Low Solubility Compounds Research Articles

Water Solubility of Flavor Compounds Influences Formation of Flavor Inclusion Complexes from Dispersed High-Amylose Maize Starch

High-amylose maize starch, with and without native lipid, was used to make inclusion complexes with flavor compounds to investigate the effect of water solubility of flavor compounds on inclusion complex formation. Two pairs of terpenes, having high and low water solubility, were used. Aqueous starches were dispersed by heat before adding the flavor compound. The amounts of starch, native lipid, and flavor compound in precipitates were determined, and inferences about the physical state were made using data from X-ray diffraction and differential scanning calorimetry. The water solubility of the flavor compound was related to the extent of inclusion complexation. For the higher water solubility flavor compounds, starch yield and flavor entrapment were higher, producing precipitates with the V 7 pattern. Complex formation with the low-solubility flavor compounds was most effective in the presence of native lipid, producing precipitates with the V 6 pattern. The lipid in native high-amylose maize starch may enhance complexation with low-solubility compounds by forming ternary coinclusion complexes of starch-lipid-flavor.

Method for screening of solid dispersion formulations of low-solubility compounds—Miniaturization and automation of solvent casting and dissolution testing

An efficient method has been developed for screening solid dispersion formulations that are intended to enhance the dissolution of poorly soluble compounds. The method is based on miniaturization and automation of sample preparation by solvent casting, and dissolution testing, in a 96-well plate format, using less than 0.1 mg of compound per well. To illustrate the method, six polymers and eight surfactants were screened, individually and in combination, for their ability to dissolve a compound with aqueous solubility of <1 μg/ml in simulated intestinal fluid. Screening was performed at an excipient/compound ratio of 10:1, and a polymer/surfactant ratio of 3:1 for ternary formulations. Sixteen of the 48 ternary formulations dissolved the compound to a level >100 μg/ml, i.e. at least a 100-fold increase over the aqueous solubility. A number of synergies were observed wherein the performance of a ternary formulation greatly exceeded that of either of the corresponding binary formulations. Thirteen ‘hits’ from screening were scaled up with melt methods, and ∼2/3 of these showed comparable dissolution enhancement when tested at larger scale. Five of these were administered to rats, and the absolute oral bioavailability ranged from 10 to 23%, versus less than 1% for the unformulated compound.

Screening Method to Identify Preclinical Liquid and Semi‐Solid Formulations for low Solubility Compounds: Miniaturization and Automation of Solvent Casting and Dissolution Testing

We have developed an efficient screening method to identify liquid and semisolid formulations for low‐solubility compounds. The method is most suitable for identifying dosing vehicles for compounds in lead optimization, where compound supply is limited and long‐term stability is not a requirement. Dilute compound and excipient stock solutions are prepared in organic solvent and then dispensed and mixed in 96‐well plates. The solvent is removed in a vacuum centrifuge evaporator, leaving neat formulation (e.g., 10–40 µg compound, 0.4mg excipient) at the bottom of each well. After an aging step, an aqueous dilution medium is added and the plates are incubated (agitation by orbital shaking). The diluted formulations are then filtered and analyzed by ultraviolet (UV) absorbance or high‐performance liquid chromatography (HPLC). To illustrate the method, two compounds (aqueous solubility ≤1 µg/mL) were combined with eight solubilizing excipients, at four drug‐loading levels (25, 50, 75, and 100mg/g) and three incubation times (0.5, 2, and 24h). This allowed identification of the excipients and loading levels, which generated the highest and most stable kinetic solubility upon dilution. The peak kinetic solubility was strongly correlated with the equilibrium solubility. Application of the method to screening compound/surfactant/oil formulations is also presented.

Carbon in Black Crusts from the Tower of London

This paper investigates the origin, fluxes, and transformation of carbon compounds within black crusts on the stone walls of the Tower of London. The crusts were analyzed for elemental and organic carbon, including the water soluble fraction. Elemental carbon and low solubility compounds such as oxalates appeared to be conserved because of long residence times. Conversely, more soluble ions, like chloride and formate would be removed from the layers relatively quickly by rainfall. At higher organic carbon concentrations acetic acid may be produced within the crusts from biological transformations. Currently, traffic sources contribute to increasingly organic rich crusts. The deposition of elemental carbon to buildings darkens surfaces and has important aesthetic implications. The increased organic content may have further aesthetic consequence by changing the color of buildings to warmer tones, particularly browns and yellows. Management of historic buildings requires us to recognize the shift away from simple gypsum crusts to those richer in organic materials.

