Determination Of Lipophilicity Research Articles

Revisiting thin-layer chromatography as a lipophilicity determination tool. Part IV — A closer look on extrapolation and averaging

Summary The paper compares linear, quadratic, and cubical regression together with several weighted and robust approaches in the context of lipophilicity determination. The comparison is done on 35 model compounds on data from different modifiers used on RP18, CN, and silica plates. It can be concluded that the use of weighted and moderately robust regression technique increases correlation between extrapolated retention and real lipophilicity, whereas polynomial and very robust techniques give visibly worse results due to their excessive flexibility and higher extrapolation uncertainty. Additionally, we have compared averaging retention from different modifiers by RF, k, and RM values. The results are similar; however, surprisingly, RF averaging performs slightly better to the other approaches.

Formulation and Evaluation of Mucoadhesive Buccal Films of Esomeprazole Magnesium Trihydrate

Abstract: In the current investigation, some newer triazines merged benzothiazole hybrids were subjected to molecular properties prediction, drug-likeness, lipophilicity and solubility parameters determination using Molinspiration, Molsoft and ALOGPS 2.1 softwares. Amongst ten proposed analogues only seven therapeutic candidates were chosen on the basis of Lipinski’s “Rule of Five”. Selected title compounds were synthesized by cyclizing 3-chloroaniline and potassium thiocyanate in presence of bromine yielded the corresponding 2-amino benzothiazole synthon, which on further treatment with different substituted aromatic aldehydes afforded Schiff's bases. The later one condensed with phenyl isothiocyanate gave triazine merged benzothiazole analogues (4a-4j). The structural confirmation of the target compounds were established on the basis of IR, 1HNMR and Mass spectral analysis and subjected to in-vitro anti-inflammatory and anti-oxidant screening. Compound 4c and 4g showed pronounced antioxidant and ant-inflammatory activity respectively. The phenyl ring of triazine bearing –OH and –OCH exhibited good biological activity and their predicted drug-likeness model score also found to be convincing among the series.

A Novel Method for High Throughput Lipophilicity Determination by Microscale Shake Flask and Liquid Chromatography Tandem Mass Spectrometry

Modern small molecule drug design requires the optimization of not only the binding characteristics of the molecule but also its physicochemical properties for ADMET performance. A key physical property is lipophilicity and medicinal chemists need rapid access to high quality data in order to drive their decision making. Traditionally lipophilicity (log D) measurements are performed with a shake flask method and UV determination. This method suffers from low sensitivity and is not easily converted to a high throughput format. Over the past decade, several groups have taken different approaches to improve this assay, including replacing the shake flask method with one that utilizes reverse phase HPLC. Here we describe a new microscale shake flask method that utilizes UPLC-MS/MS to achieve increased throughput, sensitivity and accuracy. Approaches for assessing data quality are also described. This platform technology only requires micrograms of compound and is routinely used by most small molecule drug discovery project teams at Genentech.

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.

Study of lipophilicity of alpha-asarone derivatives and their deterrent activity against the Colorado potato beetle

Abstract Five positional isomers and thirty derivatives of alpha-asarone wereobtained as a bioactive set of substances, and their deterrent activity against the Colorado potato beetle was studied. The lipophilicity values of thirty-six compounds were determined by using experimental, chromatographic and theoretical methods. The logk w values for all compounds were determined by reversed-phase high-performance liquid chromatography using five different columns. The octan-1-ol/water partition coefficients values were determined experimentally as a measure of lipophilicity. For the purpose of comparison, theoretical lipophilic parameters for all compounds were calculated with the use of chemical programs. The experimental, chromatographic and calculated values were compared using linear regression analysis. The most significant correlations were found between the chromatographic lipophilicities using methanol/water for all tested columns and calculated values. It has been found that 13 compounds have the lowest lipophilicities, which correspond to deterrent activity. The presented results show that the computational method is useful for determining the lipophilicity of a series of homologues, but not for positional isomers. In addition, this study shows that determination of lipophilicity using HPLC with various stationary phases is practical and reasonable for all alpha-asarone derivatives.

The Block Relevance (BR) analysis to aid medicinal chemists to determine and interpret lipophilicity

A major issue related to chromatographic determination of lipophilicity is the conversion to logP. The interconversion of lipophilicity indices can be made only if two systems express the same balance of intermolecular solute/system forces. The deconvolution of intermolecular interactions is generally obtained by solvation parameter models. Block Relevance (BR) analysis is a new tool specifically designed for medicinal chemists to interpret partitioning/retention phenomena in a very practical way. This paper describes the application of BR analysis to literature data (ElogP) and experimentally determined chromatographic indices on a Supelcosil™ LC-ABZ column for a series of 36 drugs. Results indicate that BR analysis is a solid and reliable tool that captures the main information encoded in any lipophilicity descriptor.

