Ester prodrugs of a potent analgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties

The aim of this work is to develop 3-acyl prodrugs of the potent analgesic morphine-6-sulfate (M6S). These are expected to have higher potency and/or exhibit longer duration of analgesic action than the parent compound. M6S and the prodrugs were synthesized, then purified either by recrystallization or by semi-preparative HPLC and the structures confirmed by mass spectrometry, IR spectrophotometry and by detailed 1- and 2-D NMR studies. The lipophilicities of the compounds were assessed by a combination of shake-flask, group contribution and HPLC retention methods. The octanol-buffer partition coefficient could only be obtained directly for 3-heptanoylmorphine-6-sulfate, using the shake-flask method. The partition coefficients (P) for the remaining prodrugs were estimated from known methylene group contributions. A good linear relationship between log P and the HPLC log capacity factors was demonstrated. Hydrolysis of the 3-acetyl prodrug, as a representative of the group, was found to occur relatively slowly in buffers (pH range 6.15-8.01), with a small buffer catalysis contribution. The rates of enzymatic hydrolysis of the 3-acyl group in 10% rat blood and in 10% rat brain homogenate were investigated. The prodrugs followed apparent first order hydrolysis kinetics, with a significantly faster hydrolysis rate found in 10% rat brain homogenate than in 10% rat blood for all compounds. (C) 1998 Elsevier Science B.V. All rights reserved.

Hydrogen and oxygen isotope behaviors during variable degrees of upper mantle melting: Example from the basaltic glasses from Macquarie Island

We present measurements of hydrogen and oxygen isotopes in MORB glasses from Macquarie Island (SW. Pacific Ocean) coupled with determination of bulk H2O content by two independent techniques: total dehydration and FTIR. The incompatible trace elements in these glasses vary by a factor of 12 to 17, with K2O varying from 0.1 to 1.7 wt.%; these ranges reflect a variable degree of closed-system mantle melting, estimated from 1 to 15%. Water concentrations determined by the two techniques match well, yielding a range from 0.25 to 1.49 wt.% which correlates positively with all of the measured incompatible trace elements, suggesting that water is un-degassed, and behaves conservatively during mantle melting. Also, the agreement between the FTIR-determined and extracted water contents gives us confidence that the measured isotopic values of hydrogen reflect that of the mantle. Comparison of the range of water content with that of other incompatible trace elements allows estimation of the water partition coefficient in lherzolite, 0.0208 (ranging from 0.017 to 0.023), and the water content in the source, 386 ppm (ranging from 370 to 440 ppm). We observe a fairly narrow range in delta D and delta O-18 values of -75.5 +/- 4.5 parts per thousand and 5.50 +/- 0 .05 parts per thousand respectively, that can be explained by partial melting of normal lherzolitic mantle. The measured delta D and delta O-18 values of Macquarie Island glasses that range from nepheline- to hypersthene-normative, and from MORB to EMORB in composition, are identical to those in average global MORB. The observed lack of variation of delta D and delta O-18 with 1 to 15% degree of mantle melting is consistent with a bulk melting model of delta D and delta O-18 fractionation, in which water is rapidly scavenged into the first partial melt. The narrow ranges of delta D and delta O-18 in normal mantle are mostly due to the buffering effect of clino- and orthopyroxenes in the residual assemblage; additionally, fast ``wet'' diffusion of oxygen and hydrogen isotopes through the melting regions may further smooth isotopic differences. (C) 2012 Elsevier B.V. All rights reserved.

Modelling 2,4-dichlorophenol bioavailability and bioaccumulation by the freshwater fingernail clam Sphaerium corneum using artificial particles and humic acids

The complex and variable composition of natural sediments makes it very difficult to predict the bioavailability and bioaccumulation of sediment-bound contaminants. Several approaches have been proposed to overcome this problem, including an experimental model using artificial particles with or without humic acids as a source of organic matter. For this work, we have applied this experimental model, and also a sample of a natural sediment, to investigate the uptake and bioaccumulation of 2,4-dichlorophenol (2,4-DCP) by Sphaerium corneum. Additionally, the particle-water partition coefficients (K-d) were calculated. The results showed that the bioaccumulation of 2,4-DCP by clams did not depend solely on the levels of chemical dissolved, but also on the amount sorbed onto the particles and the characteristics and the strength of that binding. This study confirms the value of using artificial particles as a suitable experimental model for assessing the fate of sediment-bound contaminants. (c) 2006 Elsevier Ltd. All rights reserved.

