M.J. Medina-Hernández

Biopartitioning micellar chromatography : an in vitro technique for predicting human drug absorption

The main oral drug absorption barriers are fluid cell membranes and generally drugs are absorbed by a passive diffusion mechanism. Biopartitioning micellar chromatography (BMC) is a mode of micellar liquid chromatography that uses micellar mobile phases of Brij35 under adequate experimental conditions and can be useful to mimic the drug partitioning process in biological systems. In this paper the usefulness of BMC for predicting oral drug absorption in humans is demonstrated. A hyperbolic model has been obtained using the retention data of a heterogeneous set of 74 compounds, which shows predictive ability for drugs absorbed by passive diffusion. The model obtained in BMC is compared with those obtained using the well-known systems (Caco-2 and TC-7) that use intestinal epithelium cell lines. The use of BMC is simple, reproducible and can provide key information about the transport properties of new compounds during the drug discovery process.

Biopartitioning micellar separation methods: modelling drug absorption.

The search for new pharmacologically active compounds in drug discovery programmes often neglects biopharmaceutical properties as drug absorption. As a result, poor biopharmaceutical characteristics constitute a major reason for the low success rate for candidates in clinical development. Since the cost of drug development is many times larger than the cost of drug discovery, predictive methodologies aiding the selection of bioavailable drug candidates are of profound significance. This paper has been focussed on recent developments and applications of chromatographic systems, particularly those systems based on amphiphilic structures, in the frame of alternative approaches for estimating the transport properties of new drugs. The aim of this review is to take a critical look at the separations methods proposed for describing and predicting drug passive permeability across gastrointestinal tract and the skin.

Cyclodextrins in capillary electrophoresis: Recent developments and new trends

Despite the fact that extensive research in the field of separations by capillary electrophoresis (CE) has been carried out and many reviews have been published in the last years, a specific review on the use and future potential of cyclodextrins (CDs) in CE is not available. This review focuses the attention in the CD-CE topic over the January 2013-February 2014 period (not covered by previous more general CE-reviews). Recent contributions (reviews and research articles) including practical uses (e.g. solute-CD binding constant estimation and further potentials; 19% of publications), developments and applications (mainly chiral and achiral analysis; 38 and 24% of publications, respectively) are summarized in nine comprehensive tables and are commented. Statistics and predictions related to the CD-CE publications are highlighted in order to infer the current and expected research interests. Finally, trends and initiatives on CD-CE attending to real needs or practical criteria are outlined.

Modelling of the retention behaviour of solutes in micellar liquid chromatography with organic modifiers

Abstract Most of the reported procedures for the determination of compounds by micellar liquid chromatography make use of micellar mobile phases containing an alcohol. The retention of a solute in a purely micellar eluent has been adequately described by the linear equation 1/ k′ vs . micelle concentration. This equation seems also to be valid for mobile phases with the same alcohol concentration and varying micelle concentrations. A model to describe the retention behaviour of solutes in any mobile phase of surfactant and alcohol is proposed, which makes use of the elution data in five mobile phases of surfactant with different amounts of alcohol. A function of the type 1/ k′ = A μ + B ϕ + C μϕ + D , where μ and ϕ are surfactant and alcohol concentration, respectively, proved to be satisfactory for different solutes (catecholamines, amino acids, phenols and other aromatic compounds).

Quantitative retention–structure and retention–activity relationships of barbiturates by micellar liquid chromatography

Abstract Studies on the structural requirements of chromatographic surfaces to emulate in vitro the partitioning process in biomembranes are of great interest. The use of micellar mobile phases in RPLC modifies the hydrophobicity of the stationary phase and provides hydrophobic and electrostatic sites of interaction as a consequence of the adsorption of surfactant monomers to the chromatographic surface. Modified stationary phases in MLC could be structurally similar to biomembranes, but thorough studies are necessary to confirm this. In this paper we focus our attention on barbiturates. The influence of the nature and concentration of the surfactant (Brij 35, SDS and CTAB) and the mobile phase pH on the retention of 13 barbiturates in modified C18 stationary phases is studied. Quantitative structure–retention and structure–activity relationships for the barbiturates with different surfactants are proposed and compared with those obtained using hydro–organic mobile phases.