Robustness of an Immobilized Artificial Membrane High-Performance Liquid Chromatography Method for the Determination of Lipophilicity

Hydrophobicity is an intrinsic property that relates to a chemical’s tendency to partition between a polar and a nonpolar phase. Traditionally, hydrophobicity has been described by the logarithm of...

Chromatographic lipophilicity determination using large volume injections of the solvents non-miscible with the mobile phase

A new perspective in the lipophilicity evaluation through RP-HPLC is permitted by analysis of the retention factor (k) obtained by injecting large volumes of test samples prepared in solvents immiscible with mobile phase. The experiment is carried out on representative groups of compounds with increased toxicity (mycotoxins and alkaloids) and amines with important biological activity (naturally occurring monoamine compounds and related drugs), which are covering a large interval of lipophilicity. The stock solution of each compound was prepared in hexane and the used mobile phases were mixtures of methanol or acetonitrile and water, in suited volume ratio. The injected volume was between 10 and 100μL, while the used stationary phases were RP-18 and RP-8. On both reverse stationary phases the retention factors were linearly decreasing while the injection volume was increasing. In all cases, the linear models were highly statistically significant. On the basis of the obtained results new lipophilicity indices were purposed and discussed. The developed lipophilicity indices and the computationally expressed ones are correlated at a high level of statistical significance.

Revisiting thin-layer chromatography as a lipophilicity determination tool. Part III — A study on CN adsorbent layers

Revisiting thin-layer chromatography as a lipophilicity determination tool. Part III — A study on CN adsorbent layers

A new pH/organic modifier gradient RP HPLC method for convenient determination of lipophilicity and acidity of drugs as applied to established imidazoline agents

Convenient drug candidates testing methods for lipophilicity and acidity are highly requested in modern pharmaceutical research and development strategy. Reversed-phase high-performance liquid chromatography (RP HPLC) might be particularly useful for the determination of both pKa and the apparent (pH-dependent) octanol–water partition coefficient, applicable in high-throughput analysis of multi-component mixtures. In this report the pH/organic modifier gradient RP HPLC is presented as a means of simultaneous determination of acidity and lipophilicity of a series of 26 imidazoline-like drugs. The previously theoretically elaborated approach has been applied consisting in retention measurements in a series of methanol gradient runs differing in pH range and duration of the gradient. The simultaneously determined lipophilicity and dissociation constants have been demonstrated to correlate to the respective parameters form calculation chemistry. The proposed approach can be applied to compound mixtures, it requires only minute amounts of substances, and pKa values can be determined in the range 3–10 units and lipophilicity log P parameter in the range 0–7units.

Usefulness of reversed-phase HPLC enriched with room temperature imidazolium based ionic liquids for lipophilicity determination of the newly synthesized analgesic active urea derivatives

Lipophilicity of several novel analgesic active 1-(1-arylimidazolidyn-2-ylidyn)-3-arylalkyl urea derivatives has been estimated by the use of chromatographic method. The investigated compounds were analyzed by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol or acetonitrile and water with addition of imidazolium based room temperature ionic liquids varying in an anion chaotropicity as the mobile phases. The relationships between log k values vs. concentration of organic solvent was used for determination of the log k(w) values by extrapolation technique. The partition coefficients (log P) values were calculated by means of the Pallas 3.1.1.2. and Spartan 10.0 softwares and further correlated with log k(w) measured experimentally in classical organic-aqueous eluent system and systems modified with ionic liquids addition. It was found that log k(w) values measured in eluent system modified with butyl-methyl imidazoilum chloride correlate the best with the logarithm of partition coefficient calculated by Pallas software (log P(calc.)). Furthermore, it was found that the examined compounds form H-bonding with imidazoilum cation of modifiers improving the chromatographic peak parameters (the symmetry factor, the theoretical plates number) especially when ionic liquid's anion was more chaotropic. Amphiphilic ionic liquid possessing longer alkyl chain substituent (OMIM BF(4)) can be considered as a new cationic surfactant. Micellar conditions improved separation selectivity of chloro- and methoxy substituted derivatives.