Antioxidant properties of Teaw (Cratoxylum formosum Dyer) extract in soybean oil and emulsions

The antioxidant activity of an extract from Teaw (Cratoxylum formosum Dyer) leaves was studied in soybean oil and soybean oil-in-water emulsions. Samples containing the extract or reference antioxidants including chlorogenic acid, which comprises 60% of the Teaw extract, were stored at 60 degrees C and analyzed periodically for peroxide value (PV) and thiobarbituric acid reactive substances (TBARS) to allow both hydroperoxides and hydroperoxide degradation products to be monitored. Chlorogenic acid and the Teaw extract were more effective than a-tocopherol in inhibiting lipid oxidation in bulk oil but were less effective in an oil-in-water emulsion in accordance with the polar paradox. The PV/TBARS ratio for oil samples containing chlorogenic acid was higher than for alpha-tocopherol and BHT because chlorogenic acid inhibits both hydroperoxide formation by radical scavenging and hydroperoxide decomposition by metal chelation. The importance of the metal-chelating activity in retarding hydroperoxide decomposition was confirmed by studying the decomposition of oil samples containing added ferric ions. The PV/TBARS ratio was higher for citric acid than for (x-tocopherol in the presence of added ferric chloride, but the order was reversed in samples lacking ferric chloride. Samples containing added chlorogenic acid gave the highest PV/TBARS ratios both in the presence and absence of ferric ions. The PV/TBARS ratios for the samples containing antioxidants fell rapidly to lower values in a soybean oil-in-water emulsion than in the soybean oil. This was due to increased hydroperoxide decomposition in the emulsion at the same PV. The Teaw extract contained 12% oil-soluble components, which contributed to a slightly higher oil-water partition coefficient than that of chlorogenic acid. The antioxidant activity of the aqueous phase of the Teaw extract was reduced more than that of chlorogenic acid by partitioning of the oil-soluble components into oil, which showed that the less-polar components contributed to the antioxidant activity of the Teaw extract in aqueous media.

Separation of natural colorants from the fermented broth of filamentous fungi using colloidal gas aphrons

There is a worldwide interest in the development of processes for producing colorants from natural sources. Microorganisms provide an alternative source of natural colorants produced by cultivation technology and extracted from the fermented broth. The aim of the present work was to study the recovery of red colorants from the fermented broth of Talaromyces amestolkiae using the technique of colloidal gas aphrons (CGA) comprising surfactant-stabilized microbubbles. Preliminary experiments were performed to evaluate the red colorants’ solubility in different organic solvents, octanol/water partitioning, and their stability in surfactant solutions, namely hexadecyl trimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS), and polyoxyethylenesorbitan monolaurate (Tween 20), which are cationic, anionic and nonionic surfactants, respectively. The first recovery experiments were carried out using CGA generated by these surfactants at different volumetric ratios (VR, 3–18). Subsequently, two different approaches to generate CGA were investigated at VR values of 6 and 12: the first involved the use of CTAB at pH 6.9–10.0, and the second involved the use of Tween 20 using red colorants partially dissolved in ethanol and Tween 20. The characterization results showed that red colorants have a hydrophilic nature. The highest recoveries were obtained with Tween 20 (78%) and CTAB (70%). These results demonstrated that the recovery of the colorants was driven by both electrostatic and hydrophobic interactions. The VR was found to be an important operating parameter and at VR 12 with CTAB (at pH 9) maximum recovery, partitioning coefficient (K = 5.39) and selectivity in relation to protein and sugar (SP = 3.75 and SS = 7.20 respectively) were achieved. Furthermore, with Tween 20, the separation was driven mainly by hydrophobic interactions. Overall CGA show promise for the recovery of red colorants from a fermented broth. Although better results were obtained with CTAB than with Tween 20 the latter may be more suitable for some application due to its lower toxicity.

