Hydrophobicity Parameters Determined by Reversed-Phase Liquid Chromatography. IX. Relationship between Capacity Factor and Water-Octanol Partition Coefficient of Monosubstituted Pyrimidines.

Yamagami, Chisako; Yokota, Miho; Takao, Narao

doi:10.1248/cpb.42.907

Cited by 29 publications

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“…4. This indicates that the rapid and reliable determination of log P oct values not only for neutral and acidic compounds, but also for basic analytes with high pK a values (compounds 6-12, 46, 47, 49, 51, 52) is possible by RP-HPLC with XBridge TM Shield RP 18 column, which is highly stable over a wide pH range (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Until recently, reliable determination of log P oct by RP-HPLC was achieved only for neutral and acidic drugs on silica-based stationary phases with silanol deactivation, such as LC-ABZ 15) and Discovery RP Amide C16 phases (our previous studies).…”

Section: ϭ097)mentioning

confidence: 99%

“…Some workers have used isocratic log k values, measured in an appropriate mobile phase, as a lipophilicity parameter. [8][9][10] However, the majority of investigators use the capacity factors extrapolated to the 100% water (log k w ) condition in order to eliminate the effects of organic solvent. [11][12][13][14][15] Indeed, the log k W has been proved to be useful for the investigation of a series of solutes covering broad lipophilicity range.…”

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Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

et al. 2008

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The lipophilicity of solutes, conventionally expressed by their partition coefficient in the 1-octanol/water system (log P oct ), is of high significance from both physicochemical and pharmacological viewpoints.1,2) A number of intermolecular forces between a solute and its environment (i.e., solvents) determine the partitioning process and its equilibration. In pharmacology, the forces are particularly important because they control the migration of solutes (drugs) to biomembranes. Not a few studies have been reported on the relationship between log P oct and adsorption/permeation of drugs in cell cultures and/or tissue preparations. 3-7)The reference procedure to measure log P oct is shake-flask method. The method is, however, time-consuming and narrow in applicable range (ca. Ϫ3Ͻlog PϽ4). The reversedphase HPLC (RP-HPLC) came to be a promising alternative to the shake-flask method, because it has advantages such as high throughput rate (which is of key importance to pharmaceutical industry with a vast number of potential drug candidates), insensitivity to impurities and/or degradation products, broad applicable range, low sample consumption, good accuracy and automation possibilities. In RP-HPLC, lipophilicity indices are derived from the capacity factor log k, which is calculated from Eq. 1,where t r and t 0 are the retention times of the solute and of an unretained compound, respectively. Some workers have used isocratic log k values, measured in an appropriate mobile phase, as a lipophilicity parameter. 8-10) However, the majority of investigators use the capacity factors extrapolated to the 100% water (log k w ) condition in order to eliminate the effects of organic solvent.11-15) Indeed, the log k W has been proved to be useful for the investigation of a series of solutes covering broad lipophilicity range. Generally, the extrapolation is based on a quadratic relationship between the isocratic capacity factor log k and the volume fraction of organic solvent in the mobile phase, j.16) When methanol is used as an organic modifier, a linear relationship (Eq. 2) is often obtained for neutral solutes, 17,18) log kϭϪSjϩlog k wwhere S and log k w are the slope and the intercept of the regression curve, respectively. Until recently, most lipophilicity studies based on RP-HPLC had employed octadecyl silica (ODS) stationary phases 19,20) and silanol deactivated stationary phases. 15,21,22) As for ODS stationary phases, the correlations between log P oct and log k w (or log k) are generally good for structurally related solutes. 19,20) The decrease in correlation between them with increasing structural diversity of solutes is attributed to the specific interactions between the compounds and the residual silanol groups in such stationary phases. 23)Some studies have been done on silanol deactivated stationary phases, Supelcosil LC-ABZ and Discovery RP Amide C18, where their alkyl chains contain amide groups that electrostatically shield silanols from highly polar analytes. High correlations were found between log P ...