Measurement of Drug Lipophilicity and pKa Using Acoustics

Lipophilicity of chemicals and drug candidates is normally described in terms of octanol/water partitioning and log P. We investigated an alternate approach to lipophilicity determination using a mimic of an alkyl alcohol with compound partitioning quantified using acoustic sensing. A self-assembled monolayer composed of HSC(10)(CH(2)CH(2)O)(6)C(18) was formed on planar gold electrodes of a piezoelectric acoustic sensor. The system was challenged with compounds covering a 4-log range of log D values. As compounds partitioned in the interfacial layer, changes in sensor resonant frequency were found to correlate with compound partition coefficients (log P) and with distribution coefficients (log D). Linear concordance (R(2) = 0.933) was established between log(-dF/M(w)t) and log P and with log D in both water and biological buffers at variant pH (pH 5.2 to 7.8). In turn, drug pK(a) could be determined by profiling log D changes during pH titration. The lipophilicity/pH profile of a weakly basic drug (quinine; pK(a) = 7.95) was sigmoidal with respect to -dF/M(w) values, with a profile inverse to that of a weakly acidic drug (naproxen; pK(a) = 4.15).

Revisiting thin-layer chromatography as a lipophilicity determination tool. Part II — Is silica gel a reliable adsorbent for lipophilicity estimation?

Lipophilicity is often estimated by thin-layer chromatography (TLC) as a fundamental property related to biological and pharmaceutical activity. In a recent study, we contributed some standardization to the subject by performing a comparative analysis of the different approaches in the field. This part presents an analogous study on silica, the use of which in normal-phase systems seems to be a new trend of recent times. We have compared several approaches of TLC lipophilicity determination: a single TLC run, Soczewinski-Wachtmeister equation coefficients, principal component analysis (PCA) of the retention matrix, and PARAFAC on a three-way array. All techniques were applied to 35 model solutes with simple molecules, using nine concentrations of six modifiers: acetone, dioxane, ethyl acetate, methylethylketone, propan-2-ol, and tetrahydrofuran. Comparative analysis points to several general recommendations. Ethyl acetate seems to give the best correlations with lipophilicity, and the correlations of sing...

Simple Ion Transfer at Liquid|Liquid Interfaces

The main aspects related to the charge transfer reactions occurring at the interface between two immiscible electrolyte solutions (ITIES) are described. The particular topics to be discussed involve simple ion transfer. Focus is given on theoretical approaches, numerical simulations, and experimental methodologies. Concerning the theoretical procedures, different computational simulations related to simple ion transfer are reviewed. The main conclusions drawn from the most accepted models are described and analyzed in regard to their relevance for explaining different aspects of ion transfer. We describe numerical simulations implementing different approaches for solving the differential equations associated with the mass transport and charge transfer. These numerical simulations are correlated with selected experimental results; their usefulness in designing new experiments is summarized. Finally, many practical applications can be envisaged regarding the determination of physicochemical properties, electroanalysis, drug lipophilicity, and phase-transfer catalysis.

Determination of lipophilicity for antitumor acridinone derivatives supported by gradient high-performance liquid chromatography method

Abstract The lipophilicity values of selected acridinone (imidazoacridinone and triazoloacridinone) derivatives were measured by gradient reversed-phase high-performance liquid chromatography (RP-HPLC) using a C18 stationary phase with a water/acetonitrile mixture as a mobile phase. The retention times obtained served as input data and appropriate log kw values (i.e., the retention factor log kw extrapolated to 0% organic modifier) as an alternative to log P were calculated using the DryLab program. The relationships between the lipophilicity (log kw) and the chemical structure of the studied compounds, as well as correlation between experimentally determined lipophilicities (log kw) and log P data calculated using some commonly available software, are discussed.

A quantitative structure–activity approach for lipophilicity estimation of antitumor complexes of different metals using microemulsion electrokinetic chromatography

Microemulsion electrokinetic chromatography (MEEKC) offers a valuable tool for the rapid and highly productive determination of lipophilicity for metal-based anticancer agents. In this investigation, the MEEKC technique was applied for estimation of n-octanol–water partition coefficient (log P oct) of a series of antiproliferative complexes of gallium(III) and iron(III) with 4 N-substituted α- N-heterocyclic thiosemicarbazones. Analysis of relationships between the experimental log P oct and the retention factors of compounds showed their satisfactory consistency in the case of single metal sets, as well as for both metals. Since none of available calculation programs allows for evaluating the contribution of central metal ion into log P oct (i.e. Δlog P oct) of complexes of different metals, this parameter was measured experimentally, by the standard ‘shake-flask’ method. Extension of the log P oct programs by adding Δlog P oct data resulted in good lipophilicity predictions for the complexes of gallium(III) and iron(III) included in one regression set. Comparison of metal-thiosemicarbazonates under examination in terms of log P oct vs. antiproliferative activities (i.e. 50% inhibitory concentration in cancer cells) provided evidence that their cytotoxic potency is associated with the ability to cross the lipid bilayer of the cell-membrane via passive diffusion.

