Calculated Partition Coefficients Research Articles

Magnetite solubility and iron transport in magmatic-hydrothermal environments

We have examined the effect of pressure on the apparent equilibrium constant, K′, for magnetite solubility (Fe 3O 4 mt + 6HCl fluid + H 2 fluid = 3FeCl 2 fluid + 4H 2O fluid) and the relative iron-carrying capacities of magmatic vapor and brine by conducting experiments in a rhyolite melt-vapor-brine-magnetite system at 800°C, f O 2 = NNO and pressures ranging from 100 to 145 MPa. Iron concentrations in synthetic vapor and brine fluid inclusions were quantified by using laser-ablation inductively-coupled-plasma-mass-spectrometry (LA-ICPMS). Hydrogen chloride (HCl) concentrations in magmatic vapor were inferred by potentiometric measurements of H + in quenched run product fluids. These data yield calculated values for log K′, assuming a H 2 O = X H 2 O , of 1.7, 4.9, 6.2, 6.8 and 9.1 at 100, 110, 130, 140 and 145 MPa, respectively. The concentration of iron in magmatic vapor increases by an order of magnitude, whereas the concentration of iron in magmatic brine remains constant (within 1σ) with increasing pressure as the 800°C critical pressure is approached along the vapor-brine solvus. The concentrations of iron in vapor and brine fluid inclusions yield calculated partition coefficients ( D Fe v/b) of 0.05, 0.14, 0.27 and 0.56 at 110, 130, 140 and 145 MPa, respectively. Our data reveal that pressure fluctuations may significantly affect the value of log K′. More importantly, the data demonstrate conclusively that a significant amount of iron can be transported by a low-density aqueous vapor in the magmatic-hydrothermal environment.

Computer Simulation of Small Molecule Permeation across a Lipid Bilayer: Dependence on Bilayer Properties and Solute Volume, Size, and Cross-Sectional Area

Cell membrane permeation is required for most drugs to reach their biological target, and understanding this process is therefore crucial for rational drug design. Recent molecular dynamics simulations have studied the permeation of eight small molecules through a phospholipid bilayer. Unlike experiments, atomistic simulations allow the direct calculation of diffusion and partition coefficients of solutes at different depths inside a lipid membrane. Further analyses of the simulations suggest that solute diffusion is less size-dependent and solute partitioning more size-dependent than was commonly thought.

QSAR-based toxicity classification and prediction for single and mixed aromatic compounds

Quantitative structure-activity relationships (QSARs) based on the octanol/water partition coefficient were employed to predict acute toxicities of 36 substituted aromatic compounds and their mixtures. In this study, the model developed by Verhaar et al. was modified and used to calculate octanol/water partition coefficients of chemical mixtures. To validate the model, acute toxicities of these chemicals were measured to Vibrio fischeri in terms of EC50. The results indicated that the obtained QSAR models could be used to predict toxicities of samples consisting of these substituted aromatic compounds, individually or in combinations. The obtained equations were proved to be robust enough by using the leave-one-out test method. By classifying these chemicals into two groups, polar and non-polar, the toxicities of chemical mixtures within each group can be predicted accurately from their calculated partition coefficients.

Pulsed-Field Gradient and Saturation Transfer Difference NMR Study of Enkephalins in the Ganglioside GM1 Micelle

Alteration of the conformational and dynamic properties of peptides in the presence of micelles mimics the cellular events that take place during insertion and translocation of peptides in biological membranes. We have recently reported the alteration of the conformation of neuropeptides Leu- and Met-enkephalins in the presence of ganglioside GM1 micelles.41 Here, using pulsed-field gradient-stimulated echo diffusion NMR studies, we observe that the diffusion coefficients of the peptides are greatly reduced in the presence of GM1 micelles. Partition coefficient calculations indicate a nearly total incorporation of the peptides into the micelles. The binding epitope of the enkephalins, as established from the saturation transfer difference NMR spectroscopy, indicates involvement of the Tyr1, Gly3, and Phe4 residues. The involvement of the aromatic side chains of the Tyr1 and Phe4 indicates a possible hydrophobic nature of the interaction.