Micellar liquid chromatography for prediction of drug transport

The vast majority of well absorbed drugs are transported passively across the cell membranes. Physicochemical descriptors of drug molecules that are believed to influence transcellular transport are routinely used to predict drug absorption by means of complex mathematical models. In this paper, a new in vitro method, based on the retention data in micellar liquid chromatography (MLC), is validated for the prediction of passive drug absorption. The retention of a heterogeneous drugs set in MLC using Brij 35 as surfactant in the mobile phase is compared with the retention data reported in literature obtained in red cell membrane lipid liposomes, human red cell membranes vesicles (vesicles), native membranes of adsorbed red cells (ghosts) and egg phospholipids liposomes [Beigi et al., Int. J. Pharm., 164 (1998) 129-137]. Finally, the correlation between the logarithm of retention factors in MLC and reported oral drug absorption values for barbiturates and beta-blockers is studied. Predictive regression models for estimating oral drug absorption using the logarithm of the retention values as independent variable are proposed.

Quantitative retention—structure and retention—activity relationship studies of ionic and non-ionic catecholamines by micellar liquid chromatography

SummaryWhen ionic surfactants are used as mobile phases in micellar liquid chromatography, MLC, the retention of compounds is governed by hydrophobic and electrostatic forces. In the absence of electrostatic effects, the hydrophobicity of a compound is the predominant factor affecting its retention and its interaction with micelles. Because both interactions should be considered for ionic compounds, a novel retention model is proposed which includes the hydrophobicity of a compound and the molar fraction of its charged form. High correlations between the logarithm of the capacity factors and structural parameters were obtained for ionic compounds with different degrees of ionization. The effect of the nature and composition of the mobile phase (pH, concentration of surfactant and modifier) was studied. The modelling of the retention of compounds as a function of physico-chemical parameters and experimental variables was established by means of multivariate regression methods (MLR, PLS). In addition, a predictive model for estimating the hydrophobicity of catecholamines is proposed. Finally, quantitative retention-activity relationships in MLC were also investigated for catecholamines.

Chromatographic quantitation of the hydrophobicity of ionic compounds by the use of micellar mobile phases

Abstract Many biologically active compounds of interest in structure–activity relationships are ionic at physiological pH. However, ionic organic compounds are only weakly or not retained in conventional RPLC which impedes the chromatographic estimation of their hydrophobicity and the development of quantitative retention–activity relationship studies. The use of micellar mobile phases allows the retention of ionic compounds. Hydrophobic and electrostatic forces govern the retention of ionic compounds in micellar liquid chromatography. In this paper three different retention models log k–log P for ionic compounds are tested (P=partition coefficient). The retention model (log k=a log P+bα+c) which includes the hydrophobicity and the molar total charge of compound at a given pH value has proven to be valid for all types of compounds tested, catecholamines, local anesthetics, diuretics and o-phthalaldehyde–N-acetyl- l -cysteine amino acid derivatives.

Chromatographic quantification of hydrophobicity using micellar mobile phases

Abstract In micellar liquid chromatography (MLC), the hydrophobicity of a compound is the predominant effect on its retention and interaction with micelles; however, some contradictory results have been obtained concerning whether k or log k best correlates with the logarithm of partition coefficients (log P ) in the biphasic solvent system octanol-water. An empirical model which describes the relationship between retention in MLC and log P is presented. The retention data for series of neutral compounds eluted with different pure and mixed mobile phases and alkyl-bonded stationary phases were used to test the model. The results indicate that non-linear relationships between k or log k and log P are to be expected and only in particular circumstances can linear relationships be obtained. In contrast, in all the series studied, excellent correlations between the logarithm of the retention factor at zero micellar concentration, k m , and log P , were found ( r 2 in the range 0.965–0.987 and F in the range 277–608). Log k m is proposed as the best chromatographic index for the quantification of the hydrophobicity of solutes using micellar mobile phases.

QRAR Models for Central Nervous System Drugs using Biopartitioning Micellar Chromatography

The capability of biopartitioning Micellar Chromatography, BMC, to describe and estimate pharmacokinetic and pharmacodynamic parameters of central nervous system drugs is reviewed in this article. BMC is a mode of micellar liquid chromatography, MLC, that uses micellar mobile phases of Brij35 (polyoxyethilene(23) lauryl ether) prepared in physiological conditions (pH, ionic strength). The retention of a drug in this system depends on its hydrophobic, electronic and steric properties, which also determine its biological activity. The results of BMC studies suggest that this in vitro approach is an attractive useful tool to be implemented into the lead optimization step of drug development scheme.