Calculated Partition Coefficients Research Articles

Protein partition coefficients can be estimated efficiently by hybrid shortcut calculations

The extraction of therapeutic proteins like monoclonal antibodies in aqueous two-phase systems (ATPS) is a suitable alternative to common cost intensive chromatographic purification steps within the downstream processing. Thereby the protein partitioning can be selectively changed using a displacement agent (additional salt) in order to allow for a successful purification of the target protein. Within this work a new shortcut strategy for the calculation of protein partition coefficients in polymer-salt ATPS is presented. The required protein-solute (phase-forming component, displacement agent) interactions are covered by the cross virial coefficient B23 measured by composition gradient multi-angle light scattering (CG-MALS). Using this shortcut calculation allows for an efficient determination of the partition coefficients of the target protein immunoglobulin G (IgG) and the impurity human serum albumin (HSA) within PEG-citrate and PEG-phosphate ATPS independently on the protein concentration. We demonstrate that the selection of a suitable displacement agent allowing for a selective purification of IgG from HSA is accessible by B23. Based on the determination of the protein–protein interactions via CG-MALS covered by the second osmotic virial coefficient B22 a further optimization of ATPS preventing protein precipitation is enabled. The results show that our approach contributes to an efficient downstream processing development.

Distribution of Pb, Cr, Cu and Zn in the marine-coastal region of Zanzibar (Tanzanian archipelago, East Africa)

ABSTRACTIn Tanzania, a large amount of domestic and industrial wastes are daily released to the aquatic environment without prior treatment. The present paper establishes the status of distribution and environmental implications of heavy metals in water, sediment, suspended particulate matter and biota (Anadara antiquata) from two marine coasts in Zanzibar, Tanzania. These metals are derived from the industrial areas through rivers and storm water outflows. Heavy metal concentrations in the collected samples were determined using atomic absorption spectrophotometry. Concentrations were significantly higher in the Malindi compared to the Fumba coast (ANOVA, p = .001). Calculation of metal partition coefficients shows that the relative importance of the particulate and the water phases varies in response to water parameters and suspended solid content, but that most elements achieve a conditional equilibrium in these coasts. Higher metal concentrations found in Malindi suggest a pollution effect related to anthropogenic activities. Mean metal burdens in the tissues of A. antiquata from both Malindi and Fumba coasts were significantly higher than in other compartments analysed (ANOVA, p <.05). Maximum values of contamination factor and contamination degree for metals were noticed for sediments from both Malindi and Fumba coasts. It is imperative to understand that metal concentrations of coastal environments depend not only on industrial and household waste inputs but also on the geochemical composition of the area.

Polymers as Reference Partitioning Phase: Polymer Calibration for an Analytically Operational Approach To Quantify Multimedia Phase Partitioning.

Polymers are increasingly applied for the enrichment of hydrophobic organic chemicals (HOCs) from various types of samples and media in many analytical partitioning-based measuring techniques. We propose using polymers as a reference partitioning phase and introduce polymer-polymer partitioning as the basis for a deeper insight into partitioning differences of HOCs between polymers, calibrating analytical methods, and consistency checking of existing and calculation of new partition coefficients. Polymer-polymer partition coefficients were determined for polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and organochlorine pesticides (OCPs) by equilibrating 13 silicones, including polydimethylsiloxane (PDMS) and low-density polyethylene (LDPE) in methanol-water solutions. Methanol as cosolvent ensured that all polymers reached equilibrium while its effect on the polymers' properties did not significantly affect silicone-silicone partition coefficients. However, we noticed minor cosolvent effects on determined polymer-polymer partition coefficients. Polymer-polymer partition coefficients near unity confirmed identical absorption capacities of several PDMS materials, whereas larger deviations from unity were indicated within the group of silicones and between silicones and LDPE. Uncertainty in polymer volume due to imprecise coating thickness or the presence of fillers was identified as the source of error for partition coefficients. New polymer-based (LDPE-lipid, PDMS-air) and multimedia partition coefficients (lipid-water, air-water) were calculated by applying the new concept of a polymer as reference partitioning phase and by using polymer-polymer partition coefficients as conversion factors. The present study encourages the use of polymer-polymer partition coefficients, recognizing that polymers can serve as a linking third phase for a quantitative understanding of equilibrium partitioning of HOCs between any two phases.