Iterative Least Squares Fitting of pH-Extraction Curves Using an Object-Orientated Language

A curve fitting procedure to optimise liquid-liquid extraction of weakly acid or basic drugs is presented. Data for three drugs are used to exemplify the utility of such an approach, including the determination of unknown pKa values. The potential for using calculated partition coefficients is discussed.

Interaction of Sodium Dodecyl Sulfate with Dimyristoyl-sn-glycero-3-phosphocholine Monolayers Studied by Infrared Reflection Absorption Spectroscopy. A New Method for the Determination of Surface Partition Coefficients

The interaction of the surfactant sodium dodecyl sulfate (SDS) with lipid monolayers of 1,2-dimyristoyl-d54-sn-glycero-3-phosphocholine (DMPC-d54) at the air/water interface was studied by infrared reflection absorption spectroscopy. To obtain separate information about the structural changes of both the lipid and the surfactant component during the interaction, isotopically labeled DMPC-d54 was used. With increasing surfactant concentration, the slight shift of the CD2 stretching vibration of DMPC-d54 toward lower wavenumber indicates a small increase of the lipid alkyl chain order due to the incorporation of the surfactant into the lipid monolayer. The DMPC-d54 surface density stays the same. The frequency of the antisymmetric and symmetric CH2 stretching modes of the surfactant alkyl chain also shifts toward lower wavenumber with increasing amount of surfactant in the monolayer due to increased chain ordering. For the first time, we applied the isotopic substitution method for the direct calculation of surface partition coefficients describing the amount of incorporated SDS in the DMPC-d54 monolayer. The partition coefficients were determined at different SDS concentrations and surface pressures and were compared to partition coefficients of the bilayer system, obtained under similar conditions by isothermal titration calorimetry. The best agreement between monolayer and bilayer data was obtained for a monolayer held at a pressure of 29.5−33.2 mN/m, which can be considered as the bilayer−monolayer equivalence pressure.

RP TLC evaluation of logPfor higher fatty acids, hydroxy acids and their esters

Higher fatty acids, hydroxy fatty acids, and their esters have been separated by reversed-phase thin-layer chromatography with three mobile phases. The partition coefficients ( A log P s, IA log P , C log P , log P Kowin , x log P , and log P Rek ) were calculated for the compounds by use of different theoretical procedures. New methods for calculation of partition coefficients on the basis of experimental R M values have been proposed. These methods lead to different partition coefficients for oleic and elaidic acids, geometric isomers of 9-octadecenoic acids.

Experimental determination of the ammonium partitioning among muscovite, K-feldspar, and aqueous chloride solutions

