Modeling the octanol-water partition coefficients by an optimized molecular connectivity index

A procedure that makes it possible to generate a coherent model for prediction of the octanol-water partition coefficient within the molecular connectivity formalism was put forward. The method is based on the optimization of weights for corresponding skeletal atoms and is similar to the method for calculation of a variable connectivity index proposed by Randi?. In contrast to Randi?'s method, we incorporate in the algorithm the possibility that the contribution of a term describing a carbon-heteroatom bond may be negative. When tested on a set of about 300 structurally diverse organic molecules, our procedure proved to be superior to the standard valence connectivity method. External validation on a smaller set of compounds confirmed the superiority of our procedure with respect to the standard one. Intramolecular interactions, which are operative in more complex compounds, are treated in a similar fashion to that in the Hansch-Leo or Rekker methods, by inclusion of empirical correction factors.     

Screening of octanol-water partition coefficients for pharmaceuticals by pressure-assisted microemulsion electrokinetic chromatography

A rapid screening assay for the determination of octanol-water partition coefficients (log P(OW)) of pharmaceuticals was developed by using pressure-assisted microemulsion electrokinetic chromatography (MEEKC). The microemulsion system contains 50 mM sodium dodecyl sulfate, 0.87 M l-butanol, 82 mM heptane, and 50 mM borate-phosphate (2:3) at pH 10. Ten standard compounds with known log P(OW) values from -0.26 to 4.88 were used for constructing the calibration curve of log P(OW) against the MEEKC retention factor, log k. The log P(OW) values of the compounds were calculated based on the log k values measured by MEEKC and the slope and intercept of the calibration curve. For 13 literature and 32 Roche compounds, about 90% of the log P(OW) values measured by MEEKC are within 0.5 log units of the values from the literature and potentiometric titration. The throughput is about 2 samples/h using +20 kV voltage plus 5 mbar air pressure for separation. This MEEKC method is applicable for log P(OW) screening of weakly basic, weakly acidic, and neutral pharmaceuticals with log P(OW) = 0-5 and pKa < or = 10.     

Improvement of microemulsion electrokinetic chromatography for measuring octanol-water partition coefficients

Microemulsion electrokinetic chromatography (MEEKC) has been used to indirectly measure octanol-water partition coefficients (log P(ow)) of compounds. In order to obtain an accurate log P(ow) value, the electrophoretic mobilities of the microemulsion phase (mu(me)) and the analyte (mu(eff)) in MEEKC must be accurately required. However, in conventional MEEKC, the shortage of obtaining mu(me) with a tracing method was discovered, and the influences of concentration, injection volume of analyte, and high electric field on measuring mu(eff) were also found. In this paper, a novel method called improved MEEKC (I-MEEKC) was developed to avoid the problems mentioned above. In I-MEEKC, a nonlinearity fitting program was used to obtain mu(me) to avoid the error from tracing mu(me); the extrapolating method was used to eliminate the effects of concentrations and injection volumes of analytes on mu(eff) measurement, and an enough stable microemulsion was selected to eliminate the effect of high electric field on mu(eff )measurement. Then the novel method was applied to estimate log P(ow) of uncharged compounds and charged pharmaceuticals compared to the conventional MEEKC. The log P(ow) of all analytes obtained by I-MEEKC agreed with those obtained by classical shake flask or literature values, the errors between them were within 0.1 logarithm units, better than the ones by conventional MEEKC.     

Study on octanol-water partition coefficients of benzene halides by molecular vertex distance index

A new method of molecular structural characterization (MSC) called the molecular vertex distance index (MVDI) is constructed and used to describe the structures of benzene halides. Two quantitative structureproperty relationship (QSPR) models of octanol-water partition coefficients (lgKow) are obtained through multiple linear regression (MLR) and partial least squares regression (PLSR). The estimation stability and generalization ability of the models are analyzed by both internal and external validations. The results show that the models constructed in this work can provide satisfactory estimation stability and favorable predictive ability.     