Corrosion in Wet Oil Piping: Root Cause Failure Analysis, Mitigation and Neural Networking

This paper discusses the typical corrosion anomalies likely to occur in the wet oil system of a Floating Storage and Offloading Vessel (FPSO). The root causes and operational mitigations are identified. A neural network is proposed for capturing relationships within the large volume and diversity of data and hence permit effective modelling of corrosion and integrity of specific piping sections. Novel mitigations which can minimize severity of wall loss for flowing lines include; corrosion modelling of separator fluids and consequent pressure and temperature adjustments and calculated partition coefficients P derived from corrosion inhibitor (CI) injection and residual lab data for first-pass assessment of the effectiveness of CI injections, hence providing adequate inhibition.

Two-Dimensional, pH-Responsive Oligoglycine-Based Nanocarriers.

The nanocarrier capabilities of atomically smooth two-dimensional sheets of a biantennary oligoglycine peptide C8H16(-CH2-NH-Gly5)2 (also called tectomers) are demonstrated. We show that the pH-controlled, rapid, and reversible assembly and disassembly of oligoglycine can be effectively used for controlled loading and release of the anticancer drug and fluorescent probe coralyne. The calculated partition coefficient in water is of the same order of magnitude or higher when compared to other nanocarriers such as liposomes and micelles, signifying the tectomer's impressive loading capabilities. Moreover, the loading of guest molecules in tectomers facilitates the protection from rapid photochemically induced degradation. Such efficient, pH-sensitive, stable, and biocompatible nanocarriers are extremely attractive for biosensing, therapeutic, and theranostic applications. Additionally, our results suggest that these planar self-assembled materials can also act as phase-transfer vehicles for hydrophobic cargoes further broadening their biomedical and technological applications.

Preparation and Biological Study of (68)Ga-DOTA-alendronate.

Objective(s):In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA-conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 (68Ga).Methods:DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5) at 92-95° C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation, biodistribution studies, and imaging were performed on the developed agent in normal rats.Results:The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320 GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a log P value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection.Conclusion:The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors.

Activity coefficients at infinite dilution for organic solutes dissolved in two 1-alkylquinuclidinium bis(trifluoromethylsulfonyl)imides bearing alkyl side chains of six and eight carbons

Infinite dilution activity coefficients and gas-to-liquid partition coefficients are reported for 47 and 45 organic probe molecules dissolved in 1-hexylquinuclidinium bis(trifluoromethylsulfonyl)imide ([Quin6]+[Tf2N]−) and 1-octylquinuclidinium bis(trifluoromethylsulfonyl)imide ([Quin8]+[Tf2N]−), respectively, as determined by inverse gas chromatography in the temperature range of 313K to 353K. The measured partition coefficient data were converted to water-to-liquid partition coefficients using standard thermodynamic relationships and published gas-to-water partition coefficient data. Both sets of calculated partition coefficient data for each ionic liquid solvent were analyzed in terms of the Abraham general solvation model. Mathematical correlations derived from the Abraham model described the measured partition coefficient data to within 0.14 or fewer log units.