Differences in In Vitro Dissolution Rates Using Single-Point and Multi-Point Sampling

INTRODUCTION In vitro dissolution testing is an important physicochemical tool used to measure drug release rates during both early and late stages of drug development. In both cases, a product-specific discriminating dissolution method is utilized as a quality control tool to evaluate batch-to-batch consistency and as a predictive means to gain a post-market bio-waiver in cases where there is in vitro–in vivo correlation or in vitro–in vivo relation. Developing rugged methods with appropriate discriminatory dissolution parameters is often a challenging objective regardless of the solubility of the compounds. Method development is further challenged when hydrodynamic effects within the vessel (1–4) impact method ruggedness. The hydrodynamic environment within the vessel can be affected by many variables including the position of the tablet (5, 6) and the presence and position of a measuring (7) or sampling probe (8). Thus, for poorly soluble drugs, it is challenging to develop an appropriate dissolution method that is rugged, discriminating, and maintains sufficient sink conditions. While implementing a dissolution method in a manufacturing quality control (QC) laboratory, we encountered a unique method ruggedness issue. Previously, we successfully transferred the validated discriminating dissolution method from our R&D facility to both a stability laboratory and a manufacturing QC laboratory. However, during the manufacturing validation campaign, several tablet batches exhibited slower dissolution rates in the QC laboratory when compared with the historical dissolution rates generated in the R&D and stability laboratories. Several of the process validation batches were at risk of proposed specification failure, which had required Stage II (S2) testing. An investigation was initiated to determine if the root cause of the low results was due to a method robustness or product quality issue. The drug product that exhibited this behavior was prepared using a BCS class II (low solubility and high permeability) compound in which dissolution was the Differences in In Vitro Dissolution Rates Using Single-Point and Multi-Point Sampling

Quantitative studies of allosteric effects by biointeraction chromatography: analysis of protein binding for low-solubility drugs.

A new chromatographic method was developed for characterizing allosteric interactions between an immobilized binding agent and low-solubility compounds. This approach was illustrated by using it to characterize the interactions between tamoxifen and warfarin during their binding to the protein human serum albumin (HSA), with beta-cyclodextrin being employed as a solubilizing agent for these drugs. It was confirmed in this work through several experiments that warfarin had a single binding site on HSA with an association equilibrium constant of (2-5) x 10(5) M(-1) (average, 3.9 x 10(5) M(-1)) at 37 degrees C, in agreement with previous reports. It was also found that tamoxifen had a single major binding site on HSA, with an association equilibrium constant of (3-4) x 10(7) M(-1) (average, 3.5 x 10(7) M(-1)) at 37 degrees C. When warfarin was used as a mobile-phase additive in competition studies with tamoxifen, this had a positive allosteric effect on tamoxifen/HSA binding, giving a coupling constant of 2.3 (+/-0.3). Competitive studies using tamoxifen as a mobile-phase additive indicated that tamoxifen had a negative allosteric effect on warfarin/HSA binding, providing a coupling constant of 0.79 (+/-0.03). A unique feature of the technique described in this report was its ability to independently examine both directions of the warfarin/tamoxifen allosteric interaction. This approach is not limited to warfarin, tamoxifen, and HSA but can also be used to study other solutes and binding agents.

An atomistic simulation scheme for modeling crystal formation from solution

We present an atomistic simulation scheme for investigating crystal growth from solution. Molecular-dynamics simulation studies of such processes typically suffer from considerable limitations concerning both system size and simulation times. In our method this time-length scale problem is circumvented by an iterative scheme which combines a Monte Carlo-type approach for the identification of ion adsorption sites and, after each growth step, structural optimization of the ion cluster and the solvent by means of molecular-dynamics simulation runs. An important approximation of our method is based on assuming full structural relaxation of the aggregates between each of the growth steps. This concept only holds for compounds of low solubility. To illustrate our method we studied CaF2 aggregate growth from aqueous solution, which may be taken as prototypes for compounds of very low solubility. The limitations of our simulation scheme are illustrated by the example of NaCl aggregation from aqueous solution, which corresponds to a solute/solvent combination of very high salt solubility.

