1-octanol Water Partition Coefficient Research Articles

Prediction of partition coefficient in high-pressure carbon dioxide–water systems using machine learning

A method of predicting the partition coefficients (log K) of organic compounds in high-pressure carbon dioxide–water systems using machine learning was investigated. Using the collected literature data of log K, several linear and non-linear regression models were constructed. A cross-validation using these models indicated that log K can be approximately predicted with a root-mean-squared error of 0.6–1.1. Overall, the non-linear model predicted log K better, but linear models such as lasso regression exhibited comparable performances when features describing compounds were reduced. Parity plots indicated several outliers, most of which contain several polar functional groups. The analysis of feature importance revealed that the constructed model primarily consisted of the feature of log P (the 1-octanol–water partition coefficient) and was modified using process parameters and features related to the charges of compounds. The machine-learning approach yields a physicochemically reasonable model.

Evaluation of the membrane permeability of drugs by ion-transfer voltammetry with the oil | water interface

Ion transfer voltammetry with the polarized 1,2-dichloroethane (DCE)|water (W) interface was carried out to determine the standard ion-transfer potential (∆OWϕ∘) and the distribution coefficient (logKD) for amine drugs, including desipramine, imipramine, labetalol, etc. The values of ∆OWϕ∘ and logKD are the hydrophobicity scales for the ionized and neutral forms of a drug, respectively, and were found to show a good mutual correlation. However, these hydrophobicity scales did not show a good correlation to the 1-octanol–water partition coefficient (logPoct) being conventionally used. In contrast, the permeability coefficient (logPpampa) in the parallel artificial membrane permeation assay showed a clear and characteristic dependence on ∆OWϕ∘ (or logKD). These results suggested that the solvation environment in DCE should be more similar to that in the hydrocarbon region of lipid bilayers than in 1-octanol. Thus, it was shown that ∆OWϕ∘, which can be easily determined by ion-transfer voltammetry, is a promising scale for predicting drug permeability through lipid membranes.

Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate was secreted in bile unmodified and as 3-glucuronide. Therefore, minor structural modifications profoundly influence the metabolism and biodistribution in the target organs where these analogs exert therapeutic effects by interacting with FXR and/or TGR5 receptors.

Sorption capacity of plastic debris for hydrophobic organic chemicals

The occurrence of microplastics (MPs) in the ocean is an emerging world-wide concern. Due to high sorption capacity of plastics for hydrophobic organic chemicals (HOCs), sorption may play an important role in the transport processes of HOCs. However, sorption capacity of various plastic materials is rarely documented except in the case of those used for environmental sampling purposes. In this study, we measured partition coefficients between MPs and seawater (KMPsw) for 8 polycyclic aromatic hydrocarbons (PAHs), 4 hexachlorocyclohexanes (HCHs) and 2 chlorinated benzenes (CBs). Three surrogate polymers – polyethylene, polypropylene, and polystyrene – were used as model plastic debris because they are the major components of microplastic debris found. Due to the limited solubility of HOCs in seawater and their long equilibration time, a third-phase partitioning method was used for the determination of KMPsw. First, partition coefficients between polydimethylsiloxane (PDMS) and seawater (KPDMSsw) were measured. For the determination of KMPsw, the distribution of HOCs between PDMS or plastics and solvent mixture (methanol:water=8:2 (v/v)) was determined after apparent equilibrium up to 12weeks. Plastic debris was prepared in a laboratory by physical crushing; the median longest dimension was 320–440μm. Partition coefficients between polyethylene and seawater obtained using the third-phase equilibrium method agreed well with experimental partition coefficients between low-density polyethylene and water in the literature. The values of KMPsw were generally in the order of polystyrene, polyethylene, and polypropylene for most of the chemicals tested. The ranges of log KMPsw were 2.04–7.87, 2.18–7.00, and 2.63–7.52 for polyethylene, polypropylene, and polystyrene, respectively. The partition coefficients of plastic debris can be as high as other frequently used partition coefficients, such as 1-octanol–water partition coefficients (Kow) and log KMPsw showed good linear correlations with log Kow. High sorption capacity of microplastics implies the importance of MP-associated transport of HOCs in the marine environment.

