The physicochemical properties and chemical reactivity of dissolved organic matter (DOM) are of tremendous practical significance in both natural and engineered aquatic and terrestrial systems. DOM is frequently extracted, fractionated, and concentrated from environmental samples using a variety of operationally defined physical and chemical processes in order to facilitate study of specific physicochemical properties and aspects of its chemical reactivity. This study was conducted to systematically examine the influence of operationally defined physical and chemical characterization methods on observed DOM physicochemical properties and reactivity with aqueous chlorine. The effects of chemical separation were evaluated by applying an existing resin adsorption based procedure which simultaneously extracts and fractionates DOM and inorganic constituents into hydrophobic and hydrophilic acid, base, and neutral dissolved material matrix (DMM) fractions. Physical separation based on DOM apparent molecular weight (AMW) was also evaluated using batch ultrafiltration (UF) data in conjunction with a suitable membrane permeation model. Linear independence of membrane solute transport was theoretically described using non-equilibrium thermodynamics and experimentally demonstrated for AMICON® YC/YM series UF membranes. Mass balances on DMM fraction constituents in untreated and previously coagulated natural waters indicated that quantitative recovery (100 ± 2%) of DOM constituents was achieved, while recovery of inorganic constituents such as iron and aluminum was substantially incomplete (30%-74%). Comparison of whole-water DOM properties with those mathematically reconstituted from DMM fractions demonstrated a marked shift in DOM properties toward lower AMW. Evidence of pH induced partial hydrolysis of protein, polysaccharide, and ester DOM components was also observed. Decreased specific Cl2 demand (mmol DCl2/ mmol DOM) and specific trihalomethane formation (mmol THM/mmol DOM) following chemical fractionation were attributed to increased molar DOM concentration and decreased DOM association with colloidal iron oxide surfaces. Collectively, the results of this research indicate that operational characterization methods result in alteration of DOM physicochemical properties and reactivity with aqueous chlorine, and caution is therefore advisable when interpreting the results of studies conducted using chemically extracted or fractionated DOM. / Ph. D.

Researchers use multiple sequence alignment algorithms to detect conserved regions in genetic sequences and to identify drug docking sites for drug development. In this dissertation, a novel algorithm is presented for using physicochemical properties to increase the accuracy of multiple sequence alignments. Secondary structures are also incorporated in the evaluation function. Additionally, the location of the secondary structures is assimilated into the function. Multiple properties are combined with weights, determined from prediction accuracies of protein secondary structures using artificial neural networks. A new metric, the PPD Score is developed, that captures the average change in physicochemical properties. Using the physicochemical properties and the secondary structures for multiple sequence alignment results in alignments that are more accurate, biologically relevant and useful for drug development and other medical uses. In addition to a novel multiple sequence alignment algorithm, we also propose a new protein-coding DNA reference alignment database. This database is a collection of multiple sequence alignment data sets derived from tertiary structural alignments. The primary purpose of the database is to benchmark new and existing multiple sequence alignment algorithms with DNA data. The first known comparative study of protein-coding DNA alignment accuracies is also included in this work.

No description available.

No / The surface energy of a-lactose monohydrate measured by inverse gas chromatography (IGC) is reported along with a dynamic molecular modelling study of the interaction of the various molecular probes with different surfaces of a-lactose monohydrate. The IGC results show that a-lactose monohydrate is acidic in nature. Using quantitative calculations of the energy of adsorption, the acidic nature of the surface is confirmed and the calculated values agree closely with the experimentally measured values. Along with the acidic nature, dynamic molecular modelling also reveals that the presence of a channel and water molecules on a surface affects the surface energetics of that face. The presence of water on the surface can decrease or increase the surface energy by either blocking or attracting a probe molecule, respectively. This property of water depends on its position and association with other functional groups present on the surface. The effect of a channel or cavity on the surface energy is shown to depend on its size, which determines whether the functional groups in the channel are assessable by probe molecules or not. Overall molecular modelling explains, at the molecular level, the effect of different factors affecting the surface energy of individual faces of the crystal.

