Retention Behavior of Neutral and Positively and Negatively Charged Solutes on an Immobilized‐Artificial‐Membrane (IAM) Stationary Phase

The retention behavior of neutral, positively charged, and negatively charged solutes on the IAM.PC.DD2 stationary phase was investigated and compared. A set of monofunctional compounds and complex drugs (steroids, nonsteroidal anti‐inflammatory drugs, and β‐blockers) were selected for this study, i.e., neutral solutes and solutes with acidic or basic functionalities which are positively charged or negatively charged at pH 7.0. The correlation between the retention factor log k_w at pH 7.0 on the IAM.PC.DD2 stationary phase and the partition coefficient log P_oct or the distribution coefficient log D_7.0 showed that the retention mechanism depends on the charge state and structural characteristics of the compounds. The neutrals were least retained on the IAM.PC.DD2 stationary phase, and positively charged solutes were more retained than negatively charged ones. This implies that the retention of the charged solutes is controlled not only by lipophilicity but also by the electrostatic interaction with the phospholipid, with which positively charged solutes interact more strongly than negatively charged ones.     

Interactions between Amines and Phospholipids: A Chromatographic Study on Immobilized Artificial Membrane (IAM) Stationary Phases at Various pH Values

The chromatographic capacity factors (log k′) for 23 amines were measured by High Performance Liquid Chromatography (HPLC) on a stationary phase composed of phospholipids, the so‐called `Immobilized Artificial Membrane' (IAM). The chromatographic behaviour of the compounds, which consist of primary, secondary, and tertiary amines, and compounds with endocyclic amino functions, was studied with eluents at various pH values (7.0, 5.5, and 3.0). The results were compared both to the octanol/buffer partition values of neutral forms (log P) and to those of mixtures of neutral and ionised forms, existing at the three pH values above mentioned (log D^7.0, log D^5.5, and log D^3.0). At pH 7.0, the log k′ of all secondary and tertiary amines overlapped with those previously observed for neutral isolipophilic compounds. This behaviour was also observed for primary amines, but only for compounds fully ionised at this pH. In contrast, the partially ionised primary amines at pH 7.0 and the compounds with an endocyclic amino function both showed stronger interactions with phospholipids than expected on the basis of log P. The changes in retention observed with eluents at pH 5.5 indicated that retention varies with the ionisation degree of the analytes. At pH 3.0, the interaction between phospholipids and the ionised forms of the amines considered was impaired probably by a change in the charges on the IAM surface. The present study indicates that phospholipids are a partitioning phase that better accommodates the neutral forms of primary amines than does octanol. Moreover, the phospholipid phase is much less sensitive to the ionisation of analytes than octanol, but only at pH 7.0 and 5.5; indeed, the ionised forms of all the amines considered are retained to the same extent as expected for hypothetical neutral isolipophilic compounds. We can thus conclude that, for amines, the partition scale in phospholipids is distinct from the one in octanol.     

Drug–Membrane Interaction on Immobilized Liposome Chromatography Compared to Immobilized Artificial Membrane (IAM), Liposome/Water,and Octan‐1‐ol/Water Systems

The objective of this study was to investigate drug–membrane interaction by immobilized liposome chromatography (ILC; expressed as lipophilicity index log K_s) and the comparison with lipophilicity indices obtained by liposome/H₂O, octan‐1‐ol/H₂O, and immobilized artificial membrane (IAM) systems. A set of structurally diverse monofunctional compounds and drugs (nonsteroidal anti‐inflammatory drugs and β‐blockers) were selected in this study. This set of solutes consists of basic or acidic functionalities which are positively or negatively charged at physiological pH 7.4. No correlation was found between log K_s from ILC and lipophilicity indices from any of the other membrane model systems for the whole set of compounds. For structurally related compounds, significant correlations could be established between log K_s from ILC and lipophilicity indices from IAM chromatography and octan‐1‐ol/H₂O. However, ILC and liposome/H₂O systems only yield parallel partitioning information for structurally related large molecules. For hydrophilic compounds, the balance between electrostatic and hydrophobic interactions dominating drug partitioning is different in these two systems.     