Direct calculation of 1-octanol–water partition coefficients from adaptive biasing force molecular dynamics simulations

The 1-octanol-water partition coefficient log K(ow) of a solute is a key parameter used in the prediction of a wide variety of complex phenomena such as drug availability and bioaccumulation potential of trace contaminants. In this work, adaptive biasing force molecular dynamics simulations are used to determine absolute free energies of hydration, solvation, and 1-octanol-water partition coefficients for n-alkanes from methane to octane. Two approaches are evaluated; the direct transfer of the solute from 1-octanol to water phase, and separate transfers of the solute from the water or 1-octanol phase to vacuum, with both methods yielding statistically indistinguishable results. Calculations performed with the TIP4P and SPC∕E water models and the TraPPE united-atom force field for n-alkanes show that the choice of water model has a negligible effect on predicted free energies of transfer and partition coefficients for n-alkanes. A comparison of calculations using wet and dry octanol phases shows that the predictions for log K(ow) using wet octanol are 0.2-0.4 log units lower than for dry octanol, although this is within the statistical uncertainty of the calculation.

Benchmarks for the fifth industrial fluid properties simulation challenge

The primary goal of the fifth industrial fluid properties simulation challenge was to test the ability of computer modeling (any advanced molecular simulation method) to predict the 1-octanol–water partition coefficient, K OW, and infinite-dilution activity coefficient ( γ ∞) in water. Prediction of 1-octanol–water partition coefficients (which has been widely studied by non-molecular simulation computational methods) is viewed as a stepping stone to a more difficult liquid–liquid (LLE) problem, for example, where a third component is present at a high enough level to influence the mutual solubilities of the other two. To address this primary goal, entrants were challenged to predict K OW and γ ∞ for two molecules for which, at the time of the contest, no measured data could be found in phase equilibria databases or literature. The molecules are 1-ethylpropylamine (CAS# 616-24-0) and 3-methyl-1-pentanol (CAS# 589-35-5). All four benchmark values were derived directly from experimental data measured for the simulation challenge at The Dow Chemical Company, Research and Development Department, Analytical Sciences.

Prediction of 1-octanol–water partition coefficient and infinite dilution activity coefficient in water from the PR + COSMOSAC model

The Peng–Robinson equation of state (PR EOS) is used for the prediction of 1-octanol–water partition coefficients ( K OW ) and infinite dilution activity coefficients ( γ ∞). Unlike the conventional approach where the EOS parameters must be determined from the critical properties and acentric factor of each chemical species in addition to using some mixing rule to account for composition dependence, these parameters are determined here using a solvation model developed based on first principle COSMO calculations. Consequently, this approach, denoted as PR + COSMOSAC, requires input of only molecular connectivity and is capable of describing both temperature and pressure effects in fluid phase equilibria. It is found that the predicted mutual solubility of water and 1-octanol, the partition coefficient K OW of a third chemical and γ ∞ in water are in good agreement with reported experimental data. In response to the 5th fluid challenge, linear correlation equations with the correlation coefficient ( R 2) better than 0.96 are developed for highly accurate predictions of properties specifically for alcohols and amines.

Effects of pH on the water solubility and 1-octanol–water partition coefficient of 2,4,6-tribromophenol

2,4,6-Tribromophenol (TBP) is expected to exist in both ionic and non-ionic forms in the environment due to ionisation of the phenolic group at near neutral pH. In this study, the water solubility (Sw) and 1-octanol-water partition coefficient (Kow) of aqueous solutions of TBP at various pH values were measured using the shake flask method. The ionisation resulted in increasing Sw and decreasing Kow by two to three orders of magnitude. From the experimental results, the environmental partitioning characteristics of TBP and the effect of pH on partitioning were discussed through a comparison with the properties of tetrabromobisphenol A (TBBP-A), which has two phenolic groups. Furthermore, the pH dependence of Sw and Kow was represented using a Henderson-Hasselbalch type model and the validity of the model was evaluated. The model was found to be highly useful for predicting the pH dependence within the range of pH 3 to 9.

