Correlation between retention and 1-octanol-water partition coefficients of some estrane derivatives in reversed-phase thin-layer chromatography

The retention constants (RM) of a series of estrane and secoestrane derivatives are experimentally determined on C18-modified silica gel layers with methanol-water mobile phases of various concentrations. The slopes (m) and intercepts (RMW) of the linear relationships between RM and the volume fraction of methanol are calculated. Both constants increase when the retention of compounds increases, and there is a linear dependence between them indicating their additivity; they represent the sums of particular retention contributions of skeleton and substituents. The contributions, particularly the retention fragmental constants, are calculated by combining the linear relationships RM/log P, RM/m, and RMW/log P. The log P values of the compounds and skeleton were calculated using Rekker's fragmental constants.     

Lipophilic character of cardiac glycosides: correlation between RM values and acute toxicity data in different animal species

The RM for a new series of cardiac glycosides were calculated by means of some of the delta RM values previously derived from another series of compounds. The experimental or calculated RM values of both series of derivatives were correlated with the acute toxicity data (log 1/C). The slopes of the linear equations for cats, dogs, guinea-pigs and frogs are very close, showing that the dependence of toxicity on the lipophilic character is the same in these animal species.     

Influence of mobile phase composition on evaluation of lipophilicity by partition chromatography.

The problems of the concentration dependence of retention indices and the applicability of extrapolated values in the evaluation of lipophilicity were studied. The reversed-phase high-performance liquid chromatography of arylalkanoic acids were carried out with experimental data for substituted estra-1,3,5 (10)-trienes, benzodiazepines, dermorphine derivatives and dansylamides selected from the literature for this purpose. Fair linear relationships between slopes of concentration dependences and extrapolated and non-extrapolated values of RM and log k' were found. Equivalence of these indices in the evaluation of lipophilicity can be inferred. Statistically significant dependences of log P (sigma pi) values on concentration slopes make it possible to use them as new parameters of lipophilicity. The goodness of fit of these relationships increases when the values of ET(30), as a measure of the solvatochromic solvent polarity of mobile phases, are used instead of the change in modifier concentration.     

Molecular Lipophilicity Calculations of Chemically Heterogeneous Chemicals and Drugs on the Basis of Structural Similarity and Physicochemical Parameters

Abstract

QSARs based on molecular polarizability (α) and H-bond acceptor factors (∑C_a) as independent variables provided good predictability of octanol/water partition coefficients (P) for chemicals and drugs. However, for some molecules containing few functional groups, the calculated values deviated significantly from those observed. This approach gave good results when applied to a set of 138 chemicals and drugs previously studied by Mannhold and Dross who compared other methods to calculate log P values.

At the same time, three variations on a molecular similarity approach were pursued. In this study, a large training set with experimentally determined octanol/water partition coefficients (P) was searched for structures closely related to the compound-of-interest. The most successful of these variations took the mean log P value of few most closely related compounds after each was adjusted for differences between their and the compound-of-interest's polarizabilities (α) and H-bond acceptor capacities (∑C_a).     

A comparative QSAR study using Wiener, Szeged, and molecular connectivity indices

In this study we have investigated the relative correlation potential of Wiener (W), Szeged (Sz), and molecular connectivity indices (0chiR, 1chiR and 2chiR) in developing quantitative structure-activity relationships, QSAR; log P values of benzoic acid and its nuclear-substituted derivatives were used for this purpose. The statistical analyses for univariate and multivariate correlations had indicated that both W and Sz are closely related to the connectivity indices (mchiR) and that the W, the Sz, and the 1chiR indices have similar modeling potentials. 1chiR gives slightly better results than both W and Sz. Other connectivity indices 0chiR and 2chiR correlate poorly with log P.     

Lipophilicity determination of some potential photosystem II inhibitors on reversed-phase high-performance thin-layer chromatography

The retention characteristics of 25 2-cyano-3-methylthio-3-substituted amine-acrylates are determined using reversed-phase thin-layer chromatography (RP-TLC) with methanol-water mixtures as eluents. The relationship between Rm values and partition coefficients (C log P) are established. The Rm values decrease linearly with increasing methanol concentration in the eluent. The Rm values extrapolated to zero organic modifier concentration (Rm0) in the eluent are highly related to C log P. The Rm0 value can be used to evaluate the lipophilicity of this kind of compound.     

Reversed-phase ion-pair systems to predict partition coefficients of β-carbolines by HPLC and TLC

Summary A group of 17 β-carbolines was studied in HPLC and TLC systems in order to predict their partition coefficients (log P values). On account of the basic or acid character of some of these compounds, an ion pairing system gave the best results. Both HPLC and TLC data were comparable for log P prediction but severe pH conditions required the use of TLC plates. Retention data are quantitatively related to lipophilicity (expressed as the Hansch constant) and polarity (as the inductive constant) of the solute molecule.     