Yes / Properties of a matter are intrinsically dependent upon the internal arrangement of molecules in the solid state. Therefore, knowledge of 3-dimensional structure of the matter is prerequisite for structure-property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geosciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceutical cocrystals-crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved promising for fine-tuning several important properties of APIs. This short review highlights the history of crystallography, early breakthroughs, and the role of crystallography in understanding physicochemical properties of pharmaceutical cocrystals. / S. Aitipamula gratefully acknowledges the financial support from the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore. V. R. Vangala thanks Royal Society of Chemistry for Researcher Mobility Grant (2015/17).

Yes / The role of human serum albumin (HSA) in the transport of molecules predicates its involvement in the determination of drug distribution and metabolism. Optimization of ADME properties are analogous to HSA binding thus this is imperative to the drug discovery process. Currently, various in silico predictive tools exist to complement the drug discovery process, however, the prediction of possible ligand-binding sites on HSA has posed several challenges. Herein, we present a strong and deeper-than-surface case for the prediction of HSA-ligand binding sites using multi-cavity molecular descriptors by exploiting all experimentally available and crystallized HSA-bound drugs. Unlike previously proposed models found in literature, we established an in-depth correlation between the physicochemical properties of available crystallized HSA-bound drugs and different HSA binding site characteristics to precisely predict the binding sites of investigational molecules. Molecular descriptors such as the number of hydrogen bond donors (nHD), number of heteroatoms (nHet), topological polar surface area (TPSA), molecular weight (MW), and distribution coefficient (LogD) were correlated against HSA binding site characteristics, including hydrophobicity, hydrophilicity, enclosure, exposure, contact, site volume, and donor/acceptor ratio. Molecular descriptors nHD, TPSA, LogD, nHet, and MW were found to possess the most inherent capacities providing baseline information for the prediction of serum albumin binding site. We believe that these associations may form the bedrock for establishing a solid correlation between the physicochemical properties and Albumin binding site architecture. Information presented in this report would serve as critical in provisions of rational drug designing as well as drug delivery, bioavailability, and pharmacokinetics.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with high levels of tumour necrosis factor-alpha (TNF-a) in synovial fluid and synovial tissue (Saxne et al., 1989). Thalidomide is a proven inhibitor of the biological synthesis of TNF-a (Sampaio et al., 1991) and is believed to rely on this action for its suppression of the wasting of tissue which accompanies RA. Oral administration of thalidomide has proven to be effective in RA, but unacceptable side effects are easily provoked (Gutierrez-Rodriguez, 1984). Administration of thalidomide via the dermal route can down-regulate TNF-a production in and around the affected joint, and this without raising the systemic blood level to a problematical level. Based on thalidomide's physicochemical properties, it is unlikely that it can be delivered percutaneously at a dose required for RA. Therefore, we have embraced the idea of using N-alkyl analogues of thalidomide. The most important feature that an analogue of this compound might contribute is decreased crystallinity and increased lipophilicity. Ordinarily both these parameters should favour percutaneous delivery. The current study was primarily aimed at exploring the feasibility of percutaneous delivery of thalidomide and subsequently, three of its odd chain IV-alkyl analogues (methyl, propyl and pentyl) via physicochemical characterization and assessment of their innate abilities to diffuse through skin as an initial step towards developing a topical dosage form for the best compound. The biological activities, more specifically their potential to inhibit the production of