Partitioning of rare earths in polymer-based three-liquid-phase system driven by transfer of hydrated PEGs: Understanding change of phase volume ratios

The relationship between the partitioning of rare-earth ions in polymer-based three-liquid-phase system (TLPS) of Cyanex 272/PEG 6001(NH4)(2)SO4-H2O and the change in volume ratios of PEG-rich middle phase to salt-rich bottom phase was investigated. It was found that the change in phase volume ratios might be attributed to the transfer of hydrated PEG molecules. Therefore, the partitioning of hydrated PEG is a main driving force for the partitioning of rare earths. The change in water content in PEG-rich phase should be taken into account for calculating partition coefficients of rare-earth ions. The traditional Diamond-Hsu model derived from Flory-Huggins theory considered only the partitioning of simple PEG molecules to calculate the partition coefficients of targets in polymer-based aqueous biphasic system, so that it could not reflect such influences from the change in phase volume ratios. The present work discusses the influences from the change of the concentrations of PEG and inorganic salt, Cyanex 272 concentration in top organic phase of TLPS, aqueous pH value and initial concentration of rare-earth ions, on the partitioning of rare-earth ions into PEG-rich middle phase of TLPS. Experimental results indicate

Incorporation and substitution mechanism of cadmium in cement clinker

Cement clinkers doped with CdO (0–2.0% by weight) were prepared to investigate cadmium distribution and lattice substitution during cement kiln co-processing of municipal solid and/or hazardous wastes. The contents of incorporated CdO were investigated by Energy Dispersive Spectrometer (EDS), detecting the samples packaged by epoxy resin, and Atomic Fluorescence Spectrometry (AFS), detecting the silicate and interstitial phases separated by extraction. EDS revealed that high concentrations cadmium was incorporated in silicate phases, which resulted in lower Ca/Si ratio. AFS also presented more than 90 wt.% CdO were taken by silicate phases; however, calculated partition coefficient (Kf) revealed cadmium ions had equal opportunities to be incorporated in silicate and interstitial phases. Furthermore, X-ray Diffraction showed no new phases were formed, while X-ray photoelectron spectroscopy proved the existence of Cd–O bond, which might be attributed to the lattice substitution of Cd2+ to Ca2+. This substitution resulted in shortened average chain length of C–S–H and postponed hydration of doped clinkers.

A simple and transferable all-atom/coarse-grained hybrid model to study membrane processes.

We present an efficient all-atom/coarse-grained hybrid model and apply it to membrane processes. This model is an extension of the all-atom/ELBA model applied previously to processes in water. Here, we improve the efficiency of the model by implementing a multiple-time step integrator that allows the atoms and the coarse-grained beads to be propagated at different timesteps. Furthermore, we fine-tune the interaction between the atoms and the coarse-grained beads by computing the potential of mean force of amino acid side chain analogs along the membrane normal and comparing to atomistic simulations. The model was independently validated on the calculation of small-molecule partition coefficients. Finally, we apply the model to membrane peptides. We studied the tilt angle of the Walp23 and Kalp23 helices in two different model membranes and the stability of the glycophorin A dimer. The model is efficient, accurate, and straightforward to use, as it does not require any extra interaction particles, layers of atomistic solvent molecules or tabulated potentials, thus offering a novel, simple approach to study membrane processes.

Distribution of halogens between fluid and apatite during fluid-mediated replacement processes