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.     

Study of the Lipophilic Character of Xanthine and Adenosine Derivatives: II. Relationships Between Log K', RM and Log P Values

Abstract

The log k' values of a series of xanthine and adenosine derivatives were measured by means of a reversed-phase HPLC. The HPLC data were shown to be well correlated with previously reported R_M and R_MC18 values. The equations describing the relationships log k'/R_M and log k'/R_MC18 allowed the calculation of the log k' values of some compounds, which were not tested in the HPLC system. Since the relationship log k'/log P is very close to the previously described relationships R_M/log P and R_MC18/log P one can conclude that reversed-phase TLC and HPLC are very similar in describing the lipophilicity of the compounds.     

Application of Electrotopological States in QSRR and QSAR Analysis of Isomeric Methylphenols Separated by RP-TLC

JPC – Journal of Planar Chromatography – Modern TLC - Phenol and its methyl derivatives have been separated by RP-TLC on RP-2 plates with three mobile phases. RM values, toxicity (log...     

Correlation of the reactivity of organoelement chlorides in metal oxidation in aprotic media

The reactivity of RMCl compounds [RM = Cp(CO)₃Mo, Cp(CO)₃W, Cp(CO)₂Fe, Cp(PPh₃)Ni, and Ph₂Bi] used as oxidants in reactions with metals in aprotic media was assessed to establish that the electron density of the metal atom in the RM group is linearly related to the total electronegativity of this group. The resulting electron densities correlate with the log rate constants of magnesium oxidation with the RMCl compounds in DMF. The reactivity of the oxidants in the organometallic chloride-compact metal-solvent system is a function of the physicochemical properties of the medium.     

Accreditation of reference material producers: the example of IRMM's Reference Materials Unit

The potential approaches for third-party assessment of reference material producers are revisited and the activities of the Reference Materials (RM) Unit of the Institute for Reference Materials and Measurements (IRMM) to obtain accreditation to ISO Guide 34 and ISO 17025 are described. Accreditation was related to the Unit as all matrix RM activities of the institute are concentrated there. A management system was established that allows sufficient flexibility to be applicable to a wide range of RMs while being precise enough to ensure compliance with ISO Guides 30, 31 and especially 34 and 35. Accreditation was achieved in 2004 with independent scopes for testing and RM production and was confirmed and extended in 2005. The key aspects of the RM Unit's management system for RM production are presented. Presented at BERM-10, April 2006, Charleston, SC, USA     

Estimation of phospholipophilicity of 1-[3-(arylpiperazin-1-yl)-propyl]-pyrrolidin-2-one derivatives on immobilized artificial membrane stationary phase and its correlation with biological data

A molecule library containing 42 1-[3-(arylpiperazin-1-yl)-propyl]-pyrrolidin-2-one derivatives has been designed and synthesized. The phospholipophilicity of the obtained compounds has been determined using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC). The performed analysis allowed the calculation of log k(we) values for each of the tested compounds. Experimental phospholipophilicity data (log k(we)) has been compared with the affinity of the tested compounds to alpha(2)-adrenoceptors. Performed quantitative structure-activity relationship studies indicated that, for the tested compounds, there are dependences between affinity for alpha(2)-adrenoceptors and their log k(we) values. The obtained results confirmed that the applied chromatographic IAM-HPLC method could be useful in fast characterization of the phosholipophilicity of structurally closely related compounds as well as for larger series of compounds, such as drug candidates. It could also be used as a tool for further research into this group of compounds.     

Evaluation of a Simple HPLC Correlation Method for the Estimation of the Octanol-Water Partition Coefficients of Organic Compounds

Abstract

A simple reverse-phase high performance liquid chromatographic method is evaluated for the estimation of octanol-water partition coefficients (log P) of organic compounds by correlation with their chromatographic capacity factors (k′). Using an unmodified commercial octadecylsilane column and a mobile phase consisting of methanol and an aqueous buffer, a linear relationship is established between the literature log P values of 68 compounds and the logarithms of their k′ values. For the determination of the partition coefficients of unknowns, one of two sets of standards is used to calibrate the system, the choice being dependent on the hydrogen-bonding character of the compounds being evaluated. The overall method is shown to be rapid and widely adaptable and to give log P data which are comparable to results obtained by classical or other correlation methods.     

Liquid chromatographic measurement of hydrophobicity constants for N-arylsulfonylglycine aldose reductase inhibitors

The hydrophobicity constants for a series of aldose reductase inhibitors (ARIs) are determined by reversed-phase liquid chromatography. A series of reference compounds consisting of 23 barbituric acid derivatives are separated on two phenylsilica stationary phases over a range of methanol concentrations (30-80%) in 0.05 M phosphate buffer. Linear regression analysis of the measured log k' data is used to estimate the capacity factor in 100% water (log k'w) for each compound. The log k'w values are regressed against the shake-flask-measured 1-octanol-water partition coefficients, producing a correlation of 0.953. The same procedure is then used to estimate the log k'w values for a large group of ARIs and their log P values, calculated from the established relationship between log k'w and log P from the reference compounds. An initial analysis of the aldose reductase inhibitory activity of these compounds as a function of hydrophobicity alone fails to reveal a clear relationship, demonstrating the need for a multivariant approach for quantitative structure-activity analysis in this series of compounds.     

