficiente de sorção do solo normalizado para o conteúdo de carbono orgânico (Koc) é um parâmetro físico-químico utilizado em avaliações de risco ambiental e na determinação do destino final das substâncias químicas lançadas na natureza. Vários modelos para prever este parâmetro foram propostos com base na relação entre LogKoc e LogP. A dificuldade e o custo para a obtenção de valores experimentais de LogP levaram ao desenvolvimento de algoritmos para calculá-los. Assim, no primeiro artigo desta tese foram considerados diversos algoritmos gratuitos para cálculo de LogP, e concluiu-se que os melhores modelos QSPR para predizer o coeficiente de sorção do solo de compostos orgânicos não iónicos foram obtidos usando os algoritmos ALOGPs, KOWWIN e XLOGP3. Neste estudo, foram demonstradas a importância e a utilidade do teste de equivalência estatística utilizado, dados que nos permitiram afirmar que os modelos obtidos dos algoritmos considerados são estatisticamente equivalentes. Assim, na impossibilidade de obterem-se valores de LogP a partir de um dos algoritmos, valores obtidos por outro podem ser usados. Verificou-se ainda que os modelos apresentados neste estudo possuem qualidade estatística e capacidade de predição compatíveis à de modelos mais complexos, publicados recentemente na área. Adicionalmente, a necessidade de se realizar a validação da predição de um modelo QSPR a partir de um conjunto de dados que não foi utilizado na geração do modelo é uma prática bem aceita na área. Nesse contexto, alguns trabalhos exploraram o impacto que diversos tamanhos de conjuntos de treinamento teriam na capacidade de predição dos modelos QSPR gerados, não chegando a resultados conclusivos. Assim, no segundo artigo desta tese, foi mostrado que, a partir de conjuntos de treinamento não tão grandes, modelos QSPR estatisticamente equivalentes podem ser desenvolvidos e que tais modelos têm capacidade de predição similar daqueles criados a partir de um conjunto de treinamento maior. Para isto, modelos foram gerados considerando valores de LogP do conjunto de treinamento total, calculados com o algoritmo ALOGPs e também com subconjuntos do mesmo (i.e., metades, quartos e oitavos). Este estudo, assim como o anterior, confirmou a importância do uso do teste de equivalência estatística utilizado nesta tese já que foi verificado que, seguindo os procedimentos adotados, os modelos obtidos com subconjuntos do conjunto de treinamento são estatisticamente equivalentes.

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.

Yes / The extraction of bioactive compounds, produced by plant cell cultures, directly from their culture medium, which contains other by-products, is a great challenge. Resveratrol extraction from its grapevine cell cultures is considered here as an example to improve the extraction processes from plant cell cultures using solubility parameters. Successive liquid-liquid extraction (LLE) processes were exploited to extract resveratrol from the culture medium with an extraction ratio approaching 100%, high selectivity and minimum amounts of solvents. The calculations of partition coefficients as a function of solubility parameters demonstrated that benzyl benzoate is the most suitable intermediate solvent to extract resveratrol from its aqueous medium. The calculations also illustrated the high ability of methanol and ethanol to extract resveratrol from benzyl benzoate. The physicochemical properties of benzyl benzoate and processing conditions were exploited to separate it from aqueous media and organic solvents. The agitation method, component ratios and extraction time were studied to maximize the extraction yield. Under the best studied conditions, the recovery of resveratrol from different culture media approached ∼100% with a selectivity of ∼92%. Ultimately, the improved extraction processes of resveratrol are markedly efficient, selective, rapid and economical. / Mohammad Amin Mohammad gratefully acknowledges CARA (The Council for At-Risk Academics, Stephen Wordsworth and Ryan Mundy) for providing the financial support for an academic fellowship.

No description available.