TNF-a was determined for thalidomide and its N-alkyl analogues. In order to achieve the objectives, the study was undertaken by synthesizing and determining the physicochemical parameters of thalidomide and its N-alkyl analogues. A high level of crystallinity is expressed in the form of a high melting point and heat of fusion. This limits solubility itself, and thus also sets a limit on mass transfer across the skin. Generally, the greater a drug's innate tendency to dissolve, the more likely it is that the drug can be delivered at an appropriate rate across the skin (Ostrenga et al., 1971). Therefore, the melting points and heats of fusion were determined by differential scanning calorimetry. Aqueous solubility and the partition coefficient (relative solubility) are major determinants of a drug's dissolution, distribution and availability. N-octanollwater partition coefficients were determined at pH 6.4. Solubilities in water, a series of n-alcohols and mixed solvents were obtained, as well as the solubility parameters of the compounds in study. Secondly, in vitro permeation studies were performed from these solvents and vehicles using vertical Franz diffusion cells with human epidermal membranes. Thirdly, tumour necrosis factor-alpha (TNF-a) inhibition activities were assessed for thalidomide and its N-alkyl analogues. By adding a methyl group to the thalidomide structure, the melting point drops by over 100°C and, in this particular instance upon increasing the alkyl chain length to five -CH2- units the melting points decrease linearly. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Methylation of the thalidomide molecule enhanced the aqueous solubility 6-fold, but as the alkyl chain length is further extended from methyl to pentyl, the aqueous solubility decreased exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increase in lipophilicity and consequently an increase in solubility in nonpolar media. Log partition coefficients increased linearly with increasing alkyl chain length. Solubilities in a series of n-alcohols, methanol through dodecanol, were found to be in the order of pentyl > propyl > methyl > thalidomide. The N-alkyl analogues have more favourable physicochemical properties than thalidomide to be delivered percutaneously. The in vitro skin permeation data proved that the analogues can be delivered far easier than thalidomide itself. N-methyl thalidomide showed the highest steady-state flux through human skin from water, n-alcohols and combination vehicles. Thalidomide and its N-alkyl analogues were all active as TNF-a inhibitors. Finally, active as a TNF-a inhibitor, N-methyl thalidomide is the most promising candidate to be delivered percutaneously for treatment of rheumatoid arthritis, of those studied. / Thesis (PhD (Pharmaceutics))--PU for CHE, 1999.

Le poly(butylène succinate) (PBS) est un polyester aliphatique biodégradable dont les propriétés en font un bon candidat pour le remplacement des polyoléfines. De plus, ses deux monomères, l'acide succinique et le butane-1,4-diol, peuvent être issus de la biomasse via un procédé de fermentation de sucres. L'étude réalisée ici a été séparée en deux grandes parties : le PBS linéaire d'une part et le PBS branché d'autre part. La première partie montre que la cinétique de synthèse du PBS suit bien le modèle d'estérification établi par Flory. Par la suite, l'étude des propriétés physico-chimiques du PBS a permis de remonter à des paramètres comme la masse molaire critique d'enchevêtrement, le module du plateau caoutchoutique, l'énergie d'activation du PBS fondu ou encore les paramètres de l'équation Mark-Houwink-Sakurada. Une étude sur ses propriétés thermiques a permis de décrire l'évolution de son comportement en fonction de sa masse molaire. Enfin, le profil d'énergie potentielle de l'estérification entre l'acide succinique et le butane-1,4-diol a été tracé en utilisant un outil de chimie quantique. La seconde partie traite de l'étude de PBS branchés obtenus en employant des agents de branchement (polyols) pouvant être issus de la biomasse comme l'huile de ricin, le glycérol et le polyglycérol. La stratégie adoptée a été le couplage entre un oligomère PBS fonctionnalisé acide carboxylique et les agents de branchement. L'étude en présence d'huile de ricin a mis en avant les relations entre la