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides

Using N -[4-(hexyloxy)phenyl]piperidine-3-carboxamide ( 17c ) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5′-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure–activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC 50 and lipophilicity, as assessed by RP-HPLC capacity factors and Clog P (i.e. calculated 1-octanol–water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of β-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n -propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

STACKING AND STABILITY OF RNA DUPLEXES CONTAINING FLUOROBENZENE AND FLUOROBENZIMIDAZOLE NUCLEOSIDES

Six different fluorobenzene or fluorobenzimidazole ribonucleosides and one abasic site were incorporated in oligoribonucleotides. Individual contributions of base stacking and solvation of the modified nucleosides could be determined. In fluorobenzene · fluorobenzimidazole-modified base pairs a duplex stabilizing force was found that points to a weak F…H hydrogen bond. The lipophilicity of the unprotected nucleosides were investigated by determination of 1-octanol water partition coefficients.

Determination of octanol–water partition coefficients using a micro-volume liquid-liquid flow extraction system

An extraction system consuming less than 1 μl of sample and organic solvent (combined volume) has been developed for the determination of 1-octanol–water partition coefficients (log K ow). The system comprises a capillary, a micro-volume stepper piston pump, a peristaltic pump and a detector. The stepper piston pump is programmable, enabling full control and selection of each step in the pumping sequence. Coupled to the pump is a 250 μm i.d. silica capillary, extending 240 mm from its aperture to the detector cell which houses an on-capillary spectrophotometric detector allowing direct monitoring of both the aqueous sample and the organic solvent plugs. Programmed portions of air, aqueous sample, organic solvent and a second portion of air are sequentially introduced into the capillary from respective vials. Typically, 250 nl of both the aqueous sample and organic solvent were introduced in the trials reported here. Since all liquids are aspirated directly into the capillary there is no need to pre-flush the system (as is required in most other continuous flow systems). Thus, the entire portions of the sample and the organic solvent are used in the analysis. The analytical procedure used for determining octanol–water partition coefficients is essentially an automated and miniaturised version of the batch method recommended in the OECD manual. The log K ow values obtained agreed well with literature data and/or manual batch determinations. Typical analysis time was 4 min when applying a mean flow rate of about 4 μl min −1, including a wash cycle between the samples. The system is suitable for screening purposes and could readily be automated using a robot.

Characterization of partition and thermodynamic properties of cephalosporins using micellar electrokinetic chromatography in glycodeoxycholic acid solution

Micellar electrokinetic chromatography (MEKC) was introduced to evaluate the hydrophobicity of cephalosporins (cefpim, cefpirom, cefazolin, ceftazidim, cephradin, cefuroxim, cefotaxim, cephapirin and cephalothin) (Fig. 1). Partition coefficients of cephalosporins were calculated between a micelle and an aqueous phases from the measurement of the migration time, provided the critical micelle concentration and the phase ratio are known. Thermodynamic quantities such as enthalpy and entropy changes of micellar solubilization were calculated from the temperature dependence on the partition coefficients. Sodium glycodeoxycholate in low-salt aqueous solutions was employed to prepare a micellar solution. Substances for pharmaceutical purposes have to meet several requirements to be well-tolerated. Therefore, they are often derived from naturally occurring ones, e.g., from the bile salts in bile juice. The electrophoretic velocity of a micelle and the phase ratio between the micelle of the glycodeoxycholic acid and the aqueous phase were calculated. Partial specific volumes at different temperatures (from 20 to 45°C) were measured using dynamic light scattering. The logarithm of the partition coefficients and the migration factor in the micellar system were correlated with the logarithm of the 1-octanol–water partition coefficients.