Apatite (Ca5(PO4)3(OH, F, Cl)) is one of the main host of halogens in magmatic and metamorphic rocks and plays a unique role during fluid–rock interaction as it incorporates halogens (i.e. F, Cl, Br, I) and OH from hydrothermal fluids to form a ternary solid solution of the endmembers F-apatite, Cl-apatite and OH-apatite. Here, we present an experimental study to investigate the processes during interaction of Cl-apatite with different aqueous solutions (KOH, NaCl, NaF of different concentration also doped with NaBr, NaI) at crustal conditions (400–700°C and 0.2GPa) leading to the formation of new apatite. We use the experimental results to calculate partition coefficients of halogens between apatite and fluid. Due to a coupled dissolution–reprecipitation mechanism new apatite is always formed as a pseudomorphic replacement of Cl-apatite. Additionally, some experiments produce new apatite also as an epitaxial overgrowth. The composition of new apatite is mainly governed by complex characteristics of the fluid phase from which it is precipitating and depends on composition of the fluid, temperature and fluid to mineral ratio. Furthermore, replaced apatite shows a compositional zonation, which is attributed to a compositional evolution of the coexisting fluid in local equilibrium with the newly formed apatite. Apatite/fluid partition coefficients for F depend on the concentration of F in the fluid and increase from 75 at high concentrations (460μg/g F) to 300 at low concentrations (46μg/g F) indicating a high compatibility of F in apatite. A correlation of Cl-concentration in apatite with Cl− concentration of fluid is not observed for experiments with highly saline solutions, composition of new apatite is rather governed by OH− concentration of the hydrothermal fluid. Low partition coefficients were measured for the larger halogens Br and I and vary between 0.7*10−3–152*10−3 for Br and 0.3*10−3–17*10−3 for I, respectively. Br seems to have D values of about one order of magnitude higher than I. These data allow an estimation of the D values for the other halogens based on a lattice strain model which displays a sequence with DF of ∼120, DOH of ∼100, DCl of ∼2.3 DBr ∼0.045, and DI ∼0.0025. Results from this experimental study help to better understand fluid–rock interaction of an evolving fluid, as it enables the composition of hydrothermally derived apatite to be used as a fluid probe for halogens at crustal conditions. It further shows the importance of mineral replacement as one of the key reactions to generate apatite of different composition.

Prediction of octanol/water partition coefficient of selected ferrocene derivatives using rekker method

In this work we present a theoretical approach for the determination of octanol/water partition coefficient of selected ferrocenes bearing different substituents, the calculation is based on the adaptation of the Rekker method. Our prediction of obtained theoretical partition coefficients values of logP for all studied substituted ferrocene was confirmed by comparison with known experimental values obtained mainly from literature. The results obtained show that calculated partition coefficients are in good agreement with experimental values. For estimation of the octanol/water partition coefficients of the selected compounds, the average absolute error of log P is 0.13, and The correlation coefficient is R 2 = 0.966.

Abraham model correlations for describing solute transfer into 2-butoxyethanol from both water and the gas phase at 298 K

Infinite dilution activity coefficients (γ∞) were measured at 298K for 12 different aliphatic hydrocarbons (alkanes, cycloalkanes, alkenes), 11 different aromatic compounds (benzene, alkylbenzenes, halobenzenes, naphthalene), and 2-chloro-2-methylpropane dissolved in 2-butoxyethanol at 298K using a headspace gas chromatographic method. As part of the experimental study solubilities of 19 crystalline nonelectrolyte solutes (2-hydroxybenzoic acid, acetylsalicylic acid, 3,5-dinitro-2-methylbenzoic acid, acenaphthene, trans-stilbene, xanthene, phenothiazine, 3,5-dinitrobenzoic acid, 3-chlorobenzoic acid, 2-methylbenzoic acid, 4-chloro-3-nitrobenzoic acid, 2-chloro-5-nitrobenzoic acid, benzoic acid, 4-aminobenzoic acid, benzil, thioxanthen-9-one, 3-nitrobenzoic acid, fluoranthene, and diphenyl sulfone) were determined in 2-butoxyethanol at 298K using a static, spectrophotometric method. The experimental values were converted to gas-to-2-butoxyethanol and water-to-2-butoxyethanol partition coefficients, and molar solubility ratios using standard thermodynamic relationships. Abraham model correlations for solute transfer into 2-butoxyethanol were derived from the calculated partition coefficients and solubility ratios. The derived Abraham model describes the observed partition coefficient and solubility data to within 0.14logunits (or less).

A strategy for in-silico prediction of skin absorption in man

For some time, in-silico models to address substance transport into and through the skin are gaining more and more importance in different fields of science and industry. In particular, the mathematical prediction of in-vivo skin absorption is of great interest to overcome ethical and economical issues. The presented work outlines a strategy to address this problem and in particular, investigates in-vitro and in-vivo skin penetration experiments of the model compound flufenamic acid solved in an ointment by means of a mathematical model. Experimental stratum corneum concentration–depth profiles (SC–CDP) for various time intervals using two different in-vitro systems (Franz diffusion cell, Saarbruecken penetration model) were examined and simulated with the help of a highly optimized three compartment numerical diffusion model and compared to the findings of SC–CDPs of the in-vivo scenario. Fitted model input parameters (diffusion coefficient and partition coefficient with respect to the stratum corneum) for the in-vitro infinite dose case could be used to predict the in-use conditions in-vitro. Despite apparent differences in calculated partition coefficients between in-vivo and in-vitro studies, prediction of in-vivo scenarios from input parameters calculated from the in-vitro case yielded reasonable results.

