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JPC - Journal of Planar Chromatography - Modern TLC
Authors: Gergely Völgyi, Katalin Deák, József Vámos, Klára Valkó, and Krisztina Takács-Novák

A validated reversed-phase thin-layer chromatographic (RPTLC) method is proposed for parallel estimation of the lipophilicity of chemically diverse neutral compounds or weak acids and bases. To cover a wide range of lipophilicity two optimized chromatographic systems were used — one for determination of log P of low or moderately lipophilic compounds (log P = 0–3) and one for highly lipophilic compounds (log P = 3–6). RP-diC 1 silanized silica gel plates were used as stationary phase. Mixtures of water with acetone, acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, and 1,4-dioxane were investigated as mobile phases. Acetone-water mixtures were found to be optimum for both systems in respect of correlation of R M values with octanol-water partition coefficients. Two chemically diverse sets of calibration compounds were selected to cover ranges of moderate and high lipophilicity. Correlation between log P and chromatographic R M data (log P = aR M + b ) was good for both systems; the correlation coefficients ( r ) of the calibration equations were >0.99. The universal applicability of the optimized chromatographic systems was then tested using 20 randomly selected structurally diverse compounds. There was usually good agreement between log P values obtained by the shake-flask method and by RPTLC. This validated RPTLC method can be regarded as a suitable alternative for rapid and acceptably accurate estimation of the lipophilicity of drug candidates in the early phase of drug research.

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Selected meta -and para -alkoxyphenols have been separated by RPTLC on cellulose impregnated with ethyl oleate, with ethanol-water, 40 + 60 (%, v/v ), as mobile phase. New methods of calculation of partition coefficients on the basis of the topological index ° B and experimental R F values have been proposed. These methods enable differentiation between the values of log P for the meta and para isomers of the alkoxyphenols.

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An inexpensive, simple, and reproducible SPE-TLC method has been developed and validated for analysis of haloperidol and its three main metabolites in wastewater. Analysis was performed on C 18 silica gel RPTLC plates with methanol containing 0.001% triethylamine as mobile phase. The development time for 10 cm was 70 min. Detection and quantification were performed by exposing TLC plate to iodine vapor and by UV-visible spectrometry. R F values of haloperidol, metabolite I, metabolite II, and metabolite III were 0.20, 0.05, 0.15, and 0.84 respectively. Recovery of haloperidol and its metabolites from wastewater was in the range 80–90%.

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Methyl laurate, methyl myristate, methyl palmitate, methyl isostearate, methyl stearate, and methyl arachidate have been separated by RPTLC on kieselguhr F 254 impregnated with different amounts of paraffin oil, using two different mobile phases. The R M values of these compounds for all the stationary phases and mobile phases investigated could be correlated with the dipole moments of the mobile phases, with the percentage impregnation of the stationary phase, and with numerical values of one topological index from among those based on the distance matrix ( W , A , ° B , 1 B ) or on the adjacency matrix ( 1 X , 1 X v ). The theoretical partition coefficient (log P ) for methyl isostearate was calculated from R M values or from one of the topological indexes mentioned above.

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A simple, rapid, and stability-indicating RPTLC method has been established and validated for quantitative analysis of two oral antidiabetic agents, the sulfonylureas gliclazide and glipizide, in tablets. Analysis was performed on RP-18 plates with 60% ( v/v ) acetonitrile in pH 2.3 phosphate buffer as mobile phase. Compact spots were obtained for gliclazide ( R F 0.38 ± 0.02, mean ± SD) and glipizide ( R F 0.51 ± 0.03). Detection and quantification were performed by classical densitometry at 215 nm, the wavelength of maximum absorption of gliclazide and glipizide. Calibration plots were constructed in the range 0.8–1.8 μg per 10 μL (per spot) for both drugs and were linear with good correlation coefficients ( r = 0.998 ± 0.001, mean ± SD, for gliclazide and r = 0.993 ± 0.002 for glipizide). The limits of detection and quantification were 50 and 200 ng per spot, respectively, for gliclazide and 60 and 300 ng for glipizide. The method was validated for robustness, precision, accuracy, stability, and specificity. The drugs were subjected to acidic and alkaline hydrolysis, oxidation, photo-degradation, and heating and were found to be susceptible to some stress conditions. However, the degradation products were well resolved from the pure drugs with significantly different R F values.