The performance of 1‐ethyl‐3‐methylimidazolium tetrafluoroborate ionic liquid as mobile phase additive in HPLC‐based lipophilicity assessment

Ionic liquids have been widely used as green alternative mobile phase additives to shield the residuals silanols groups and modify the stationary/mobile phase HPLC systems. The present study aimed to evaluate the performance of the ionic liquid 1‐ethyl‐3‐methylimidazolium tetrafluoroborate ([EMIM][BF4]) in producing extrapolated logk_w indices suitable to substitute for octanol–water logP or logD values. The effect of [EMIM][BF4] was investigated for a set of basic and neutral drugs using two different columns, BDS and ABZ⁺. [EMIM][BF4] was added simply alone or in combination with n‐octanol and was compared with the conventional masking agent n‐decylamine. [EMIM][BF4] reduced the retention by suppressing silanophilic interactions, althoug to a lower extent than n‐decylamine. Addition of n‐octanol further decreased the retention by shielding silanol sites on BDS and/or interacting with polar groups through hydrogen bonding on ABZ⁺. Logk_w/logD_7.4 relationships proved moderate compared with those derived upon addition of n‐decylamine. They were considerably improved upon the introduction of protonated fraction F⁺ in the correlation, reflecting ion pair formation between the chaotropic anion [BF4]^‐ and the protonated basic compounds. In this aspect, the ionic liquid [EMIM][BF4], although efficient as a masking agent, cannot be recommended as mobile phase additive to reproduce octanol–water partitioning. Copyright © 2010 John Wiley & Sons, Ltd.     

Centrifugal Partition Chromatography. V. Octanol-Water Partition Coefficients,Direct and Indirect Determination

Abstract

Octanol-water partition coefficients (K_oct) are one of the accepted physico-chemical parameters for predicting the biological effects of organic chemicals. It is demonstrated that centrifugal partition chromatography (CPC) can be used to determine directly the K_oct values from about 0.003 to 300. The mobile phase must be water and the stationary phase must be octanol for accurate determination of the larger K_oct values. To reduce retention times and volumes, the stationary phase volume can be decreased. This can be done using an original mode: the “underload” mode. The “underloading” procedure is described. To extend the K_oct range which can be determine by CPC, the system hexane (60%) octanol (40%)-water was used. A single linear relationship between log K in this system and log K_oct was established allowing to determine the K_oct values up to 1000 (log K_oct=3).     

Exploring the elution mechanism of selenium species on liquid chromatography

In the present work, the chromatographic behavior of eight selenium species, namely selenites (Se(IV)), selenates (Se(VI)), seleno‐DL ‐methionine (Se‐Met), selenocystine (Se‐Cyst), selenocystamine (Se‐CM), selenourea (Se‐U), dimethylselenide ((CH₃)₂Se) and dimethyldiselenide ((CH₃)₂Se₂), was investigated under different stationary and mobile phase conditions, in an effort to unravel secondary interferences in their underlying elution mechanism. For this purpose, two end‐capped and a polar‐embedded reversed‐phase stationary phases were employed using different mobile phase conditions. Retention factors (log k_w) were compared with octanol–water distribution coefficients (log D) as well as with log k_w values on two immobilized artificial membrane (IAM) columns and two immobilized artificial plasma proteins stationary phases, obtained in our previous work. The role of electrostatic interactions was confirmed by introducing the net charge of the investigated Se species as an additional term in the log k_w/log D interrelation, which in most cases proved to be statistically significant. Principal component analysis of retention factors on all stationary phases and octanol–water log D values, however, showed that the elution of the investigated selenium species is mainly governed by partitioning mechanism under all different chromatographic conditions, while the pH of the mobile phase and the special column characteristics have only a minor effect.     