Chromium Oxidation State Imaging in Mammalian Cells Exposed in Vitro to Soluble or Particulate Chromate Compounds

Hexavalent chromium compounds are known carcinogens for the respiratory tract in humans. The mechanism of cell transformation by hexavalent chromium compounds is not fully understood although a role for intracellular reduction is sought. The aim of this study was to determine the distribution of Cr valence states in human cells after in vitro exposure to soluble or particulate chromium compounds. A synchrotron X-ray-based microprobe was used to investigate the cellular reduction of Cr(VI) and to image chromium oxidation states in cells. It was shown that soluble Cr(VI) compounds are fully reduced to Cr(III) in cells. Cr(III) is homogeneously distributed within the cell volume and therefore present within the nucleus. In the case of low solubility particulate chromate compounds, Cr(VI) can coexist in the cell environment, as particles in the perinuclear region, together with intracellular and intranuclear Cr(III). Chemical distribution maps also suggest that intracellular Cr(III) originates from extracellular dissolution and reduction of lead chromate rather than from intracellular engulfed particles. The possible stronger carcinogenicity of low solubility chromate vs soluble chromate compounds may derive from the combinative genotoxic effects of intranuclear Cr(III) and the persistent exposure to a strong oxidant, Cr(VI).

Environmental applications for biosurfactants

Biosurfactants are surfactants that are produced extracellularly or as part of the cell membrane by bacteria, yeasts and fungi. Examples include Pseudomonas aeruginosa which produces rhamnolipids, Candida (formerly Torulopsis) bombicola, one of the few yeasts to produce biosurfactants, which produces high yields of sophorolipids from vegetable oils and sugars and Bacillus subtilis which produces a lipopeptide called surfactin. This review includes environmental applications of these biosurfactants for soil and water treatment. Biosurfactant applications in the environmental industries are promising due to their biodegradability, low toxicity and effectiveness in enhancing biodegradation and solubilization of low solubility compounds. However, more information is needed to be able to predict and model their behaviour. Full scale tests will be required. The role of biosurfactants in natural attenuation processes has not been determined. Very little information is available concerning the influence of soil components on the remediation process with biosurfactants. As most of the research until now has been performed with rhamnolipids, other biosurfactants need to be investigated as they may have more promising properties.

Synthesis of struvite by ion exchange isothermal supersaturation technique

Recovery and recycling of phosphorus (P) from effluents and waste waters of different types is among the most important tasks of modern environmental chemistry. The importance of this task is determined by the rapid depletion of phosphate ore deposits, which are intensively exploited. The most pessimistic forecasts predict almost complete disappearance of high quality rock phosphates by the beginning of the next century. Phosphates are removed and recovered from the water under treatment as struvite (MgNH 4PO 4 · 6H 2O) or other low solubility compounds. The advantage of P recovery in the form of struvite lies in the possibility of using it as valuable mineral fertiliser. Ion exchange can be used both to recover phosphates from waste waters and to synthesize struvite of sufficiently high purity. This paper describes the results obtained by studying the conditions of struvite synthesis by using the ion exchange isothermal supersaturation (IXISS) technique. The IXISS phenomenon is observed in a number of ion exchange systems when using certain ion exchange separation techniques enabling the target substance to be concentrated beyond its solubility level at a given temperature. Moreover, this supersaturated solution remains stable for a long period, and after leaving the column it crystallizes spontaneously. Stable supersaturated struvite solutions were obtained by stripping magnesium from Lewatite CNP80 cation exchange resin in Mg-form by using ammonium phosphate and dihydrophosphate solutions under batch and dynamic conditions. The pH of struvite formation is around 8.0 at all eluate concentrations and temperatures studied. The results of X-ray diffraction analysis of the precipitates obtained confirm the formation of struvite crystals.

Zinc and lead sequestration in an impacted wetland system

The fate and bioavailability of pollutant metals is important to the long-term health of freshwater wetland systems, particularly in areas with elevated background levels of trace metals. Precipitation of some authigenic mineral phases in wetland sediments can potentially limit metal bioavailability through sequestration in low-solubility compounds, such as metal sulfides. Zinc and Pb concentrations were analyzed in water, plant and sediment samples taken from a metal-contaminated wetland in Chicago, IL, USA in order to assess metal fate and bioavailability, while X-ray absorption spectroscopy (XAS) studies were conducted to determine zinc speciation in the wetland sediments. The results showed sequestration of metal into the pond sediments, most likely in iron precipitate phases. In surface sediments, re-release of Zn and Pb into pore waters was correlated with microbial iron reduction, while the presence of sulfide in anoxic pore waters corresponded to decreased dissolved concentrations of both elements. Analysis of extended X-ray absorption fine structure (EXAFS) data confirmed that sulfide compounds dominated zinc speciation throughout the sediment. Uptake of trace metals in Phragmites plants was limited primarily to plant roots, while concentrations of both Pb and Zn in aquatic vegetation were significantly elevated, representing a potential bioaccumulation hazard.

Intestinal absorption characteristics of the low solubility thiocarboxanilide UC-781

The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.

Effects of nonionic surfactants on the UV/visible absorption of bacterial cells.

