Lipophilicity Evaluation of the Products Obtained in the Reaction of N3-Substituted Amidrazones with cis-1,2-Cyclohexanedicarboxylic Anhydride

The lipophilicity of the novel 12 products of the reaction of N³-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).

     

SDS-Based Biomembrane Mimetic Chromatography for Prediction of Human Drug Transport as an in Vitro Technique

The main oral drug absorption barriers are fluid cell membranes, and generally drugs are absorbed by a passive diffusion mechanism. On the other hand, the blood–brain barrier (BBB) is considered to be the main barrier to drug transport into the central nervous system (CNS). The BBB restricts the passive diffusion of many drugs from blood to brain. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography that uses micellar mobile phases in adequate experimental conditions, can be useful as an in vitro system in mimicking the drug partitioning process into biological systems. In this study, relationships between the BMC retention data of a heterogeneous set of 12 drugs and their pharmacokinetics parameters (human oral drug absorption and BBB penetration ability) are studied and the predictive ability of the models is evaluated. Modeling of log k _BMC of these compounds was established by multiple linear regression in two different concentrations (0.07 and 0.09 M) of sodium dodecyl sulfate (SDS). The results showed a fair correlation between human oral drug absorption and BMC retention data in 0.09 M SDS (R ² = 0.864) and a good correlation between the blood–brain distribution coefficient and BMC retention data in 0.07 M of SDS (R ² = 0.887). Application of the developed models to a prediction set demonstrated that the model is also reliable with good predictive accuracy. The external and internal validation results showed that the predicted values are in good agreement with the experimental value.

     

STEREOCHEMISTRY OF SIX-COORDINATE OCTAHEDRAL SILICON(IV) COMPLEXES CONTAINING 2,2-BIPYRIDINE

Abstract

[Si(bpy)₃]⁴⁺ (bpy = 2,2′-bipyridine), synthesized from Sil₄ and 2′.-bipyndine. was optically resolved by a chromatographic method using an SP-Sephadex C-25 column as an adsorbent and a 0.16M aqueous solution of sodium (2R,3R)-(-)-O,O′-dibenzoyltartrate as an eluent. The optical isomers were characterized by measurement of their electronic absorption, circular dichroism, and ¹H NMR spectra. The chromatographic resolution of [SKbpyb]⁴⁺ was also attempted with an aqueous solution of potassium [(2R,3R)-(+)-tartrato]antimonate(III). sodium (2R,3R)-(+)-hydrogentartrate, and sodium (2R,3R)-(+)-tartrate as eluents. Force-field calculations were used to elucidate the chromatographic elution mechanism. [Si(OH)₂(bpy)₂]I₂was also synthesized from Sil₄ and 2′,-bipyridine. The optical resolution of this complex was achieved with sodium [(2R,3R)-(+)-tartrato]antimonate(III).     

Conductivity of crosslinked poly(N-vinylpyrrolidone) gel film containing surfactant as electrolyte salt

New polymeric solid electrolyte films, consisting of crosslinked poly(N-vinylpyrrolidone) (PVPD) as matrix, and surfactant, sodium deoxycholate (NaDC), lithium deoxycholate (LiDC), sodium laulylsulfate (R₁₂OSO₃Na), or sodium palmitate (R₁₅COONa) as electrolyte salt, are prepared; their basic structure and conductivity dependence on temperature are reported. The structure of the electrolytes is amorphous. Their conductivity is 3.1 × 10^?5 S cm^?1 (containing NaDC), 8.42 × 10^?6 S cm^?1 (LiDC), 2.18 × 10^?4 S cm^?1 (R₁₂OSO₃Na), and 7.27 × 10^?5 S cm^?1 (R₁₅COONa) at 20°C. Their temperature dependence of the conductivity is similar to that of liquid electrolyte rather than that of usual polymeric solid electrolyte, i.e., the WLF-type dependence. The values of activation energy of conductivity (E_a) were PVPD, 25.5 kJ mol^?1; PVPD/NaDC, 21.4 kJ mol^?1; PVPD/LiDC, 25.3 kJ mol^?1; PVPD/R₁₂OSO₃Na, 17.2 kJ mol^?1; PVPD/R₁₅COONa, 18.7 kJ mol^?1. © 1993 John Wiley & Sons, Inc.     