Relationship between structure and photoactivity of porphyrins derived from protoporphyrin IX

Protoporphyrin (Pp IX) derivatives were prepared to study the relationship between photosensitizer structure and photoactivity, with an emphasis on understanding the role of membrane interactions in the efficiency of photosensitizers used in photodynamic therapy (PDT). The synthetic strategies described here aimed at changing protoporphyrin periferic groups, varying overall charge and oil/water partition, while maintaining their photochemical properties. Three synthetic routes were used: (1) modification of Pp IX at positions 3(1) and 8(1) by addition of alkyl amine groups of different lengths (compounds 2-5), (2) change of Pp IX at positions 13(3) and 17(3), generating alkyl amines (compounds 6 and 7), a phosphate amine (compound 8), and quarternary ammonium compounds (compounds 9 and 10), and (3) amine-alkylation of Hematoporphyrin IX (Hp IX) at positions 3(1), 8(1), 13(3) and 17(3) (compound 12). Strategy 1 leads to hydrophobic compounds with low photocytotoxicity. Strategy 2 leads to compounds 6-10 that have high levels of binding/incorporation in vesicles, mitochondria and cells, which are indicative of high bioavailability. Addition of the phosphate group (compound 8), generates an anionic compound that has low liposome and cell incorporation, plus low photocytotoxicity. Compound 12 has intermediate incorporation and photocytotoxic properties. Compound modification is also associated with changes in their sub-cellular localization: 30% of 8 (anionic) is found in mitochondria as compared to 95% of compound 10 (cationic). Photocytotoxicity was shown to be highly correlated with membrane affinity, which depends on the asymmetrical and amphiphilic characters of sens, as well as with sub-cellular localization.

A novel concentration dependent amino acid ion pair strategy to mediate drug permeation using indomethacin as a model insoluble drug

Assessment of oral drug bioavailability is an important parameter for new chemical entities (NCEs) in drug development cycle. After evaluating the pharmacological response of these new molecules, the following critical stage is to investigate their in vitro permeability. Despite the great success achieved by prodrugs, covalent linking the drug molecule with a hydrophobic moiety might result in a new entity that might be toxic or ineffective. Therefore, an alternative that would improve the drug uptake without affecting the efficacy of the drug molecule would be advantageous. The aim of the current study is to investigate the effect of ion-pairing on the permeability profile of a model drug: indomethacin (IND) to understand the mechanism behind the permeability improvement across Caco-2 monolayers. Arginine and lysine formed ion-pairs with IND at various molar ratios 1:1, 1:2, 1:4 and 1:8 as reflected by the double reciprocal graphs. The partitioning capacities of the IND were evaluated using octanol/water partitioning studies and the apparent permeabilities (P app) were measured across Caco-2 monolayers for the different formulations. Partitioning studies reflected the high hydrophobicity of IND (Log P = 3) which dropped upon increasing the concentrations of arginine/lysine in the ion pairs. Nevertheless, the prepared ion pairs improved IND permeability especially after 60 min of the start of the experiment. Coupling partitioning and permeability results suggest a decrease in the passive transcellular uptake due to the drop in IND portioning capacities and a possible involvement of active carriers. Future work will investigate which transport gene might be involved in the absorption of the ion paired formulations using molecular biology technologies. © 2014 Elsevier B.V. All rights reserved.