The cation exchange equilibria Muscovite+ NH 4 Cl⇔ Tobelite+ KCl KAl 2 AlSi 3 O 10( OH) 2+ NH 4 Cl aq ⇔ NH 4 Al 2 AlSi 3 O 10( OH) 2+ KCl aq K- feldspar+ NH 4 Cl⇔ Buddingtonite+ KCl KAlSi 3 O 8+ NH 4 Cl aq ⇔ NH 4 AlSi 3 O 8+ KCl aq are determined by hydrothermal experiments at 400, 500, 600 °C at 400 MPa, and piston cylinder experiments at 500, 600 °C at 1500 MPa along the entire K–NH 4 compositional range. The composition of solid phases are determined by XRD, EMP and FTIR-methods, NH 4–K ratios in coexisting 2–3 molal chloride solutions by ion chromatography. Muscovite–tobelite and K-feldspar–buddingtonite form complete solid solutions series at all conditions. Consistent phase relations and mass balances indicate equilibrium between solid solutions and fluids. In both the (K,NH 4)-muscovite and (K,NH 4)-feldspar-fluid systems, NH 4 strongly fractionates into the fluid. In the range from 400 to 600 °C, 400 to 1500 MPa, fractionations are slightly temperature and pressure-dependent. The distribution coefficient K D solid- fluid = X NH 4 solid X K solid X K fluid X NH 4 fluid varies within the experimental range from 0.10 at X K bulk=0.81 to 0.46 at X K bulk=0.20 for muscovite-fluid, and from 0.05 at X K bulk=0.91 to 0.70 at X K bulk=0.15 for feldspar-fluid. NH 4 is preferentially incorporated into feldspar relative to mica with K D fsp-ms ranging between 1.36 and 2.0 at 400 MPa, and between 1.13 and 1.5 at 1500 MPa as X K bulk varies from 0.15 to 0.89. Results are evaluated thermodynamically assuming equal mixing of NH 4Cl and KCl in the fluid. Mixing energies of solids were estimated using multidimensional regression and a regular solution model. For the muscovite–tobelite equilibrium, values of Δ s°=−11.7 J K −1 mol −1, Δ v°=−2.1 J MPa −1 mol −1, and W=4.6 kJ mol −1, and for the K-feldspar–buddingtonite equilibrium, Δ s°=−8.8 J K −1 mol −1, Δ v°=−1.1 J MPa −1 mol −1, and W=5.4 kJ mol −1 were derived. Results are used to calculate partition coefficients D among phases at very low NH 4 bulk concentrations. Between 400 and 600 °C, D NH 4 fluid-ms ranges from 7 to 8 at 400 MPa and is 5 at 1500 MPa. D NH 4 fluid-ms is 6 to 7 at 400 MPa, and about 5 at 1500 MPa. D NH 4 fsp-ms is between 1 and 1.2 at all conditions. Partition coefficients are valid for NH 4 contents of up to several hundred ppm in mica and feldspar, well within the concentration range observed in many rocks. Combining the data with that of K–NH 4-partitioning between phlogopite and fluid results in D NH 4 phl-ms≈3.5 and D NH 4 phl-ms≈3 at 550 °C, 200 to 400 MPa. NH 4 concentrations in coexisting muscovite, biotite, and K-feldspar from a variety of rocks show near-equilibrium distributions. NH 4–K-partitioning between major K-bearing minerals and saline fluids allows for assessment of the dehydration history of metamorphic rocks. During prograde metamorphism, water is progressively produced by dehydration reactions and expelled along rock's P– T path. Nitrogen is subsequently removed due to preferred fractionation of NH 4 into fluids. The remaining NH 4 is continuously redistributed among muscovite and biotite, and at higher grades, K-feldspar with biotite as the main solid phase carrier of ammonium. The large fractionation effect of NH 4 among most phases highlights its potential as tracer of devolatilization processes and fluid–rock interactions.

Separation and determination of biphenyl nitrile compounds by microemulsion electrokinetic chromatography with mixed surfactants

A mixture of six biphenyl nitrile compounds and three related substances with high hydrophobicity and similar structures was successfully separated by microemulsion electrokinetic chromatography (MEEKC) within 30 min. The microemulsion system contained 100 mM sodium dodecyl sulfate (SDS), 80 mM sodium cholate (SC), 0.81% v/v heptane, 7.5% v/v n-butanol, 10% v/v acetonitrile, and 10 mM borate. The addition of SC, organic modifiers, sample preparation, and temperature all showed remarkable effects on the separation. The capacity factor (k) was calculated by using dodecyl benzene as the marker for microemulsion, and the calculated partition coefficient log P(o/w) of the solutes was in the range of 3.35-7.38. The log k values matched well with the log P(o/w) with a correlation coefficient of 0.96. In addition, the linear correlation coefficients of each compound between peak area and concentration were from 0.996 to 0.998 with the repeatability RSD value < 1.2% for migration time and < 4.8% for peak area, and the highest theoretic plate number was > 586000. MEEKC was compared with micellar electrokinetic chromatography (MEKC) indicating that the former method is more suitable for this separation and can be used for the quality control of biphenyl nitrile compounds in the synthesis of liquid crystals.