structure, déterminée en SEC-Triple Détection, et les propriétés physico-chimiques du PBS branché. L'optimisation de la synthèse en présence de glycérol ou de polyglycérol a été abordée à partir de la méthode des plans d'expériences. Comparé à la méthode « un facteur à la fois », des résultats prometteurs et semblables à ce qui est rapporté dans la littérature ont été obtenus pour l'étude du PBS branché en présence de glycérol. / Poly(butylene succinate) (PBS) is a biodegradable aliphatic polyester whose properties make it a promising polymer for the replacement of polyolefins. Moreover, its two monomers, succinic acid and 1,4-butanediol, can be produced via a fermentation process of sugars. This study has been separated into two great parts: linear PBS on the one hand and branched PBS on the other hand. In the first part, kinetics of the PBS synthesis showed a good agreement with the esterification model of Flory. We determined some fundamental parameters of PBS like critical molecular weight of entanglement, the rubbery plateau modulus, the energy of activation of melt PBS and parameters of the Mark-Houwink-Sakurada relationship. We have also realized a study on the influence of the molecular weight on the thermal properties of PBS. Finally, we constructed the potential energy profile of the esterification between succinic acid and 1,4-butanediol through a quantum chemistry study. The second part dealt with the study of branched PBS in the presence of biosourced polyols like castor oil, glycerol and polyglycerol. These syntheses were realized between an acid-functionalized PBS oligomer and the branching agents. We put forward the relationships between the structure, determined by SEC-Triple Detection, and the physicochemical properties of branched PBS in presence of castor oil. Syntheses of branched PBS in presence of glycerol or polyglycerol were optimized with design of experiments technique. Promising and similar results from the literature were obtained in the case of branched PBS in presence of glycerol compared to the method of “one parameter at a time”.

Foram sintetizadas duas séries de tensoativos catiônicos de estruturas gerais RCONH(CH2)2-N+(CH3)3 Cl- e RCONH(CH2)2-N+(CH3)2-CH2-C6H5 Cl-, sendo RCO uma cadeia acílica contendo 10, 12, 14 e 16 átomos de carbono. Estes tensoativos foram sintetizados pela reação do ácido carboxílico puro com N,N-dimetiletilenodiamina resultando na amidoamina correspondente. A quaternização desta última foi feita pela reação com cloreto de benzila ou com iodeto de metila. Os iodetos foram convertidos nos correspondentes cloretos por troca-iônica. A localização média da interface micelar e a conformação do grupo hidrofílico na micela foram investigadas por IV e RMN. A adsorção na interface solução-ar e a micelização foram estudadas por diversas técnicas: calorimetria, condutância, FEM (força eletromotriz), IV de FT, RMN e tensão superficial. Os resultados foram comparados com os de tensoativos catiônicos comuns, como R\'N+(CH3)3R\" Cl-, sendo R\' = grupo alquílico contendo de 10 a 16 carbonos e R\" = um grupo metila ou benzila. A adsorção e a micelização dos tensoativos contendo o \"espaçador\" (CONH-CH2-CH2) são mais favoráveis. Os valores de ΔGºads e ΔGºmic mais negativos para estes tensoativos, refletem principalmente a transferência mais favorável do grupo polar da solução aquosa para a interface solução/ar e/ou para a micela. Isto ocorre devido à formação de ligações de H, diretas e/ou via água, entre os grupos amida dos monômeros de tensoativo na interface e micela. As diferenças nos valores de ΔGºcabeça+CH3 dos tensoativos com e sem o grupo amida na adsorção (ΔΔGº ads cabeça+CH3 = -17.2 kJ mol-1) e micelização (ΔΔGº ads cabeça+CH3 = -5 a -7 kJ mol-1) estão de acordo com a energia de ligações de H fracas. Os resultados de IV de FT e RMN de 1H comprovaram a formação destas ligações de H e indicaram que a carbonila está presente na interface e o grupo benzila está voltado para o interior da micela. / Two series of cationic surfactants have been synthesized: benzyl-(2acylaminoetil) dimethylammonium chlorides, RCONH(CH2)2-N+(CH3)3 Cl-, and (2-acylaminoethyl)dimethylammonium chlorides, RCONH(CH2)2-N+(CH3)2-CH2-C6H5 Cl-, where RCO refers to an acyl group with 10, 12, 14 and 16 carbon atoms. These surfactants were obtained by reacting