Mercury interactions with suspended solids at the Upper East Fork Poplar Creek, Oak Ridge, Tennessee

A water quality model was developed to analyze the impact of hydrological events on mercury contamination of the Upper East Fork Poplar Creek, Tennessee. The model simulates surface and subsurface hydrology and transport (MIKE SHE and MIKE 11) and it is coupled with the reactive transport of sediments and mercury (ECOLAB). The model was used to simulate the distribution of mercury contamination in the water and sediments as a function of daily hydrological events. Results from the model show a high correlation between suspended solids and mercury in the water due to the affinity of mercury with suspended organics. The governing parameters for the distribution of total suspended solids and mercury contamination were the critical velocity of the stream for particle resuspension, the rates of resuspension and production of particles, settling velocity, soil-water partition coefficient, and desorption rate of mercury in the water. Flow and load duration curves at the watershed exit were used to calibrate the model and to determine the impact of hydrological events on the total maximum daily load at Station 17. The results confirmed the strong link between hydrology and mercury transport.

Identifying the major spilled oil constituents and fate in harsh offshore environments

The behaviour and fate of spilled oil in harsh marine environments, such as the North Atlantic and the Arctic Ocean are complex due to environmental factors and the composition of the crude. In order to develop appropriate oil spill prevention and management methods, we must first understand how the oil behaves in these harsh environmental conditions. This study focuses on determining the fate of oil in harsh marine environments by first identifying target compounds in the oil that can be used to determine the fate of a spill. This thesis presents the partitioning behaviour of six polycyclic aromatic hydrocarbons (PAHs), which represent different groups, and phenols in cold conditions. The smallest PAH, naphthalene, dominated in terms of concentration in water accommodated fraction (WAF) of oil, while the larger ringed PAHs presented at lower concentrations. The smallest oil-water partition coefficient was recorded by phenol which partitioned into the seawater more quickly than PAHs. The partitioning of larger PAHs was slower and they indicated high partition coefficients. The oil partitioning increased slightly as temperature increased from 4ᴼC to 15ᴼC. The oil loading (0.1 g/L to 10 g/L) also contributed in deciding the concentrations in water. The use of chemical dispersants is a common response to spills. This study identified that chemical dispersants can change the fate of an oil spill by increasing the availability of oil in seawater. The concentration of larger PAHs such as pyrene and chrysene increased significantly with the application of dispersants. The information obtained are used in developing a molecular imprinted polymer (MIP) sensor to identify oil spills in the North Atlantic Ocean.

Formulation and nebulization of fluticasone propionate-loaded lipid nanocarriers.

International audience

Pesticide bioconcentration modelling for fruit trees.

The model presented allows simulating the pesticide concentration in fruit trees and estimating the pesticide bioconcentration factor in fruits of woody species. The model allows estimating the pesticide uptake by plants through the water transpiration stream and also the time in which maximum pesticide concentration occur in the fruits. The equation proposed presents the relationships between bioconcentration factor (BCF) and the following variables: plant water transpiration volume (Q), pesticide transpiration stream concentration factor (TSCF), pesticide stem-water partition coefficient (KWood,w), stem dry biomass (M) and pesticide dissipation rate in the soil-plant system (kEGS). The modeling started and was developed from a previous model ?Fruit Tree Model? (FTM), reported by Trapp and collaborators in 2003, to which was added the hypothesis that the pesticide degradation in the soil follows a first order kinetic equation. The model fitness was evaluated through the sensitivity analysis of the pesticide BCF values in fruits with respect to the model entry data variability.

Thermodynamic quantities of solvation and dilution for some acetanilide derivatives in octanol and water mutually saturateds

Based on published thermodynamic quantities for solution, partitioning and sublimation of acetanilide (ACN), acetaminophen (ACP) and Phenacetin (PNC), the thermodynamic quantities for drugs solvation in octanol-saturated water (W(ROH)) and water-saturated octanol (ROH(W)) as well as the drugs dilution in ROH(W) were calculated. The Gibbs energies of solvation were favourable in all cases. The respective enthalpies and entropies were negative indicating an enthalpy-driving for the solvation process in all cases. On the other hand, the Gibbs energies of dilution were favourable for ACP and PNC but unfavourable for ACN, whereas the respective enthalpies and entropies were negative for ACP and PNC but positive for ACN indicating enthalpy-driving for the dilution process in the case of the former drugs and entropy-driving for the latter. From the obtained values for the transfer processes, an interpretation based on solute-solvent interactions was developed.