New method of calculation of the partition coefficients of selected alkoxyphenols investigated by RPTLC

Selected meta -and para -alkoxyphenols have been separated by RPTLC on cellulose impregnated with ethyl oleate, with ethanol-water, 40 + 60 (%, v/v ), as mobile phase. New methods of calculation of partition coefficients on the basis of the topological index ° B and experimental R F values have been proposed. These methods enable differentiation between the values of log P for the meta and para isomers of the alkoxyphenols.

Thermodynamic modeling of the partitioning of biomolecules in aqueous two-phase systems using a modified Flory–Huggins equation

A modified Flory–Huggins equation accounting for the solvation of polymer molecules by water molecules was used to model the phase behavior of aqueous two-phase systems (ATPS) formed by poly(ethylene glycol) (PEG) and dextran. The parameters of the equation were obtained by fitting experimental equilibrium data either accounting for or disregarding dextran polidispersity. The modified equation was subsequently applied to calculate partition coefficients of biomolecules in these systems. It was found that accounting for polidispersity did not affect significantly the calculated phase equilibrium, but increased the agreement of calculated partition coefficients with experimental data. Further improvement was obtained by using a size dependent interaction parameter for dextran pseudo-components.

Use of RP‐TLC and Structural Descriptors to Predict the log P Values of Higher Fatty Acids, Hydroxy Acids, and Their Esters

Selected higher fatty acids, hydroxy acids, and their esters were chromatographed on RP‐TLC plates using methanol:water as mobile phase. R F values obtained by RP‐TLC and log P values by Rekker were used for the new methods of calculation of partition coefficients for investigated compounds. The partition coefficient values estimated by the Rekker method for higher fatty acids, hydroxy acids, and their esters were also correlated with the numerical values of selected structural descriptors. The most accurate prediction of the partition coefficient values of the acids and esters was achieved by use of biparametric equations relating to the topological index A and electrotopological state E ΣOH. These methods enable differentiation between the values of log P for the geometric isomers of 9‐octadecenoic acids, namely for oleic acid and elaidic acid.

Molecular Properties of WHO Essential Drugs and Provisional Biopharmaceutical Classification

The purpose of this study is to provisionally classify, based on the Biopharmaceutics Classification System (BCS), drugs in immediate-release dosage forms that appear on the World Health Organization (WHO) Essential Drug List. The classification in this report is based on the aqueous solubility of the drugs reported in commonly available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. The WHO Essential Drug List consists of a total of 325 medicines and 260 drugs, of which 123 are oral drugs in immediate-release (IR) products. Drugs with dose numbers less than or equal to unity [Do = (maximum dose strength/250 mL)/solubility < or = 1] are defined as high-solubility drugs. Drug solubility for the uncharged, lowest-solubility form reported in the Merck Index or USP was used. Of the 123 WHO oral drugs in immediate-release dosage forms, 67% (82) were determined to be high-solubility drugs. The classification of permeability is based on correlations of human intestinal permeability of 29 reference drugs with the estimated log P or CLogP lipophilicity values. Metoprolol was chosen as the reference compound for permeability and log P or CLogP. Log P and CLogP were linearly correlated (r2 = 0.78) for 104 drugs. A total of 53 (43.1%) and 62 (50.4%) drugs on the WHO list exhibited log P and CLogP estimates, respectively, that were greater than or equal to the corresponding metoprolol value and are classified as high-permeability drugs. The percentages of the drugs in immediate-release dosage forms that were classified as BCS Class 1, Class 2, Class 3, and Class 4 drugs using dose number and log Pwere as follows: 23.6% in Class 1, 17.1% in Class 2, 31.7% in Class 3, and 10.6% in Class 4. The remaining 17.1% of the drugs could not be classified because of the inability to calculate log P values because of missing fragments. The corresponding percentages in the various BCS classes with dose number and CLogP criteria were similar: 28.5% in Class 1, 19.5% in Class 2, 35.0% in Class 3, and 9.8% in Class 4. The remaining 7.3% of the drugs could not be classified since CLogP could not be calculated. These results suggest that a satisfactory bioequivalence (BE) test for more than 55% of the high-solubility Class 1 and Class 3 drug products on the WHO Essential Drug List may be based on an in vitro dissolution test. The use of more easily implemented, routinely monitored, and reliable in vitro dissolution tests can ensure the clinical performance of drug products that appear on the WHO Essential Medicines List.