Evaluation of N-Substituted 2,4-Dihydroxyphenylthioamide Fungicide Lipophilicity Using the Chromatographic Techniques HPLC and HPTLC

2,4-Dihydroxyphenylthioamide derivatives modified on the N-aryl ring have substantial fungicidal activity. To determine their quantitative structure–activity relationships their lipophilicity was determined by use of the chromatographic methods column liquid chromatography and thin-layer chromatography. Methanol–water systems were used as mobile phases and the linear dependences of retention (R_M and log k) on volume fraction of organic modifier, φ, were determined. This enabled precise determination of lipophilicity (R_Mw and log k_w) by extrapolation. Correlations were found between quantities characterizing the lipophilicity of the compounds. Deviations enabled discovery of compound structural features which increase or reduce lipophilicity. When these data were correlated with biological activity against the phytopathogenic fungi Alternaria alternata and Botrytis cinerea parabolic dependences were obtained.     

The green's functions of the Schrödinger equation for the simplest systems

The Green's functions for the simplest quantum mechanical systems the linear harmonic oscillator, the three-dimensional isotropic oscillator, the Morse oscillator, the Kratcer potential, and the double-minimum potential V_(x) = (mw²/2)(/x/?R)² are presented in closed analytical forms.     

Retention data from reverse‐phase high‐performance thin‐layer chromatography in characterization of some bis‐salicylic acid derivatives

The chromatographic behaviour of salicylic acid derivatives was investigated using reversed‐phase high performance thin‐layer chromatography (RP HPTLC) with methanol–water and dioxane–water binary mixtures as mobile phase in order to establish relationships between chromatographic data and selected physico‐chemical parameters that are related to ADME (absorption, distribution, metabolism and elimination). Some of the investigated compounds were screened for antioxidant activity. Examination of chromatographic behaviour revealed a linear correlation between R_M values and the volume fraction of mobile phase modifier. Obtained R_M⁰ values were correlated with lipophilicity, solubility, human intestinal absorption, plasma‐protein binding, and blood–brain barrier data. The comparison among chromatographic data obtained by two mobile phase was performed with a statistical technique, principle component analysis. Copyright © 2009 John Wiley & Sons, Ltd.     

SDS-Based Biomembrane Mimetic Chromatography for Prediction of Human Drug Transport as an in Vitro Technique

The main oral drug absorption barriers are fluid cell membranes, and generally drugs are absorbed by a passive diffusion mechanism. On the other hand, the blood–brain barrier (BBB) is considered to be the main barrier to drug transport into the central nervous system (CNS). The BBB restricts the passive diffusion of many drugs from blood to brain. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography that uses micellar mobile phases in adequate experimental conditions, can be useful as an in vitro system in mimicking the drug partitioning process into biological systems. In this study, relationships between the BMC retention data of a heterogeneous set of 12 drugs and their pharmacokinetics parameters (human oral drug absorption and BBB penetration ability) are studied and the predictive ability of the models is evaluated. Modeling of log k _BMC of these compounds was established by multiple linear regression in two different concentrations (0.07 and 0.09 M) of sodium dodecyl sulfate (SDS). The results showed a fair correlation between human oral drug absorption and BMC retention data in 0.09 M SDS (R ² = 0.864) and a good correlation between the blood–brain distribution coefficient and BMC retention data in 0.07 M of SDS (R ² = 0.887). Application of the developed models to a prediction set demonstrated that the model is also reliable with good predictive accuracy. The external and internal validation results showed that the predicted values are in good agreement with the experimental value.     

Determination of lipophilicity of γ‐butyrolactone derivatives with anticonvulsant and analgesic activity using micellar electrokinetic chromatography

The lipophilicity of a library of 30 derivatives of dihydrofuran‐2(3H)‐one (γ‐butyrolactone) was determined by MEKC. Calibration curve prepared for ten reference drugs enabled to calculate partition coefficient (log P) for novel compounds. The results of MEKC analysis were compared with lipophilicity coefficients determined by RP‐TLC (R_M0) and computational (Mlog P, Clog P) methods. Good correlation was observed between the results obtained by both experimental methods: the MEKC parameters log k and relative lipophilicity R_MO. The relationship between determined log P values and results of the computational prediction was weaker. Analysis of the relationship between lipophilicity and anticonvulsant activity showed statistically significant differences between mean values of log P coefficients for group of active (2.18) and inactive (1.51) compounds in the maximal electroshock test.     

