Numerical simulation of two-phase partition chromatography in microchannels for moderated log P measurements.

A finite element simulation has been used in order to study the partition chromatography process of one species between an aqueous mobile phase and an organic stationary phase located at the bottom of a rectangular microchannel. The transient model incorporates convection--diffusion of the species in the water phase coupled to the diffusion in the stationary organic phase by the way of the partition kinetics at the interface. The time evolution of the injected species concentration is analyzed versus the velocity of the mobile phase, the detecting position and the thickness of the stationary phase. The comparison of simulation results with both experimental data and analytical model confirm its validity. These simulations show that thin channels can be used to measure log P of molecules from their retention time. Finally, we have shown how the sample velocity can be optimized for a given geometry of the channel and diffusion coefficient of the species.

Liposome/water lipophilicity: methods, information content, and pharmaceutical applications.

This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.

Partition coefficients of ionizable compounds in o-nitrophenyl octyl ether/water measured by the potentiometric method.

The objective of this study was to investigate the reliability of potentiometric measurements of partition coefficients (log P) in the o-NPOE/water system, o-nitrophenyl octyl ether being an organic solvent widely used for the voltammetric determination of the partition coefficient of ions. Three sets of ionizable model compounds were explored in this study. The results showed that the potentiometric technique gave precise and reliable log P(npoe) values in the explored range of 0.1-4.3.

Water-oil partition profiling of ionized drug molecules using cyclic voltammetry and a 96-well microfilter plate system.

PURPOSE: A new experimental set-up for studying partitioning of ionizable drugs at the interface between two immiscible electrolyte solutions (ITIES) by amperometry is presented. The method is quite general, as it can be applied to any charged drug molecule. METHODS: The procedure is based on 96-well microfilter plates with microporous filters to support 96 organic liquid membranes. The new methodology is first validated using a series of tetra-alkylammonium ions and subsequently used to construct the ion partition diagrams of 3,5-N,N-tetramethylaniline and 2,4-dinitrophenol. The lipophilicity of these drugs was examined by potentiometry and cyclic voltammetry in the NPOE/water system. RESULTS: Cyclic voltammetry resulted in potential-pH profiles of the studied drugs. When the aqueous phase pKa is already known, the logP(NPOE) of lipophilic drugs could be determined using a very little amount of solvents and drugs. The values of the partition coefficients for the neutral forms agree well with those obtained by potentiometry. CONCLUSIONS: The procedure based on commercially available 96-well microfilter plates is shown to be useful for determining logP of ionized drugs in a rapid and efficient way.

Theoretical and experimental exploration of the lipophilicity of zwitterionic drugs in the 1,2-dichloroethane/water system.

PURPOSE: This work examines the lipophilic behavior of various zwitterions and shows how distribution profiles in biphasic systems and ionic partition diagrams may improve our understanding of pH-absorption profiles of drugs. METHODS: The lipophilicity of various zwitterionic drugs was examined by potentiometry and cyclic voltammetry in the 1,2-dichloroethane/water system to study the intramolecular interactions and conformational effects affecting absorption and activity of zwitterions, as well as to draw their theoretical and experimental ionic partition diagrams. RESULTS: Different theoretical partition diagrams are reported according to the tautomeric constant of the zwitterion. Shifts of apparent PKa are obtained in the ionic partition diagrams of raclopride and eticlopride and compared to the deviations from pH-absorption profile described in the literature for lipophilic drugs. The physicochemical origin of these shifts is discussed. CONCLUSIONS: The comparison between pH-absorption profiles and ionic partition diagrams of zwitterions is shown here to be of value for a better mechanistic understanding of absorption processes, thus opening new perspectives in studying pH-absorption profiles of ionizable drugs.

Lipophilicity and solvation of anionic drugs.

This paper first gives a brief review of the main techniques used to measure the lipophilicity of neutral and ionic drugs, namely the shake-flask method, potentiometry, and cyclic voltammetry at liquid-liquid interfaces. The lipophilicity of 28 acidic compounds with various functional groups was studied by potentiometry and cyclic voltammetry in the n-octanol/water and 1,2-dichloroethane/water systems in order to complement our understanding of the lipophilicity of neutral and ionized acids and to clarify the solvation mechanisms responsible for their partition. The parameter diff (log P(N-A)(dce)) (i.e., log P of the neutral acid minus standard log P of the conjugated anion in 1,2-dichloroethane/water) was shown to depend not only on intramolecular interactions and conformational effects in the neutral and anionic forms, but also on the delocalization of the negative charge in the anion, confirming the ability of Born's solvation model to describe qualitatively the effect of the molecular radius on the lipophilicity of ions.

Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling.

A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [(35)S]-GTP gamma S binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.