Prediction of Human Pharmacokinetics from Animal Data and Molecular Structural Parameters using Multivariate Regression Analysis: Oral Clearance

The aim of the study reported here was to develop a regression equation for predicting oral clearance of various kinds of drugs in humans using experimental data from rats and dogs and molecular structural parameters. The data concerning the oral clearance of 87 drugs from rats, dogs, and humans were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, the molecular weight, calculated partition coefficient (c log P), and the number of hydrogen bond acceptors were used as possible descriptors related to oral clearance in human. Multivariate regression analyses, multiple linear regression analysis, and the partial least squares (PLS) method were used to predict oral clearance in human, and the predictive performances of these techniques were compared by allometric approaches, which have been used in interspecies scaling. Interaction terms were also introduced into the regression analysis to evaluate the nonlinear relationship. For the data set used in this study, the PLS model with the tertiary term descriptors gave the best predictive performance, and the value of the squared cross‐validated correlation coefficient (q2) was 0.694. This PLS model, using animal oral clearance data for only two species and easily calculated molecular structural parameters, can generally predict oral clearance in human better than the allometric approaches. In addition, the molecular structural parameters and the interaction term descriptors were useful for predicting oral clearance in human by PLS. Another advantage of this PLS model is that it can be applied to drugs with various characteristics. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2427–2440, 2003

The 4-arylaminocoumarin derivatives log P values calculated according to Rekker's method

In the QSAR (quantitative structure-activity relationship) and QSPR (quantitative structure-property-activity relationship) study physico-chemical property, lipophilicity is used, to predict bioactivity of the newly synthesized coumarin compounds. Lipophilicity is a property of a molecule which depends on and can be changed by modifications in molecular structure. The parameter of the lipophilicity, partition coefficient (log P), is commonly used in drug designing and it is a numeric characteristic of lipophilicity of the examined substance, potential drug. The synthesis of 4-arylaminocoumarins derivatives from 4-hydroxycoumarin, has been carried out. In this work we described the fragmental method of calculation of partition coefficient according to the Rekker's method, because the best correlation between calculated and experimental values log P was determined according to the Rekker model. 4-Arylaminocoumarin has negative value of log P, but substitution with alkyl or allyl groups on the position 3 increases lipofilicity. Introduction of methyl or ethyl group into position 3 increases lipofilicity, suggesting that by increasing the chain length the values of log P become higher. The influence of allyl substituent in position three increases lipophilicity similar to methyl group. The aryl supstitent decreases lipoflicity, but a general relationship among them could not be established. The results obtained in this study enable further synthesis of new coumarin derivatives and predict their biological activity and properties.

Lead and Zinc Partition Coefficients of Selected Soils Evaluated by Langmuir, Freundlich, and Linear Isotherms

The paper outlines some approaches that should be considered in the calculation of partition coefficients based on Langmuir, Freundlich and Linear isotherms. It was found that the Langmuir partition coefficient (K Lg ), whose calculation involved the maximal amount of lead (Pb) and zinc (Zn) adsorbed and their appropriate bonding term energy, seemed more “precise” than the Freundlich (K F ) and Linear (K Li ) based partition coefficients. The Freundlich partition coefficients were decidedly lower than the Langmuir and Linear ones and appeared to “resist” to changes of equilibrium lead and zinc equilibrium concentrations. This feature may lead to a potential underestimation of calculated K F coefficients due to the heterogenic nature of soil adsorptive surface. The “adequate” Linear partition coefficient should unconditionally be obtained from the slope of the C‐type plot (isotherm) of the amount adsorbed versus its solution concentration. This step will occur when the Freundlich exponent n = 1. Langmuir partition coefficient (K Lg ) as a convenient and reliable parameter to be applied for soil adsorption capacities assessment should be recommended.