Rapid estimation of octanol-water partition coefficients using synthesized vesicles in electrokinetic chromatography

Vesicle electrokinetic chromatography (VEKC) using vesicles synthesized from the oppositely charged surfactants cetyltrimethylammonium bromide (CTAB) and sodium octyl sulfate (SOS) and from the double-chained anionic surfactant bis(2-ethylhexyl)sodium sulfosuccinate (AOT) was applied to the indirect measurement of octanol-water partition coefficients (log Po/w). A variety of small organic molecules with varying functional groups, pesticides, and organic acids were evaluated by correlating log Po/w and the logarithm of the retention factor (log k') and comparing the calibrations. A linear solvation energy relationship (LSER) analysis was conducted to describe the retention behavior of the vesicle systems and compared to that of octanol-water partitioning. The solute hydrogen bond donating behavior is slightly different with the vesicle interactions using CTAB-SOS vesicles as compared to the octanol-water partitioning model. The AOT vesicle and octanol-water partitioning systems showed similar partitioning characteristics. VEKC provides rapid separations for determinations of log Po/w in the range of 0.5 to 5 using CTAB-SOS vesicles and 0 to 5.5 using AOT vesicles.     

Determination of octanol-water partition coefficients for carbonate esters and other small organic molecules by microemulsion electrokinetic chromatography

Microemulsion electrokinetic chromatography (MEEKC) was assessed as a tool for determination of octanol-water partition coefficients using 34 solutes encompassing 8 carbonate esters. It was confirmed that microemulsions containing 1.44-2.88% w/w SDS, 6.49% w/w 1-butanol, and 0.82% w/w n-heptane constitute a good model of octanol-water partitioning in the pH range of 1.4-7.4. Use of the migration index concept led to improved repeatability of the MEEKC method compared to the use of retention factors. Using a dynamical coating, a high electroosmotic flow at pH 1.4 and 4.75 was achieved expanding the practical pH working range of the MEEKC system. The correlation obtained between the migration index and log P was unaffected by pH indicating that the properties of the microemulsion droplets and, thus, partitioning are independent of pH. No evidence for congeneric behavior was found for the sample set comprising solutes with different hydrogen bonding properties suggesting that simple reference compounds can be used as calibrators. Lipophilicity estimates for the series of carbonate esters were obtained. The increase in lipophilicity with chain length was smaller than expected from the Hansch substituent constant, pi.     

Aqueous solubilities and octanol-water partition coefficients of binary liquid mixtures of organic compounds at 25°C

From thermodynamics and certain assumptions it is shown that, under the usual experimental conditions, the octanol-water partition coefficient (K_o/w) of a given organic liquid should be the same whether the substance is partitioned neat or as part of a mixture. Measurements of several mixtures of n-propylbenzene (log K_o/w=3.71±0.04)+ethylbenzene (log K_o/w=3.16±0.01) clearly confirm this. It is also shown that the aqueous solubility (S_w) of a neat organic liquid can be related to its aqueous solubility (S _w ), when it is present at volume fraction in an organic liquid mixture, by S _w =S_w, where is its activity coefficient in the organic mixture. The measured S _w values for n-propylbenzene + ethylbenzene (1), n-hexane + nitrobenzene (>1) and di-isopropyl ether + chloroform (<1) are found to be in good agreement with the predicted values (average differences of, respectively, <2%, 8% and 6%). In general, the bounds on S _w are expected to be 0w w.     

Analysis of anticancer platinum(II)-complexes by microemulsion electrokinetic chromatography: separation of diastereomers and estimation of octanol-water partition coefficients