Estimation of pollutant partition in sandy soils with different water contents

The objectives of this work were: (1) to identify an isotherm model to relate the contaminant contents in the gas phase with those in the solid and non-aqueous liquid phases; (2) to develop a methodology for the estimation of the contaminant distribution in the different phases of the soil; and (3) to evaluate the influence of soil water content on the contaminant distribution in soil. For sandy soils with negligible contents of clay and natural organic matter, contaminated with benzene, toluene, ethylbenzene, xylene, trichloroethylene (TCE), and perchloroethylene (PCE), it was concluded that: (1) Freundlich’s model showed to be adequate to relate the contaminant contents in the gas phase with those in the solid and non-aqueous liquid phases; (2) the distribution of the contaminants in the different phases present in the soil could be estimated with differences lower than 10% for 83% of the cases; and (3) an increase of the soil water content led to a decrease of the amount of contaminant in the solid and non-aqueous liquid phases, increasing the amount in the other phases.

Cork industry wastewater partition by ultra/nanofiltration: A biodegradation and valorisation study

Wastewater from cork processing industry present high levels of organic and phenolic compounds, such as tannins, with a low biodegradability and a significant toxicity. These compounds are not readily removed by conventional municipal wastewater treatment, which is largely based on primary sedimentation followed by biological treatment. The purpose of this work is to study the biodegradability of different cork wastewater fractions, obtained through membrane separation, in order to assess its potential for biological treatment and having in view its valorisation through tannins recovery, which could be applied in other industries. Various ultrafiltration and nanofiltration membranes where used, with molecular weight cut-offs (MWCO) ranging from 0.125 to 91 kDa. The wastewater and the different permeated fractions were analyzed in terms of Total Organic Carbon (TOC), Chemical Oxygen Demand (COD), Biochemical Oxygen Demand (BOD), Total Phenols (TP), Tannins, Color, pH and Conductivity. Results for the wastewater shown that it is characterized by a high organic content (670.5-1056.8 mg TOC/L, 2285-2604 mg COD/L, 1000-1225 mg BOD/L), a relatively low biodegradability (0.35-0.38 for BODs/COD and 0.44-0.47 for BOD20/COD) and a high content of phenols (360-410 mg tannic acid/L) and tannins (250-270 mg tannic acid/L). The results for the wastewater fractions shown a general decrease on the pollutant content of permeates, and an increase of its biodegradability, with the decrease of the membrane MWCO applied. Particularly, the permeated fraction from the membrane MWCO of 3.8 kDa, presented a favourable index of biodegradability (0.8) and a minimized phenols toxicity that enables it to undergo a biological treatment and so, to be treated in a municipal wastewater treatment plant. Also, within the perspective of valorisation, the rejected fraction obtained through this membrane MWCO may have a significant potential for tannins recovery. Permeated fractions from membranes with MWCO lower than 3.8 kDa, presented a particularly significant decline of organic matter and phenols, enabling this permeates to be reused in the cork processing and so, representing an interesting perspective of zero discharge for the cork industry, with evident environmental and economic advantages. (C) 2010 Elsevier Ltd. All rights reserved.

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

In order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), herein we explore a modular ionic liquid synthetic strategy for improved APIs. Ionic liquids containing l-ampicillin as active pharmaceutical ingredient anion were prepared using the methodology developed in our previous work, using organic cations selected from substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, with the intent of enhancing the solubility and bioavailability of l-ampicillin forms. In order to evaluate important properties of the synthesized API-ILs, the water solubility at 25 °C and 37 °C (body temperature) as well as octanol–water partition coefficients (Kow's) and HDPC micelles partition at 25 °C were measured. Critical micelle concentrations (CMC's) in water at 25 °C and 37 °C of the pharmaceutical ionic liquids bearing cations with surfactant properties were also determined from ionic conductivity measurements.