chromatographically pure carboxylic acids with N,N-dimethylethylenediamine to give an intermediate amidoamine. The latter was quaternized with benzyl chloride or methyl iodide. Surfactants with iodide counter-ion were transformed into the corresponding chlorides by ion exchange on a macro-porous resin. The average position of micellar interface and conformation of the headgroup were studied by FTIR and NMR. A multi-technique approach has been employed in order to study the effects of the presence of the \"spacer\" group (-CONH- CH2-CH2) on the adsorption and aggregation of these surfactants. The techniques employed were: calorimetry, conductance and EMF measurements, FTIR, NMR, surface tension, and Iight scattering. Surfactants with the spacer group (CONH-CH2-CH2) have more favorable Gibbs free energies of adsorption and/or micellization due to the more favorable transfer of the head-group from bulk phase to the interface and/or the micelle. This is attributed to the formation of direct, and/or water-mediated H-bonding between the surfactant amide groups. Differences in values of ΔGºHead-group+CH3 of surfactants with and without spacer group (ΔΔGº ads Head-group+CH3 = -17.2 kJ mol-1 and ΔΔGº ads Head-group+CH3 = -5 a -7 kJ mol-1 for adsorption and/or micellization, respectively) are in agreement with weak hydrogen bonding. Additional evidence for H-bond formation and for the (average) conformation of the benzyl head-group in the micelle was provided by FTIR and NMR data. The former showed that the amide group is highly hydrated, whereas the latter showed shielding/deshielding of the methylene groups of the surfactant hydrophobic tail, in agreement with a conformation in which the benzyl group is \"bent\" toward the micellar interior.

O objetivo deste trabalho foi produzir pigmentos em pó a partir dos subprodutos de vinificação da uva tinta, variedade Bordô (Vitis labrusca), através da secagem em spray dryer utilizando maltodextrina como agente carreador. Foram estudados os efeitos das condições de processo sobre algumas propriedades físico-químicas, além da estabilidade e da atividade biológica do material obtido. Extratos etanólicos das cascas e sementes da uva foram obtidos e concentrados até um terço do volume inicial. Este extrato foi então misturado com o agente carreador maltodextrina 10 DE nas concentrações de 10, 20 ou 30% e atomizado em spray dryer, com vazão de alimentação de 44 mL/min e temperaturas do ar de entrada de 130, 150 ou 170°C, num total de nove ensaios. Além disso, foi obtida uma amostra de extrato concentrado liofilizado, sem a presença do agente carreador, para efeito de comparação. Avaliou-se o rendimento do processo de atomização; e para as amostras obtidas determinou-se o teor de umidade, retenção de antocianinas, higroscopicidade e solubilidade em água, a fim de verificar a influência das condições de processo sobre essas características. Estas amostras também foram avaliadas quanto à morfologia, distribuição do tamanho de partículas e isotermas de sorção de umidade. Todas as amostras obtidas (atomizadas e liofilizada) foram avaliadas quanto à cor instrumental, espectroscopia de infravermelho, estabilidade durante a estocagem, presença de compostos bioativos (fenólicos, flavonóides, antocianinas e proantocianidinas), além de atividade antioxidante, antimicrobiana e de inibição da arginase de Leishmania. As condições de processo avaliadas (temperatura de secagem e concentração de agente carreador) tiveram forte influência nas características estudadas. O teor de umidade, a retenção de antocianinas, a morfologia e o tamanho das partículas, foram bastante influenciados pela temperatura de secagem e pela concentração de agente carreador, enquanto que a higroscopicidade sofreu maior influência da concentração de agente carreador. Esse parâmetro também apresentou grande influência nas isotermas de sorção de umidade das amostras. Não houve grande interferência do processo de secagem na composição química do material obtido, evidenciada pelos espectros de infravermelho. Quanto à avaliação da estabilidade durante a estocagem, foi observado que as amostras contendo maltodextrina conservaram mais as antocianinas e a cor, quando comparadas com as amostras sem carreador e os extratos líquidos, indicando, que o processo de secagem e a presença do