Octanol/water partitioning simulation by RP‐HPLC for structurally diverse acidic drugs: Comparison of three columns in the presence and absence of n‐octanol as the mobile phase additive

The advantageous effect of n‐octanol as a mobile phase additive for lipophilicity assessment of structurally diverse acidic drugs both in the neutral and ionized form was explored. Two RP C₁₈ columns, ABZ⁺ and Aquasil, were used for the determination of logk_w indices, and the results were compared with those previously reported on a base‐deactivated silica column. At pH 2.5, the use of n‐octanol‐saturated buffer as the mobile phase aqueous component led to high‐quality 1:1 correlation between logk_w and logP for the ABZ⁺ column, while inferior statistics were obtained for Aquasil. At physiological pH, the correlations were significantly improved if strongly ionized acidic drugs were treated separately from weakly ionized ones. In the latter case, 1:1 correlations between logD_7.4 and logk_w^oct indices were obtained in the presence of 0.25% n‐octanol. Concerning strongly ionized compounds, adequate correlations were established under the same conditions; however, slopes were significantly lower than unity, while large negative intercepts were obtained. According to the absolute difference (diff = logD_7.4–logk_w) pattern, base‐deactivated silica showed a better performance than ABZ⁺, however, the latter seems more efficient for the lipophilicity assessment of highly lipophilic acidic compounds. Aquasil may be the column of choice if logD_7.4<3 with the limitation, however, that very hydrophilic compounds cannot be measured.     

The calcium‐binding properties of pamidronate,a bone‐resorption inhibitor

The title compound, calcium bis(3‐ammonio‐1‐hydroxy­propyl­idene‐1,1‐bis­phospho­nate) dihydrate, Ca²⁺·2C₃H₁₀N­O₇P₂^?·2H₂O, consists of calcium octahedra arranged in columns along the c axis and coordinated by hydrogen‐bonded molecular anions. The Ca²⁺ cation lies on a twofold axis. Pamidronate adopts a twisted conformation of the hydroxy­alkyl­amine backbone that enables the formation of an intramolecular N—H?O hydrogen bond. The molecular anion is chelating monodentate as well as bidentate, with an O?O bite distance of 3.0647 (15) Å.     

(Z)‐1‐Ferrocenyl‐3‐(3‐hydroxy­anilino)­but‐2‐en‐1‐one and (Z)‐1‐ferrocenyl‐3‐(4‐hydroxy­anilino)­but‐2‐en‐1‐one

The title compounds, both [Fe(C₅H₅)(C₁₅H₁₄NO₂)], crystallize with Z′ = 2 in the centrosymmetric space group P. In each compound, there is an intra­molecular N—H⋯O=C hydrogen bond, and pairs of inter­molecular O—H⋯O=C hydrogen bonds link the mol­ecules into chains, parallel to [10] in the 3‐hydr­oxy compound and parallel to [10] in the 4‐hydr­oxy compound.     

Solvation in octanol: parametrization of the continuum MST model

This study reports the parametrization of the HF/6‐31G(d) version of the MST continuum model for n‐octanol. Following our previous studies related to the MST parametrization for water, chloroform, and carbon tetrachloride, a detailed exploration of the definition of the solute/solvent interface has been performed. To this end, we have exploited the results obtained from free energy calculations coupled to Monte Carlo simulations, and those derived from the QM/MM analysis of solvent‐induced dipoles for selected solutes. The atomic hardness parameters have been determined by fitting to the experimental free energies of solvation in octanol. The final MST model is able to reproduce the experimental free energy of solvation for 62 compounds and the octanol/water partition coefficient (log P_ow) for 75 compounds with a root‐mean‐square deviation of 0.6 kcal/mol and 0.4 (in units of log P), respectively. The model has been further verified by calculating the octanol/water partition coefficient for a set of 27 drugs, which were not considered in the parametrization set. A good agreement is found between predicted and experimental values of log P_o/w, as noted in a root‐mean‐square deviation of 0.75 units of log P. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1180–1193, 2001     