Lipophilicity Evaluation of the Products Obtained in the Reaction of N3-Substituted Amidrazones with cis-1,2-Cyclohexanedicarboxylic Anhydride

The lipophilicity of the novel 12 products of the reaction of N³-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).     

Rapid Estimation of Octanol–Water Partition Coefficient for Triazole Fungicides by MEKC with Sodium Deoxycholate as Surfactant

A rapid estimation of octanol–water partition coefficient (log P _ow) was developed for triazole fungicides by micellar electrokinetic chromatography (MEKC). Five standard compounds with known log P _ow values from 2.9 to 4.3 (cyproconazole, bromuconazole, epoxiconazole, bitertanol and difenoconazole) were used for constructing the calibration curve of the log P _ow against the MEKC retention factor, log k. A linear relationship was achieved between log P _ow and log k, in the MEKC system containing 40 mM sodium deoxycholate (SDC) and 4 mM borate buffer at pH 9.3, with a correlation of determination, r ² = 0.9905. The log P _ow values of four test compounds of triazole fungicides (triadimenol, myclobutanil, propiconazole and penconazole) were calculated based on the log k values measured by MEKC and the slope and intercept of the calibration curve. This MEKC method can give good estimation of the log P _ow of the four test compounds of triazole fungicides with the differences between the literature log P _ow values and estimated log P _ow from the MEKC method were from 0.15 to 0.23 log units.     

Rapid Screening of Drug Absorption Potential Using the Immobilized Artificial Membrane Phosphatidylcholine Column and Molar Volume

The immobilized artificial membrane phosphatidylcholine (IAMPC) chromatography was evaluated for the predictability of oral absorption potential of 40 structurally unrelated drugs. The chromatographic capacity factors (k_IAM) were determined as a function the pH and composition of the mobile phase, and were corrected for the molar volume of the solutes (k_IAM/MWⁿ). The correlation between k_IAM/MWⁿ and the human fraction of intestinal absorption (F_a) was highest when measured at 20% acetonitrile (pH 5.5) with the power function n = 2.5. The best-fit equation for the sigmoid relationship between k_IAM/MWⁿ and F_a was obtained: F_a (%) = 94.3 × {1-exp[-17.9 × (k_IAM/MW^2.5) × 10⁶]}^2.1 (r = 0.925). This in vitro prediction method may be useful in a rapid screening of drug candidates with high oral absorption potential in humans.     

Stability-Indicating Chromatographic Methods for Simultaneous Determination of Mosapride and Pantoprazole in Pharmaceutical Dosage Form and Plasma Samples

Simple, sensitive, selective, precise, and stability-indicating thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) methods for the determination of mosapride and pantoprazole in pharmaceutical tablets were developed and validated as per the International Conference on Harmonization guidelines. The TLC method employs aluminum TLC plates precoated with silica gel 60F₂₅₄ as the stationary phase and ethyl acetate/methanol/toluene (4:1:2, v/v/v) as the mobile phase to give compact spots for mosapride (R _f 0.73) and pantoprazole (R _f 0.45) separated from their degradation products; the chromatogram was scanned at 276 nm. The HPLC method utilizes a C18 column and a mobile phase consisting of acetonitrile/methanol/20 mM ammonium acetate (4:2:4, v/v/v) at a flow rate of 1.0 mL min⁻¹ for the separation of mosapride (t _R 11.4) and pantoprazole (t _R 4.4) from their degradation products. Quantitation was achieved with UV detection at 280 nm. The same HPLC method was successfully used in performing calibrations in lower concentration ranges for both drugs in human plasma using ezetimibe as internal standard. The methods were validated in terms of accuracy, precision, linearity, limits of detection, and limits of quantification. Mosapride and pantoprazole were exposed to acid hydrolysis and then analyzed by the proposed methods. As the methods could effectively separate the drugs from their degradation products, these techniques can be employed as stability-indicating methods that have been successively applied to pharmaceutical formulations without interference from the excipients. Moreover the HPLC method was successfully used in the determination of both drugs in spiked human plasma.

