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

Abstract

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 ...

Simultaneous determination of hydrophobicity and dissociation constant for a large set of compounds by gradient reverse phase high performance liquid chromatography–mass spectrometry technique

“…Nevertheless, in this work (performed on XBridge column) we found that either the number of H-donor and acceptor bonds does not improve the calibration and simple linear relationship is sufficient. Similar results were obtained by Liu et al [33], where it is shown that the retention on Xbridge column and partitioning in 1-octanol/water are controlled by the same balance of structural properties, namely van der Waals volume, H-bond acceptor basicity and dipolarity/polarizability. Thus, there seems to be a linear relationship between log k w and log P values on XBridge, making this column particularly suitable for the determination of lipophilicity by means of HPLC.…”

Structure−Activity Relationships in Human Toll-Like Receptor 7-Active Imidazoquinoline Analogues

“…A comparison of observed retention times on C 18 -reverse-phase mass-chromatograms (a measure of hydrophobicity)51;52 with the potencies of the active compounds indicate a distinct deviation from the trend of 54 , suggesting specific and idiosyncratic effects, rather than bulk-effects (Fig. 5).…”

Characterization of AQX‐1125, a small‐molecule SHIP1 activator

“…AQX‐MN115 was used as a control (Yang et al ., ; Andersen et al ., ). Lipophilicity measurements of the compounds were conducted as described (Liu et al ., ).…”