The use of phospholipid modified column for the determination of lipophilic properties in high performance liquid chromatography

A new chromatographic stationary phase obtained by coating a reversed phase amide column with phosphatidylcholine based liposomes solution to yield a phospholipid modified column (PLM). The modification is achieved by the dynamic coating method which recycles the coating solution through the column in a closed loop for a period of 24 h. The chromatographic properties of the new column have changed significantly as compared to the original amide column due to the phospholipid coating. A good correlation was observed between n-octanol/water log P values and the logarithm of the retention factor obtained on the PLM column for a large number of solutes. In addition the PLM column was characterized using the linear solvation energy relationship (LSER). The values of the LSER system constants for the PLM column were calculated and were found to be very close to those of the n-octanol/water extraction system thus suggesting that the PLM column can be used for the estimation of n-octanol/water partition coefficient and serve as a possible alternative to the shake-flask method for lipophilicity determination. In addition, the results suggest that the PLM column can provide an alternative to other phospholipid-based column such as the IAM and the DPC columns.

Lipophilicity determination of N-( benzothiazol-2-yl )-α-amino alkyl phosphonic diesters by RP-HPLC and RP-HPTLC

Using methanol-water mixtures as the mobile phase, the chromatographic retention parameters k' and Rf were determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and reversed-phase high-performance thin-layer chromatography (RP-HPTLC) for N-(benzothiazol-2-yl)-α-amino alkyl phosphoric diesters and the correlation with lipophilicity parameter (Clog P) was established. Log Kw values obtained from RP-HPLC and Rm values obtained from RP-HPTLC can be used to evaluate the lipophilicity of this kind of compounds. Chromatographic method is a good alternative for lipophilicity measurement.

Revisiting thin-layer chromatography as a lipophilicity determination tool—A comparative study on several techniques with a model solute set

The lipophilicity of a compound is a fundamental property related to pharmaceutical and biomedical activity. As many approaches are mixed together in every-day published studies, the subject needs some standardization. The paper presents a comparative study on several approaches of TLC lipophilicity determination: a single TLC run, extrapolation of a retention, principal component analysis of a retention matrix, PARAFAC on a three-way array and a PLS regression. All techniques were applied to 35 model solutes with simple molecules, using nine concentrations of six modifiers: acetonitrile, acetone, dioxane, propan-2-ol, methanol and tetrahydrofurane. The elaborated comparative analysis formed several general recommendations. Methanol and dioxane were the best modifiers, while acetonitrile gave the worst and inacceptable correlation of retention with lipophilicity. Surprisingly, good correlations were obtained for the single TLC runs and this method is underestimated in the literature. The advanced chemometric processing proposed recently, such as PCA, PARAFAC and PLS did not show a visible advantage comparing to classical methods. A need to use a robust regression and robust correlation measures, due to presence of significant outliers, was also noticed and studied.

Advances in LC platforms for drug discovery

Importance of the field: The major application areas of liquid chromatography (LC) in modern drug discovery are the identification and structural characterization of new potential lead compounds from natural and/or synthetic sources and the determination of their physico-chemical and pharmacokinetic properties.Areas covered in this review: Significant advances in terms of LC platforms achieved in the last 5 years are highlighted in this review. Special attention is paid to novel LC strategies used in the discovery of new bioactive molecules and the determination of lipophilicity, pKa values, passive drug permeability and in vitro metabolism of new chemical entities.What the reader will gain: Many improvements were achieved in terms of LC instrumentation, columns technology and analytes detection to attain ultra-fast and/or high-resolution chromatographic separations. These advances are particularly beneficial to face the complexity and high number of samples studied in the early phases of the discovery process. Advantages and drawbacks of each strategy are discussed.Take home message: LC and ultra high pressure liquid chromatography coupled with mass spectrometry detection constitute the most promising strategies to achieve high-throughput and/or high-resolution analyses in a drug discovery environment.