Lipophilicity study of eight cephalosporins by reversed-phase thin-layer chromatographic method.

The lipophilicity (R(M0)) and specific hydrophobic surface area for the representatives of four generation cephalosporins have been determined by reversed-phase thin-layer chromatography, and the effect of different mobile-phase modifiers (such as methanol, acetonitrile, acetone, 1,4-dioxane and 2-propanol) on the retention has been studied. The compounds studied showed typical retention behavior; their R(M) values decreased linearly with increasing concentration of the organic modifier in the eluent. The linear correlations between the volume fraction of the organic solvent and the R(M) values over a limited range were established for each solute, resulting in high values of correlation coefficients (>0.95 in most cases). R(M) values were determined by various concentrations of organic modifier, and the correlation obtained was extrapolated to 0% of organic modifier. Chromatographically established logP (R(M0)) parameters were compared with computationally calculated partition coefficients values (AClogP, ALOGP, KOWWIN, ALOGPs, XLOGP2, MLOGP and XLOGP3) and experimental octanol-water logP values (measured by the shake flask method). The received results demonstrate that RP-TLC may be a good alternative technique for analytics in describing the lipophilic nature of investigated cephalosporins as well as the activity.

Abraham model correlations for solute transfer into 2-ethoxyethanol from water and from the gas phase

Infinite dilution activity coefficients (γ∞) were measured at 298K for 13 different aliphatic hydrocarbons (alkanes, cycloalkanes, alkenes), 12 different aromatic compounds (benzene, alkylbenzenes, halobenzenes, naphthalene), and 2-chloro-2-methylpropane dissolved in 2-ethoxyethanol, along with solubilities for 11 crystalline organic compounds (xanthene, phenothiazine, acenaphthene, diphenyl sulfone, 3,5-dinitro-2-methylbenzoic acid, 3-chlorobenzoic acid, 2-methylbenzoic acid, 4-chloro-3-nitrobenzoic acid, 3,5-dinitrobenzoic acid, benzil, and thioxanthen-9-one) dissolved in 2-ethoxyethanol at 298K. The experimental values were converted to gas-to-2-ethoxyethanol partition coefficients, water-to-2-ethoxyethanol partition coefficients, and molar solubility ratios using standard thermodynamic relationships. The calculated partition coefficient data and molar solubility ratios, combined with published literature values, were used to derive Abraham model correlations for solute transfer into 2-ethoxyethanol from both water and the gas phase. The derived Abraham model correlations predicted the observed values to within 0.15 log units (or less).

New biomimetic barrier Permeapad™ for efficient investigation of passive permeability of drugs

In this work the suitability of a newly invented physical patch comprising a biomimetic barrier (named Permeapad™) for drug permeability tests has been investigated. Exemplars of Permeapad™ were adapted to Franz diffusion cells and apparent permeability (Papp) of a series of drugs were measured and compared with calculated partition coefficients (logPcal) of the investigated drugs as well as literature reference values obtained from Parallel Artificial Membrane Permeation Assay (PAMPA) and the cellular based method Caco-2. Moreover, tightness of the barrier to hydrophilic marker’s permeation, resistance of these barriers to proton permeation (pH changes) and shelf-life functionality were also investigated. Comparison with the published data indicated a good correlation between the permeability values measured and partition coefficients (logPcal). Moreover, a good correlation between the permeabilities measured with the new barrier and well-established in vitro permeability methods (PAMPA and Caco-2 respectively) was found for both highly absorbed and poorly permeable compounds. Permeapad™ also proved to maintain high integrity over time and in different pH environments. In conclusion, Permeapad™ as an innovative barrier appears to be a promising tool for fast, cost effective and reliable screening of drugs and chemical entities’ passive permeability.