Nonionic surfactants are used in a number of different microbiological applications, including solubilization of cell membranes, washing bacterial cultures prior to experimentation, and enhancing biodegradation of low-solubility compounds. An important consideration in these applications is the potential for the surfactant to alter the cell membrane. One potential means to monitor the impact of surfactants on the bacterial cell membrane is through monitoring the absorbance spectrum of the bacterial suspension. This is due to the colloidal nature of bacteria, where the absorbance of a bacterial suspension is related to the size and refractive index of the bacterial cells. Through a systematic study it was shown that there can be a significant change in the bacterial absorbance spectrum due to the presence of nonionic surfactants, with the effect a function of surfactant structure and concentration, solution ionic strength and cation valence. The effects were most pronounced with Na(+) as the cation, with surfactants having mid-range hydrophile-lipophile balance (HLB) values, and with surfactant concentrations above the CMC. The results indicate that measurement of the absorbance spectrum of bacterial cultures can provide a means to monitor the effects of nonionic surfactants on the bacterial cell membrane. In addition, depending on the specific application, appropriate selection of surfactant structure and media composition can be made to enhance or minimize the effects.

Capillary zone electrophoretic (CZE) study of uranium(VI) complexation with humic acids

The interaction of UO2 2+ with various humic acids (HA's) has been studied by capillary zone electrophoresis (CZE). The experiments were done in 10 mM acetate buffer with pH 3.3 and 4.0, to avoid hydrolysis of uranium. It was found that in slightly acidic media and low HA concentration (<3 mM), two complexes with uranium(VI) are formed by fast kinetics and uranyl migrates as cationic species. Electrophoretic mobilities are decreasing with the increasing HA/uranium ratio and a low soluble neutral compound is also formed. In addition, it was found that at HA concentrations higher than 3 mM negatively charged species are formed. Similar results were obtained for HA's of different origin (soil, peat, coal derived, IHSS standards). Conditional stability constants of the complexes UO2 2+-HA for Fluka I HA, were estimated to be log β1 = 4.18±0.06 and log β2 = 7.28±0.18.

The estimation of organic gas vapour pressure

The base 10 logarithm of vapour pressure for each of 39 structural classes of hydrocarbons and substituted hydrocarbons is a linear function of carbon number, and a cubic polynomial of temperature. These functions may be used to estimate the vapour pressures of compounds for which no laboratory measurements are available. Comparison of the resulting vapour pressure predictions with field measurement data of organic particulates has suggested that vapour pressures lower than approximately 5E−05mmHg are necessary for low-solubility compounds to partition significantly to particulates. Soluble compounds may enter the particle phase at much higher vapour pressures. A hierarchy of species’ likelihood to partition to the particulate phase, based on vapour pressure, has been suggested for the compounds studied, from diacids being the most likely to partition, to iso-alkyl ketones as the least likely to partition.

Assessment of the Water-Extractable Genotoxic Potential of Soil Samples from Contaminated Sites

A screening method for the evaluation of the water-extractable genotoxic potential of soil is proposed. Due to the low sensitivity of genotoxicity test systems, PAD-1 resin was used as solid phase to concentrate less hydrophilic compounds from aqueous soil extracts. Concentrated and nonconcentrated aqueous soil extracts from 19 soil samples were evaluated using three genotoxicity assays: the umu test according to the German standard method with Salmonella typhimurium TA1535/pSK1002, the NM2009 test with S. typhimurium NM2009, and the SOS Chromotest with Escherichia coli PQ37. All tests were performed according to a uniform protocol using microplates. Results indicate that the nonconcentrated water elutriates should be tested because the genotoxic potential of some soil samples is extremely high. Additionally, water elutriates should be concentrated by solid phase extraction to avoid false-negative results. The results of this study show that the genotoxic risk of sites contaminated with PAHs or mineral oils may be underestimated if only nonconcentrated samples are tested. The solid-phase extraction method with a concentration factor of 30 for these low soluble compounds is suitable for distinguishing between background genotoxicity of noncontaminated sites and anthropogenic contaminations.

Effect of Nonionic Surfactants on Dissolution of Polycyclic Aromatic Hydrocarbons from Coal Tar

The remediation in the subsurface of low solubility compounds such as polycyclic aromatic hydrocarbons (PAHs) might be limited by their dissolution kinetics. Other studies have already proven that the addition of surfactants will enhance the solubility and dissolution rates of pure single-hydrophobic compounds in water. The purpose of this study is to investigate whether the addition of two nonionic surfactants (Tween 20 and Tween 21) to a complex mixture (coal tar) would similarly enhance the dissolution rates of five PAHs contained within the coal tar. The five PAHs analyzed were naphthalene, phenanthrene, fluoranthene, pyrene, and benzo(a)pyrene. Through a series of partitioning experiments, it was discovered that the partitioning coefficients increased with increasing PAH ring structure. Dissolution experiments showed that the solubilities and dissolution rates of the PAHs also increased in the presence of the two surfactants. Finally, it was found that Tween 21, being the more hydrophobic surfactant, caused a greater enhancement in PAH dissolution rates than did Tween 20.