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Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

et al. 2008

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“…[10][11][12][13][14][15] One explanation for these phenomena could be that residual silanols which act as H-donors would interact with H-accepting solutes via H-bondings. To explore this possibility, we attempted to examine the influence of residual silanols by comparing log k values for the same compounds measured on the C18-UG column with the previous data obtained on the SG-column.…”

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“…3,5,8) In our experience, this log k W approach works well for non-polar solutes but tends to provide overestimated log P oct values for strong H-acceptors. [10][11][12][13][14][15] From systematic studies of log k obtained under various HPLC conditions for typical heteroaromatic compounds such as (di)azines, furans and thiophenes, we were led to the conclusion that the use of an eluent containing around 50% methanol, which usually provides a more direct correlation with log P oct , is the most convenient and practical procedure for rapid estimation of log P oct provided H-donors (amphiprotic compounds) are treated separately.11-15) Our results so far obtained are illustrated graphically in Fig. 1.…”

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Hydrophobicity Parameters Determined by Reversed-Phase Liquid Chromatography. XV: Optimal Conditions for Prediction of log Poct by Using RP-HPLC Procedures.

Yamagami

Kawase

Iwaki

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recently, in connection with the remarkable development of computational technologies for rational drug designs, the necessity has become apparent of rapid measurement or estimation of molecular properties of chemicals having a potential for medical use. In particular, hydrophobicity (as expressed by the logarithm of 1-octanol/water partition coefficient, log P oct ) is identified as one of the most important properties that govern potencies; its prediction has attracted much attention from medicinal chemists, agrochemists and many investigators in various fields such as pharmacology, toxicology, environmental chemistry and food chemistry. 1,2)Instead of measuring log P oct by the standard but time-consuming shake-flask method, reversed-phase chromatography (RP-HPLC) has increasingly been used as a powerful tool to predict log P oct from the readily accessible retention factor, log k, (given by kϭ(t R Ϫt 0 )/t 0 where t 0 and t R express elution times of the non-retained substance and sample, respectively).Extensive studies have been made to establish an optimal RP-HPLC system providing a good linearity between log P oct and log k.3-10) Many workers have used an ODS-type column with methanol-water mobile phases to obtain a normalized parameter, log k W (k W : the retention factor extrapolated to 0% organic modifier), as an alternative to log P oct . 3,5,8) In our experience, this log k W approach works well for non-polar solutes but tends to provide overestimated log P oct values for strong H-acceptors. [10][11][12][13][14][15] From systematic studies of log k obtained under various HPLC conditions for typical heteroaromatic compounds such as (di)azines, furans and thiophenes, we were led to the conclusion that the use of an eluent containing around 50% methanol, which usually provides a more direct correlation with log P oct , is the most convenient and practical procedure for rapid estimation of log P oct provided H-donors (amphiprotic compounds) are treated separately.11-15) Our results so far obtained are illustrated graphically in Fig. 1. This conclusion has been derived from the following results.First, we have shown that, for each series of monosubstituted (di)azines, log P oct can be excellently correlated with log k in different compositions of methanol-water eluents by a general formula Eq. 1 containing two terms correcting for H-bonding effects: 16) log kϭalog P oct ϩrs I ϩsS HA ϩconst.( 1) where the s I parameter represents the Charton's inductive electronic substituent constant, 17) and S HA designates the substituent H-acceptor scale that we have recently defined where the value of S HA is set at unity for H (the unsubstituted * To whom correspondence should be addressed. The use of log k derived from reversed phase (RP)-HPLC retention times provides a convenient method for estimating log P oct values (P oct : 1-octanol/water partition coefficient). In order to establish optimal HPLC conditions, the difference between chromatographic (C18 modified column and aqueous methanol eluents) and bulk solve...

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“…Mono-and di-substituted diazines were selected as the compounds to be analyzed because their K D values in various solvents systems have been extensively explored in the studies of quantitative structure-activity relationships. [6][7][8][9][10][11] …”

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Application of a Stepwise Flow Ratiometry without Phase Separation to the Determination of the Chloroform/Water Distribution Coefficients of Volatile Diazines

Tanaka

Liu

Kawabata

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Hydrophobicity Parameters Determined by Reversed-Phase Liquid Chromatography. IX. Relationship between Capacity Factor and Water-Octanol Partition Coefficient of Monosubstituted Pyrimidines.

Cited by 29 publications

References 0 publications

Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

Hydrophobicity Parameters Determined by Reversed-Phase Liquid Chromatography. XV: Optimal Conditions for Prediction of log Poct by Using RP-HPLC Procedures.

Application of a Stepwise Flow Ratiometry without Phase Separation to the Determination of the Chloroform/Water Distribution Coefficients of Volatile Diazines

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