carreador, promoveram um efeito protetor aos compostos e sua cor. Todas as amostras apresentaram altos teores de flavonóides totais, antocianinas, proantocianidinas e elevados valores de atividade antioxidante variando de 314,06 a 441,04 µmolesTE/g de extrato seco pelo método DPPH e de 993,32 a 1138,68 µmolesTE/g de extrato seco pelo método FRAP. Apresentaram atividade antimicrobiana principalmente contra Staphylococcus aureus e Listeria monocytogenes. Além disso, tiveram grande capacidade de inibir a enzima arginase de Leishmania com porcentagem de inibição variando de 54,60 a 83,43%. Os resultados encontrados sugeriram que o processo de secagem em spray dryer com maltodextrina, dos extratos obtidos dos subprodutos da uva Bordô, produziu pós com diversas características interessantes, como baixa higroscopicidade, alta solubilidade e estabilidade, além de grande potencial biológico. Tais resultados evidenciam que este subproduto da indústria vinícola pode ser aproveitado como fonte natural de ingredientes funcionais. / The aim of this work was to produce powder pigments from grape byproducts of Bordo variety (Vitis labrusca) by spray drying using maltodextrin as carrier agent. The effects of process conditions on some physicochemical properties, stability and biological activity of the product were studied. Ethanol extracts were obtained from grape pomace (skins and seeds) and concentrated to one-third the initial volume. This extract was then mixed with the carrier agent 10 DE maltodextrin at concentrations of 10, 20 or 30% and atomized in a spray dryer, with feed flow rate of 44 mL/min and inlet drying air temperatures of 130, 150 or 170°C a total of nine tests. In addition, a sample of freeze-dried concentrated extract without carrier agent was obtained for comparison. It was evaluated process yield and the samples obtained were initially evaluated for moisture content, anthocyanins retention, hygroscopicity and solubility in water, in order to verify the influence of process conditions on these characteristics. These samples were also evaluated for morphology, particle size distribution and moisture sorption isotherms. All samples (spray-dried powders and freeze-dried extract) were evaluated for instrumental color, infrared spectroscopy, stability during storage, presence of bioactive compounds (phenols, flavonoids, anthocyanins and proanthocyanidins) plus antioxidant activity, antimicrobial activity and inhibition of Leishmania arginase. Process conditions evaluated (inlet drying air temperature and carrier agent concentration) had a strong influence on the characteristics studied. The moisture content, anthocyanin retention, morphology and particle size of the samples were strongly influenced by drying temperature and carrier agent concentration while the hygroscopicity suffered greater influence of the carrier agent concentration. The concentration of carrier agent also had great influence on the moisture sorption isotherms of the samples. There was no significant interference of the drying process on the chemical composition of the material evidenced by infrared spectroscopy. Regarding the evaluation of stability during storage, it was observed that the samples containing maltodextrin, retained much more anthocyanins and original color when compared with the sample without a carrier or liquid extracts, indicating both, the drying process and the presence of carrier, promoted a protective effect to the compounds and its color. All samples showed high levels of flavonoids, anthocyanins, proanthocyanidins and high levels of antioxidant activity ranging from 314.06 to 441.04 µmolTE/g of extract (dry weight), by DPPH and 993.32 to 1138.68 µmolTE/g of extract (dry weight) by FRAP method. Most samples showed antimicrobial activity against Staphylococcus aureus and Listeria monocytogenes. Moreover, had great ability to inhibit the enzyme arginase of Leishmania with inhibition percentage ranging from 54.60 to 83.43%. The results suggest that the drying process of Bordo grape pomace extracts in a spray dryer with maltodextrin, produced powders with various interesting characteristics such as low hygroscopicity, high solubility and stability, and large biological potential. This shows that this byproduct of wine industry can be used as a natural source of functional ingredients.