Lipophilicity Study of Salicylic and Acetylsalicylic Acids Using Both Experimental and Calculations Methods

In this work the lipophilicity of salicylic acid (SA) and acetylsalicylic acid (ASA) by means of both experimental and calculations methods were determined. The chromatographic parameters of lipophilicity (RMW) of the studied compounds were determined using RP-TLC method on different chromatographic plates with methanol–water mixture as the mobile phases (at various pH of water). Chromatographic conditions such as RP18W plates and methanol–water (pHwater = 2.56) as the mobile phase are suitable for the estimation of lipophilicity of examined salicylic and acetylsalicylic acids. Experimental n-octanol-water partition coefficients (logPexp) determined by traditional shake-flask method were equal to 2.35 and 1.14 for salicylic and acetylsalicylic acids, respectively. The results of lipophilicity measurements obtained by both analytical methods were compared with the theoretical values of partition coefficients estimated by use of well-known software products and also with those that were calculated by a newly developed method based on numerical values of the topological indexes (M, oB, 1B, W, and IB). Comparison of these results indicates that our new method of calculation of partition coefficients, the theoretical n-octanol-water partition coefficients, and also chromatographic lipophilicities are powerful tools in the determination of logP values of salicylic and acetylsalicylic acids.

STUDYING RETENTION BEHAVIOR, LIPOPHILICITY AND PHARMACOKINETIC CHARACTERISTICS OF N-SUBSTITUTED PHENYL-2-CHLOROACETAMIDES

The biological activity of compounds is mostly determined by its physical and structural characteristics. Among the many molecular descriptors that may indicate a potential biological activity of a compound, lipophilicity occupies the most important place. Since chloroacetamides show a variety of physiological activity, the task of this study was to investigate the potential biological activity of newly synthesized derivatives of selected N-substituted phenyl-2-chloroacetamides. Analysis was performed by thin layer chromatography on reversed phase (RP18 F254s TLC), and the mobile phase consisted of mixtures of water-acetic acid and water-dimethylformamide. By varying the volume fraction of organic modifier chromatographic retention constants, R M 0 , of the compounds were determined. Тhen R M 0 were correlated with the software calculated partition coefficient, log P , as a standard measure of lipophilicity. Also, R M 0 were correlated with selected pharmacokinetic parameters: intestinal absorption, HIA , the ability to bind to plasma proteins, PPB, and the distribution through the blood-brain barrier, BBB.

Magnetic resonance imaging dynamic contrast enhancement (DCE) characteristics of healed myocardial infarction differ from viable myocardium

PurposeTo determine whether healed myocardial infarction alters dynamic contrast-enhancement (DCE) curve shapes as well as late gadolinium-enhancement (LGE). Materials and methodsTwenty patients with chronic myocardial infarction underwent MR imaging at 1.5T with blood and myocardial T1 measurements before and after contrast administration for forty minutes. Viable and infarcted myocardial partition coefficients were calculated using multipoint slope methods for ten different DCE sampling intervals and windows. Partition coefficients and coefficients of determination were compared with paired statistical tests to assess the linearity of DCE curve shapes over the 40min time period. ResultsCalculated partition coefficients did not vary significantly between methods (p=0.325) for viable myocardium but did differ for infarcted myocardium (p<0.001), indicating a difference in infarcted DCE. There was a significant difference between viable and infarcted myocardial partition coefficients estimates for all methods with the exception of methods that included measurements during the first 10min after contrast agent administration. ConclusionMyocardial partition coefficients calculated from a slope calculation vary in healed myocardial infarction based on the selection of samples due to non-linear DCE curve shapes. Partition coefficient calculations are insensitive to data sampling effects in viable myocardium due to linear DCE curve shapes.