High-performance liquid chromatographic measurement of the 1-octanol–water partition coefficient of s-triazine herbicides and some of their degradation products

1-Octanol–water partition coefficients ( K ow) of s-triazines and some of their degradation products were determined using two reversed-phase high-performance liquid chromatography (HPLC) methods. In the first method, an octadecyl column was coated with 1-octanol and eluted with 1-octanol–saturated water. Using this method, a maximum log K ow of 2.86 could be determined. For higher values a recently developed gradient HPLC method was used. The determined 1-octanol–water partition coefficients are helpful for studies and mathematical models dealing with the fate of s-triazine herbicides and their degradation products in the environment.

Determination of octanol-water partition coefficients of polar polycyclic aromatic compounds (N-PAC) by high performance liquid chromatography

Prediction of 1-octanol water partition coefficients for a range of polar N-PAC from HPLC capacity coefficients has been investigated. Two commercially available columns, an ODS column and a Diol column were tested with water-methanol eluents. The best prediction of log K ow for N-PAC was achieved using a Diol column with an eluent of 35% MeOH and 65% water. The results indicate that the Diol column, in reversed phase mode, is able to form hydrogen bonds with a solute. Different LFERs between retention and log K ow was found for polar and nonpolar compounds. In general log K ow increased with size and log K ow for N-PAC was 1.1-1.3 lower than log K ow for the equivalent PAH. Shielding of the nitrogen atom in the N-PAC compounds caused an increase in log K ow.

Unified Model for the Corneal Permeability of Related and Diverse Compounds with Respect to Their Physicochemical Properties

Corneal permeability data taken from the literature were analyzed for possible quantitative relationships with physicochemical properties. Although a parabolic relationship was obtained with good correlation between lipophilicity, as expressed by the 1-octanol–water partition coefficients, log Poctanol (or the distribution coefficients, log D for ionizable compounds), and the permeability in individual analyses of compound classes such as β-adrenoceptor blockers and steroids, the correlation was reduced when taken together. However, Δ log P (i.e., log Poctanol−log Palkane) correlated inversely with the combined permeability data for β-blockers and steroids and played a key role as a unifying variable. To a lesser extent, lipophilicity itself also contributes positively to corneal permeation. Even with the addition of miscellaneous compounds such as methanol and ibuprofen, the Δ log P and lipophilicity terms were still significant. However, small molecules were likely to be underestimated, which is consistent with penetration via another pathway besides that governed by Δ log P and lipophilicity.

New chromatographic hydrophobicity index (ϕ 0) based on the slope and the intercept of the log k′ versus organic phase concentration plot

A new chromatographic hydrophobicity index (ϕ 0) is suggested as a measure of the lipophilic character of compounds in reversed-phase high-performance liquid chromatography (RP-HPLC). The parameter ϕ 0 is defined as the organic phase concentration (methanol or acetonitrile) in the mobile phase which is required for log k′ = 0 (retention time is double the dead time), that is, the molar fraction of the compound is identical in the mobile and the stationary phases. The ϕ 0 values therefore range from 0 to 100%, and the higher the value the more hydrophobic is the compound. It is shown that the value of ϕ 0 is characteristic for a compound and depends only on the type of organic modifier, pH and temperature. It is independent of the RP column type and length, flow-rate and the mobile phase compositions where the actual retention measurements are carried out. The other advantages of ϕ 0 are that it can be precisely measured, as it has a concrete physical meaning, namely the organic phase concentration of the mobile phase at which the retention time is exactly double the dead time (not like log k′ values extrapolated to water as mobile phase), and it is independent of the linear or quadratic function of the log k′ versus ϕ 0 relationships. The ϕ 0 values not only reflect the hydrophobic character of compounds but also provide a valuable means for method development in RP-HPLC as they reveal a mobile phase composition with known retention time values. The ϕ 0 values for over 500 compounds were calculated and are presented on the basis of their published retention data. The ϕ 0 values obtained with methanol and acetonitrile showed an excellent correlation with each other. Significant correlations were found between the ϕ 0 values and the logarithm of 1-octanol—water partition coefficients (log P).