     

Chromatographic Evaluation of the Lipophilic Properties of Selected Pesticides

Monolinuron, chlortoluron, diuron, isoproturon, linuron, diflubenzuron, dimefuron, teflubenzuron, and lufenuron have been chromatographed on an RP-HPLC column and on RP-HPTLC plates with methanol–water in different volume proportions as mobile phases. The retention values log k, and R_M were extrapolated to zero methanol content. Chromatographic lipophilicities (log k_w, R_Mw, _o(HPLC), and _{o (TLC)}) were compared with measured (log P_exp) partition coefficients and with values (A log Ps, IA log P, C log P, log P_Kowin, and x log P) calculated by use of five different software products. The most significant correlations were found between the chromatographic lipophilicities and C log P values. Satisfactory linear correlation was also obtained between lipophilicity (log k_w, R_Mw) and the valence Gutman index (M).     

Potential of High-Performance Liquid Chromatography for Distribution Coefficient Determination of 3-Hydroxyquinolin-4(1H)-one Derivatives

The potential of reversed-phase HPLC for the determination of distribution coefficient D _7.4 of selected 3-hydroxyquinolin-4(1H)-ones (3HQs) as compounds with significant biological activity was studied. Various stationary phases with C18 as well as hexyl-phenyl modification reflect current trends in RP-HPLC development such as higher sorbent silanophilicity, core–shell technology, hybrid and/or charged surface particles. Because of significant peak tailing of 3HQs at physiological pH on reversed-phase sorbents the separations at pH 3 were performed as well. Surprisingly, the pH change did not affect significantly the partition coefficients of 3HQs. Very affordable and common standards such as anisole, acetophenone, benzyl alcohol, brombenzene, ethylbenzoate and trichlorethylene were applied in the described methodology. The best linearity (R ² 0.9895) of the correlation between log P and log k _w for standards was obtained for hexyl-phenyl sorbent, but this stationary phase was shown to be unsuitable for HPLC separation of 3HQs. The highest linearity (R ² 0.9499) of the relationship between log D _7.4 determined by the classic shake-flask method and log D determined by means of HPLC for 3HQs was attained with Cortecs C18+ column at pH 7.4. The described methodology with Cortecs C18+ as stationary phase offers fast and accurate estimation of log D _7.4 of the tested 3HQs. In an effort to increase the throughput of the HPLC method for log D _7.4 determination, we evaluated almost aqueous mobile phase that contained only 3 % of acetonitrile. Although a worse correlation between log D _7.4 determined by shake-flask method and HPLC with almost aqueous mobile phase was observed, the described procedure offers a very simple and high-throughput alternative for the estimation of log D _7.4.

     

The development of an evaluation method for capture columns used in two-dimensional liquid chromatography

Capture columns are important interface tools for on line two-dimensional liquid chromatography (2D-LC). In this study, a systematic method was developed to evaluate and optimize the capture ability of capture columns by off-line method. First, the parameter Δt_R (Δt_R = t₂−t₁−t₀−W) was introduced to quantitatively represent the capture ability of the capture column by connecting a capture column behind the first dimensional column. Based on the value of Δt_R, an appropriate capture column was selected after the first dimensional column was fixed. Then, the capture ability of the selected column was promoted by adjusting the mobile phase of the first dimensional column. Capture ability was also optimized using complex sample analysis software system (CSASS) software. Second, the elution mode of the trapped compounds on the capture column was investigated by connecting the capture column before the second dimensional column. More specifically, in mode I, capture column was connected to the second dimension without changing the flow rate direction and the trapped compounds must pass through the capture column and be eluted into the second dimensional column. The contrary connection mode was mode II. It was found that mode I is more suitable method for 2D-LC. Finally, an off-line reversed-phase/hydrophilic interaction liquid chromatography two-dimensional liquid chromatography (RP/HILIC 2D-LC) system with a C18 capture column was developed to demonstrate the practical application of this method.