Microemulsion electrokinetic chromatography (MEEKC) was applied for the separation and lipophilicity estimation of oxaliplatin and eight novel anticancer oxaliplatin derivatives. Solubility and permeability have to be balanced in modern drug development, and the octanol-water partition coefficient (log P) still represents one of the most useful quantifiable parameters providing a reasonable estimation of a drug's lipophilicity. Therefore, the capacity factors from MEEKC were correlated to log P values derived by the traditional shake flask method. The MEEKC method was accomplished using a microemulsion of heptane/sodium dodecyl sulfate (SDS)/butanol in phosphate buffer at pH 7.4 and 37 degrees C with all analytes being in a neutral state during the run. This experimental setup allowed a baseline separation of all platinum complexes within 11 min. Remarkably, beside the very good resolution and precision of the measurements, separation of diastereomers of the complexes and quantification of the diastereomeric ratios could be achieved. Correlating the capacity factors with the corresponding log P values resulted in a linear dependency with a correlation factor of r = 0.9935. Consequently, the applied MEEKC method was found to be a highly valuable technique not only for the separation of platinum complexes but as well for the estimation of the octanol-water partition coefficient with many advantages in comparison to other methods.     

Potentiometric determination of octanol-water and liposome-water partition coefficients (log P) of ionizable organic compounds

The logarithm of the octanol-water partition coefficient, log P, is a key physicochemical property for both pharmaceutical drugs and agrochemicals. It is also required by legislation as part of the physicochemical properties profile for high volume production chemicals. This Letter describes a simple method for determining log P values (over a wide range from −0.8 to 5.3) for 12 organic weak acids and bases using potentiometric titrations, with octanol or phosphatidyl choline liposomes as the partitioning medium. Such titrations take comparatively little time (about 30-45 min per titration), are easy to implement, and can be carried out with an inexpensive laboratory titrator.     

Evaluation of a reversed-phase column (supelcosil LC-ABZ) under isocratic and gradient elution conditions for estimating octanol-water partition coefficients

The solvation parameter model is used to identify suitable chromatographic models for estimating the octanol-water partition coefficient for neutral compounds of varied structure by reversed-phase liquid chromatography. The stationary phase Supelcosil LC-ABZ with methanol-water mobile phases affords a series of suitable correlation models for estimating the octanol-water partition coefficient (log KOW) under isocratic and gradient elution conditions. Isocratic separations with mobile phase compositions containing from about 25 to 40% (v/v) methanol provide the most accurate results for log KOW values in the range -0.1 to 4.0. Gradient separations programmed from 5 to 100% (v/v) methanol are suitable for faster separations of compounds with large log KOW values. The standard error in the estimate for the regression models of the predicted log KOW values against literature values are 0.135 log units for the 30% (v/v) methanol-water isocratic system and 0.263 log units for the methanol-water gradient system. Isocratic retention factors predicted from two gradient separations with gradient times of 15 and 45 min afford a poorer fit for the correlation models between log KOW and the estimated retention factors than that of either the above isocratic and gradient models. Plots of the retention factor (log k) as a function of mobile phase composition are generally non-linear. Values of log kw obtained by non-linear extrapolation to a volume fraction of 0% (v/v) methanol do not afford a useful model for estimating log KOW.     

Increasing fluorous partition coefficients by solvent tuning

Low partition coefficients of fluorous components have been a persistent problem in liquid-liquid separations using perfluoroalkanes as the fluorous phase. Solvent tuning of both the nonfluorous and the fluorous phase dramatically enhances the partitioning of light or polar fluorous molecules into the fluorous liquid phase, while minimally effecting partition coefficients of nonfluorous molecules. These findings suggest an expanded scope for liquid-based separations in fluorous biphasic catalysis, fluorous-tagged reagents, fluorous-supported oligomer synthesis, and related areas. [reaction: see text]     

Determination of gas-liquid partition coefficients by gas chromatography

This review covers theoretical principles and experimental procedures for the determination of gas-liquid partition coefficients, KL, by gas chromatography. In order to precisely define the relationship between KL, retention time and experimental parameters, the retention theory, both for ideal and for imperfect gas phase, is expounded. The most important sources of systematic error, as peak asymmetry, mixed retention mechanisms, column hold-up time and stationary phase mass determination, are discussed. Although the review is focussed on packed columns, comparison to capillary columns is discussed in those aspects in which these last show advantages.     