Mechanism of Transcorneal Permeation of Pilocarpine

The mechanism of transcorneal permeation of pilocarpine has been investigated in relation to the physicochemical properties of the permeating species and its interaction with the membrane biophase. In vitro corneal transport experiments suggested the transport of unionized as well as ionized pilocarpine species across the corneal membrane. However, the permeability of the ionized pilocarpine species was 4.818 × 10−6 cm s−1, a value only one-half of that obtained for the un-ionized pilocarpine species (9.744 × 10−6 cm s−1). Further evidence of ion transport across the cornea was obtained by examining the transport of the quaternized pilocarpine compound (i.e., pilocarpinium methyl iodide). The quaternized compound had a corneal permeability of 4.66 × 10−6 cm s−1, similar to that obtained for the ionized pilocarpine species. The lipoidal epithelial layer of the corneal membrane appears to be the predominant barrier to the transport of polar species. Therefore, the transport of pilocarpinium cations across the lipoidal epithelium might have occurred as tightly bound ion pairs with dihydrogen phosphate and/or nitrate counter ions. Excellent linear correlation has been obtained between pilocarpine corneal permeability and the 1-octanol–water partition coefficient as a function of the state of ionization of pilocarpine. The ratio of un–ionized to ionized drug permeability across the cornea is expected to be much higher for drugs with higher 1-octanol–water partition coefficients.

Quantitative Analysis of Partition Behavior of Substituted Phenols from Aqueous Phase into Liposomes Made of Lecithin and Various Lipids

Abstract The partition coefficient of a series of substituted phenols in lecithin-liposome–water systems, P(L/W), was quantitatively analyzed by use of physicochemical molecular and substituent parameters. The effects on the P(L/W) value of the incorporation of cholesterol and charged lipids such as cardiolipin or stearylamine into the liposomal membranes were examined with the perturbation of the bilayered membrane structure induced by these lipids being taken into account. The partition behavior of phenols was primarily decided by the hydrophobicity, represented in terms of the 1-octanol–water partition coefficient, P(O/W). The partitioned phenols seemed to be in membrane close to the interface. The steric and electronic effects of substituents on the partitioning into liposomes varied significantly depending upon the type of lipids incorporated. The variations in these effects reflect differences in the structure of the interfacial region of the lecithin bilayer modified by the incorporation of various lipids.

Selection of gas chromatographic stationary phase pairs for characterization of the 1-octanol—water partition coefficient

Stationary phase pairs are recommended for the gas chromatographic estimation of log K values for the partition of organic compounds in 1-octanol—water. These pairs model the solute—solvent interactions in 1-octanol and water. The applicability of EPON 1001 as a polar and OV-1 as a non-polar phase was tested experimentally by measuring the retention indices of eight compounds with known log K values. The standard error in the log K determination was less than ± 0.16. The suggested method seems to be appropriate for the estimation of log K values without resorting to a large reference series.

Effects of different buffer species on partition coefficients of drugs used in quantitative structure–activity relationships

A study was conducted in which the same organic solvent, 1-octanol, and different buffer systems were used to obtain intercorrelations among log Pcorr values given by log P (octanol–water) = a log P (octanol–buffer) + b, where a and b are different constants for the different systems used. The range of a was 0.418–1.156 and that of b was -1.962–1.176 for the four buffer systems examined. Only with neutral drugs was the slope (a) close to 1.0 and the intercept (b) close to 0.0 for the three buffer systems studied. For acidic drugs, only 1-octanol–phosphate buffer gave a 1:1 correlation with 1-octanol–water partition coefficients. Acetate and bicarbonate buffer systems gave different correlations. For basic drugs, none of the three systems examined gave a 1:1 correlation with 1-octanol–water partition coefficients.