Lipophilicity of Selected Bile Acids as Determined by TLC. I

The selected bile acids were chromatographed on RP‐HPTLC plates using methanol–water in different volume proportions as mobile phases. The linear relationships were found between R M values of bile acids and the volume fraction of methanol in the mobile phase. The retention parameters R MW were extrapolated to zero methanol content and were compared with measured (log P exp), as well as calculated partition coefficients (IAlog P and log P Kowin). It was stated that the investigated bile acids might be considered as compounds belonging to the same group. The most significant correlation was found between the R MW and log P Kowin values. The results indicate that chromatographic R MW values may be used as a measure of lipophilicity of the investigated bile acids.

Comparison of chromatographically determined values of the lipophilicity of anticonvulsant activeN-substituted amides of α-arylalkylamine-γ-hydroxybutyric acid with values estimated by computational methods

The lipophilicity of five series of anticonvulsant active N -substituted amides of α -arylalkylamine- γ -hydroxybutyric acid (compounds 1–37) has been investigated. The lipophilicity of nine N -substituted amides of α -arylalkylamine- γ -hydroxybutyric acid was determined by reversed-phase thin-layer chromatography (RPTLC) using mixtures of methanol, pH 7.4 Tris buffer, and acetic acid as mobile phases. Mobile-phase methanol concentrations were in the range 25–65%. The R M values of the compounds investigated were linearly dependent on methanol concentration. Partition coefficients (log P ) were calculated for all the compounds by means of the software Prolog P (Pallas) and SciLogP (Alchemy 2000), and compared with the relative lipophilicity ( R M0 ). It was found that log P values estimated by SciLogP correlated better with values obtained by TLC, and thus the methodology of Bodor and co-workers based on the use of molecular properties method for calculation of partition coefficients was a better tool fo...

Atomistic simulation of mineral–melt trace-element partitioning

We discuss recent advances in computational approaches to trace-element incorporation in minerals and melts. It is crucial to take explicit account of the local structural environment of each ion in the solid and the change in this environment following the introduction of a foreign atom or atoms. Particular attention is paid to models using relaxation (strain) energies and solution energies, and the use of these different models for isovalent and heterovalent substitution in diopside and forsterite. Solution energies are also evaluated for pyrope and grossular garnets, and pyrope–grossular solid solutions. Unfavourable interactions between dodecahedral sites containing ions of the same size and connected by an intervening tetrahedron lead to larger solubilities of trace elements in the garnet solid solution than in either end member compound and to the failure of Goldschmidt’s first rule. Our final two examples are the partitioning behaviour of noble gases, which behave as ‘ions of zero charge’ and the direct calculation of high-temperature partition coefficients between CaO solid and melt via Monte Carlo simulations.

Quantitative structure-fungitoxicity relationships of some monohydric alcohols.

The fungitoxicity data of some monohydric alcohols on the mycelial growth inhibition of Colletotrichum gloeosporioides were subjected to quantitative structure-activity relationship (QSAR) studies. The very large variation in the median effective concentrations ranging from >24000 mg/L [pEC(50) (mol/L) = 0.11] in the case of methanol to <100 mg/L [pEC(50) (mol/L) = 3.27] in the case of citronellol was found to depend mainly on changes in calculated partition coefficients (CLogP) of the compounds. The other three factors that affected the variation in fungitoxicity are the number of hydrogen atoms on the carbon bearing the hydroxyl group (N(H)), which determines the class of the alcohol to be primary, secondary, or tertiary, the number of double bonds (N(=)), and the branching of the alkyl moiety. Because many compounds in the set under study belonged to homologous series, there was a collinearity between CLogP values and Kier's molecular connectivity values (chi), which are usually used as branching indices. The problem of collinearity between CLogP values and branching indices was overcome by taking the relative molecular connectivity (chi(rel)), which is defined as the ratio of molecular connectivity of the alcohol under consideration to the molecular connectivity of the corresponding straight-chain primary alcohol with the same number of carbon atoms. Apart from the excellent correlations obtained in the equations, the credibility of the QSAR model could also be demonstrated by its application to published data taken from the literature.