Removing and stabilizing as from copper refining circuits by hydrothermal processing

Experimental testwork has shown that arsenic can be removed from arsenic-bearing solutions by hydrothermal precipitation at temperatures in the 170–200°C range. The presence of Fe(III) is required for combination with As(V) to form the crystalline hydrated ferric arsenate known as scorodite (FeAsO4·2H2O). The contained arsenic is effectively immobilized by incorporation into a crystalline, low-solubility compound. Process options are suggested for disposing of arsenic in copper electrorefinery bleed liquors.

Contribution of low molecular weight water soluble compounds to the taste of cheeses made of cows', ewes’ and goats’ milk

Abstract Fractions isolated by gel filtration from the water soluble extracts of cheeses made of cows', ewes’ and goats’ milk, under the same manufacturing conditions, were subjected to organoleptic evaluation and chromatographic separation in order to elucidate the contribution of small peptides, free amino acids and volatile components to their sensory properties. Differences were found in intensity and predominance of individual tastes in the various fractions of cheeses made from milk of the three species. Fractions from the bovine milk cheese were mainly salty and sour. Umami tastes predominated in the fraction from the ovine milk cheese, while the fractions from the caprine milk cheese were regarded as umami, astringent and bitter. The highest cheese taste intensity was found in the fractions with the highest concentration of amino acids and volatile compounds, but it was difficult to correlate the organoleptic characteristics to the presence of particular components.

Anaerobic metabolism of aromatic compounds via the benzoyl-CoA pathway

Aromatic compounds are important growth substrates for microorganisms. They form a large group of diverse compounds including lignin monomers, amino acids, quinones, and flavonoids. Aerobic aromatic metabolism is characterized by the extensive use of molecular oxygen which is essential for the hydroxylation and cleavage of aromatic ring structures. The anaerobic metabolism of low molecular mass soluble aromatic compounds requires, of necessity, a quite different strategy. In most known cases, aromaticity is broken by reduction and the ring is subsequently opened hydrolytically. A small number of different central aromatic intermediates can be reduced, the most common of which is benzoyl-CoA, a compound that is formed as a central intermediate in the degradation of a large number of aromatic growth substrates. This review concentrates on the anaerobic aromatic metabolism via the benzoyl-CoA pathway. The peripheral pathways that transform growth substrates to benzoyl-CoA include various types of novel reactions, for example carboxylation of phenolic compounds, reductive elimination of ring substituents like hydroxyl or amino groups, oxidation of methyl substituents, O-demethylation reactions and shortening of aliphatic side chains. The central benzoyl-CoA pathway differs in several aspects in the denitrifying, phototrophic and fermenting bacteria studied. In denitrifying and phototrophic bacteria it starts with the two-electron reduction of benzoyl-CoA to a cyclic dienoyl-CoA driven by the hydrolysis of two molecules of ATP to ADP+P i. This ring reduction is catalyzed by benzoyl-CoA reductase and requires a low-potential ferredoxin as an electron donor. In Rhodopseudomonas palustris the cyclic diene is further reduced to cyclohex-1-ene-1-carboxyl-CoA. In the denitrifying species Thauera aromatica, the cyclic diene is hydrated to give 6-hydroxycyclohex-1-ene-1-carboxyl-CoA. Subsequent β-oxidation results in the formation of a cyclic β-oxo compound, followed by hydrolytic carbon ring opening yielding 3-hydroxypimelyl-CoA in the case of T. aromatica and pimelyl-CoA in the case of R. palustris. These intermediates are further β-oxidized via glutaryl-CoA; final products are 3 acetyl-CoA and 1 CO 2. In fermenting bacteria benzoyl-CoA may possibly be reduced to the level of cyclohex-1-ene-1-carboxyl-CoA in an ATP-independent reaction. The genes coding for the enzymes of the central benzoyl-CoA pathway have been cloned and sequenced from R. palustris, T. aromatica, and Azoarcus evansii. Sequence analyses of the genes support the concept that phototrophic and denitrifying bacteria use two slightly different pathways to metabolize benzoyl-CoA. The gene sequences have in some cases been very helpful for the identification of possible catalytic mechanisms that were not obvious from initial characterizations of purified enzymes.