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Dual retention behavior is observed for triphenylmethane (TPM) derivatives in RPTLC on silica gel plates when the composition of acetone-water mobile phases is varied. The physicochemical and molecular properties of the TPM derivatives causing this unusual retention behavior have been investigated by traditional quantitative structure-retention relationship (QSRR) modeling and by 3D molecular modeling. The QSRR studies were performed by using PLS regression analysis based upon use of selected sets of Dragon molecular descriptors and pharmacokinetically relevant VolSurf descriptors to identify the physicochemical properties that govern chromatographic behavior. Comparative molecular similarity indices analysis (CoMSIA) was used to create the 3D isoenergy contours of favored and unfavored contributions of the molecular fields around the molecules in the RPTLC systems used. The dual retention behavior of the TPM derivatives can be attributed to the propensity of these molecules to become oriented with different parts of their surface toward the silica gel layer when mobile phases with high or low water content are used. This hypothesis was supported by the 3D modeling results, which revealed that the isoenergy contours of the electrostatic, hydrophobic, and hydrogen bond acceptor fields of CoMSIA around the molecules were very different in systems with high or low water content. Furthermore, the VolSurf descriptors, which represent pharmacokinetic properties, correlated better with R M values measured using mobile phases with high water content than with those measured using mobile phases with low water content, and thus may be related to chromatographic behavior. Statistically significant PLS models with high predictive power ( q 2 > 0.8) have been developed for prediction of R M values for the four mobile phases used. Lipophilicity was found to be the most important molecular property governing the retention of TPM derivatives.

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The reversed-phase TLC retention behavior of 26 structurally diverse basic and neutral drugs has been investigated under different chromatographic conditions by varying the aqueous component and pH of the mobile phase. Phosphate buffer, phosphate-buffered saline, morpholinepropanesulfonic acid at pH 7.4, phosphate buffer at pH 11.0, and pure water were used with different proportions of methanol as the mobile phase. Use of n -octanol as mobile phase additive was also investigated. Different sets of extrapolated R Mw values were compared and the effect of electrolytes on retention is discussed. Retention was correlated with lipophilicity log P and log D 7.4 . Use of log P with an ionization correction term Q at pH 7.4 led to good correlation and confirmed a reduced effect of protonation on retention. Finally, linear solvation energy relationships were established for all data sets. Apart from the reduced effect of ionization, hydrogen-bond basicity and volume were found to effect to an almost equal extent octanol-water partitioning and RPTLC retention under all conditions at pH 7.4, indicating close similarity between the different processes. At pH 11 a lower negative contribution of hydrogen-bond basicity to retention compared with noctanol water partitioning, was noticed.

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The lipophilicity of thirty-seven N -[(4-arylpiperazin-1-yl)alkyl]-2-azaspiro[4.4]nonane-and [4.5]decane-1,3-dione derivatives has been determined by reversed-phase thin-layer chromatography with n -propanol-Tris buffer (pH 7.0) mixtures as mobile phases. All the compounds examined were basic molecules with calculated p K a values ranging from 6.20 to 8.95. Examination of the chromatographic behavior of the compounds revealed a linear correlation between corrected R M value ( R Mcorr ) and the concentration of n -propanol in the mobile phase. An extrapolation method was used for the estimation of relative retention parameters, R M 0 . The results obtained provided a good basis for evaluation of structure-lipophilicity relationships. The role of lipophilicity in the anticonvulsant activity of the set of compounds investigated is discussed: in general, the higher the value of R M 0 , the stronger the anticonvulsant efficacy.

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The lipophilicity of 2,6-disubstituted 7-methylpurines and 6-mercaptopurine has been determined by reversed-phase thin-layer chromatography. Chromatography was performed on precoated RP-18F 254 plates with mixtures of acetone and buffer (sodium acetate-veronal, pH 7.0) as mobile phases. R MW values of all the compounds decreased linearly with increasing concentration of acetone in the mobile phase. Experimental lipophilicity (log P TLC ) was determined by use of a calibration plot obtained for five standards. The partition coefficient C log P was calculated for all the compounds by use of the software CS Chem3D. Dissociation constants, p K a , for all the compounds were calculated by use of software available from the internet and p K a values were also determined experimentally for monosubstituted 2-or 6-thioxo-7-methylpurines, by means of a UV spectrophotometric method. When experimental log P TLC values were compared with theoretical C log P values high correlation was achieved. Larger differences between the log P TLC and C log P values obtained for monosubstituted 2-or 6-thioxo-7-methylpurines suggest the presence of both ionic and neutral forms in aqueous solution.

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