RM values of some colchicines and colchiceinamides determined by reversed-phase thin-layer chromatography.

The RM values of twelve colchicines and eight colchiceinamides were measured using reversed-phase thin-layer chromatography. The RM values were calculated by extrapolation from the linear range of a plot of RM values versus the composition of the mobile phase. The results showed that in the colchicine series substitution at the nitrogen in position C7 decreases the lipophilicity, whereas in the colchiceinamide series substitution at the nitrogen in position C10 increases lipophilicity. The influence of other substituent groups on the RM values are considered.     

Prediction of retention time of phenols in liquid chromatography

The chromatographic behavior of phenols in reversed-phase mode liquid chromatography differs from that of non-ionic compounds such as alkyl alcohols, alkylbenzenes, halogenated benzenes, polyaromatic hydrocarbons, and aromatic acids. Therefore, the retention times of 61 phenols were measured in a system of an octadecyl bonded silica gel and acetonitrile/water mixtures. The logarithm of the capacity ratio (log k') was found to be a linear function of the hydrophobicity (log P) in acidic acetonitrile/water mixtures. This result was applied to a different octadecyl bonded silica gel. Eight phenols were selected as standard compounds, and their log k' values were measured in 0.05 M phosphoric acid in 10 to 90% acetonitrile/water mixtures. An empirical polynomial relation was obtained between the concentration of acetonitrile and the slope of the log k' vs log P curve. Finally the capacity ratio of all phenols were calculated in given eluents by the equations derived from the measurements of standard compounds and the calculated log P values. The difference between predicted capacity ratios and measured ones was within 10%.     

Prediction of 3-hydroxypyridin-4-one (HPO) log K(1) values for Fe(iii)

As a means to aid in the design of 3-hydroxypyridin-4-ones (HPOs) intended for use as therapeutic Fe(3+) chelating agents, a novel methodology has been developed using quantum mechanical (QM) calculations for predicting the iron binding affinities of the compounds (more specifically, their log K(1) values). The reported/measured HPO log K(1) values were verified through their correlation with the corresponding sum of the compounds' ligating group pK(a) values. Using a training set of eleven HPOs with known log K(1) values, reliable predictions are shown to be obtained with QM calculations using the B3LYP/6-31+G(d)/CPCM model chemistry (with Bondi radii, and water as solvent). With this methodology, the observed log K(1) values for the training set compounds are closely matched by the predicted values, with the correlation between the observed and predicted values giving r(2) = 0.9. Predictions subsequently made by this method for a test set of 42 HPOs of known log K(1) values gave predicted values accurate to within ±0.32 log units. In order to further investigate the predictive power of the method, four novel HPOs were synthesised and their log K(1) values were determined experimentally. Comparison of these predicted log K(1) values against the measured values gave absolute deviations of 0.22 (13.87 vs. 14.09), 0.02 (14.31 vs. 14.29), 0.12 (14.62 vs. 14.50), and 0.13 (15.04 vs. 15.17). The prediction methodology reported here is the first to be provided for predicting the absolute log K(1) values of iron-chelating agents in the absence of pK(a) values.     

Summary of an interlaboratory characterization (certification) campaign to establish the elemental composition of a new series of agricultural/food reference materials

Summary Ten new Agricultural/Food Reference Materials (RMs) were characterized with respect to their elemental compositions via an interlaboratory characterization (certification) campaign. Chemical analyses were conducted in 73 cooperating laboratories applying 13 major classes of independently different analytical methods. A total of 213 best estimate values, and 65 informational values were obtained for Al, As, B, Ba, Br, Ca, Cd, Cl, Co, Cr, Cs, Cu, F, Fe, Hg, I, K, Mg, Mn, Mo, N, Na, Ni, P, Pb, Rb, S, Sb, Se, Sr, Ti, V, W and Zn in the following RMs: Bovine Muscle Powder (NIST RM 8414), Whole Egg Powder (NIST RM 8415), Microcrystalline Cellulose (NIST RM 8416), Wheat Gluten (NIST RM 8418), Corn Starch (NIST RM 8432), Corn Bran (NIST RM 8433), Whole Milk Powder (NIST RM 8435), Durum Wheat Flour (NIST RM 8436), Hard Red Spring Wheat Flour (NIST RM 8437) and Soft Winter Wheat Flour (NIST RM 8438).