Determination of liquid-liquid partition coefficients by separation methods

By essence, all kinds of chromatographic methods use the partitioning of solutes between a stationary and a mobile phase to separate them. Not surprisingly, separation methods are useful to determine accurately the liquid-liquid distribution constants, commonly called partition coefficient. After briefly recalling the thermodynamics of the partitioning of solutes between two liquid phases, the review lists the different methods of measurement in which chromatography is involved. The shake-flask method is described. The ease of the HPLC method is pointed out with its drawback: the correlation is very sensitive to congeneric effect. Microemulsion electrokinetic capillary electrophoresis has become a fast and reliable method commonly used in industry. Counter-current chromatography (CCC) is a liquid chromatography method that uses a liquid stationary phase. Since the CCC solute retention volumes are only depending on their partition coefficients, it is the method of choice for partition coefficient determination with any liquid system. It is shown that Ko/w, the octanol-water partition coefficients, are obtained by CCC within the -1 < log Ko/w < 4 range, without any correlation or standardization using octanol as the stationary phase. Examples of applications of the knowledge of liquid-liquid partition coefficient in the vast world of solvent extraction and hydrophobicity estimation are presented.     

High-performance liquid chromatography of substituted p-benzoquinones and p-hydroquinones. II. Retention behavior, quantitative structure-retention relationships and octanol-water partition coefficients

The retention behavior of methoxy-substituted p-benzoquinones and the corresponding hydroquinones in reversed-phase chromatography was examined on octylsilica and two octadecylsilica stationary phases and with five hydroorganic mobile phases containing acetonitrile, methanol or tetrahydrofuran and additionally in most cases (NH3OH)3PO4 used as a reducing and buffering agent. The retention order of benzoquinones and hydroquinones was the same on each stationary phase with either methanol or acetonitrile as the organic modifier. On the other hand, minor differences in the retention order were observed with the various stationary phases. In all cases, satisfactory quantitative structure-retention relationships (QSRRs) were found and the data suggest that the differences in the retention behaviour of octadecylsilicas used in this study are silanophilic interactions which, together with solvophobic interaction contribute to the retention of these eluites. Further analysis showed that QSRRs of sterically crowded molecules must take into account reduced surface area available for binding. The retention data obtained with use of aqueous tetrahydrofuran as mobile phase failed to give rise to satisfactory QSRRs. This was attributed to selective solvation of eluite by tetrahydrofuran and/or nearly equipotent binding of eluite and tetrahydrofuran to stationary phase.     

Calculation of single-ion partition coefficients

Single-ion partition coefficients have been calculated for NBu ₄ ⁺ and I⁻ in the system water—chloroform. The standard free energy of transfer of each ion was separated into an electrostatic and a neutral term. The electrostatic term was calculated with the aid of the Born equation. In the case of I⁻ the neutral term was calculated with the aid of the xenongas assumption, whereas in the case of NBu ₄ ⁺ the tetrabutylmethane assumption was used. The results of the calculation were compared with the experimentally found partition coefficient of the completely dissociated ion-pair NBu₄I.     

Determination of octanol-water partition coefficient for terpenoids using reversed-phase high-performance liquid chromatography

Octanol-water partition coefficients (Kow) for 57 terpenoids were measured using a RP-HPLC method. Sample detection was achieved with standard UV and refractive index detectors and required no special column treatment. Measured log Kow values for the terpenoids ranged from 1.81 to 4.48 with a standard error of between 0.03 and 0.08 over the entire range. Partition coefficients determined by the RP-HPLC method were compared against shake flask, atom/fragment contribution, fragment and atomistic methods. The HPLC values were found to give the best correlation with shake flask results. Log Kow values calculated by the atom/fragment contribution method gave the best correlation with the HPLC values when compared to fragment and atomistic methods.     

A structural analogue approach to the prediction of the octanol-water partition coefficient

A new strategy for the calculation of n-octanol/water partition coefficients is presented. Log P calculations of unknown chemicals are based on their closest structural analogues from a database of molecules with known experimental log P values. The contribution of the differing molecular parts is then estimated from a compilation of fragment contributions. Such a strategy is found to be superior to conventional group contribution methods and promises an overall enhancement of the prediction's accuracy.