7‐Carboxyl­ato‐8‐hydroxy‐2‐methyl­quinolinium monohydrate and 7‐carboxy‐8‐hydroxy‐2‐methyl­quinolinium chloride monohydrate at 100 K

Both 7‐carboxyl­ato‐8‐hydroxy‐2‐methyl­quinolinium monohydrate, C₁₁H₉NO₃·H₂O, (I), and 7‐carboxy‐8‐hydroxy‐2‐methyl­quinolinium chloride monohydrate, C₁₁H₁₀NO₃⁺·Cl⁻·H₂O, (II), crystallize in the centrosymmetric P space group. Both compounds display an intramolecular O—H⋯O hydrogen bond involving the hydroxy group; this hydrogen bond is stronger in (I) due to its zwitterionic character [O⋯O = 2.4449 (11) Å in (I) and 2.5881 (12) Å in (II)]. In both crystal structures, the HN⁺ group participates in the stabilization of the structure via intermolecular hydrogen bonds with water mol­ecules [N⋯O = 2.7450 (12) Å in (I) and 2.8025 (14) Å in (II)]. In compound (II), a hydrogen‐bond network connects the Cl⁻ anion to the carboxylic acid group [Cl⋯O = 2.9641 (11) Å] and to two water mol­ecules [Cl⋯O = 3.1485 (10) and 3.2744 (10) Å].     

Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections

Ultra-high-pressure liquid chromatography (UHPLC) systems able to work with columns packed with sub-2 μm particles offer very fast methods to determine the lipophilicity of new chemical entities. The careful development of the most suitable experimental conditions presented here will help medicinal chemists for high-throughput screening (HTS) log P _oct measurements. The approach was optimized using a well-balanced set of 38 model compounds and a series of 28 basic compounds such as β-blockers, local anesthetics, piperazines, clonidine, and derivatives. Different organic modifiers and hybrid stationary phases packed with 1.7-μm particles were evaluated in isocratic as well as gradient modes, and the advantages and limitations of tested conditions pointed out. The UHPLC approach offered a significant enhancement over the classical HPLC methods, by a factor 50 in the lipophilicity determination throughput. The hyphenation of UHPLC with MS detection allowed a further increase in the throughput. Data and results reported herein prove that the UHPLC-MS method can represent a progress in the HTS-measurement of lipophilicity due to its speed (at least a factor of 500 with respect to HPLC approaches) and to an extended field of application. Figure The UHPLC approach described here greatly enhanced the time required for log P determination (5' min by compound using UV detection) and, at least, 8 compounds measured in a 5' run when Mass Spectrometry detection in used. These developments offer to medicinal chemists a high-throughput method to estimate the lipophilicity of NCEs Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Experimental section for capillary electrophoresis (CE) measurements, list of the 38 compounds of the calibration set and solvatochromic analyses of the extrapolated retention factors and partition coefficients.     

Solvent effects on kinetics of an aromatic nucleophilic substitution reaction in mixtures of an ionic liquid with molecular solvents and prediction using artificial neural networks

Kinetics of the reaction between 1‐chloro‐2,4‐dinitrobenzene and aniline was studied in mixtures of 1‐ethyl‐3‐methylimidazolium ethylsulfate ([EMIM][EtSO₄]) with methanol, chloroform, and dimethylsulfoxide at 25°C. Single‐parameter correlations of log k_A versus normalized polarity parameter (E^N_T), hydrogen‐bond acceptor basicity (β), hydrogen‐bond donor acidity (α), and dipolarity/polarizability (π*) of media do not give acceptable results. Multiparameter linear regression (MLR) of log k_A versus the solvatochromic parameters demonstrates that the reaction rate constant increases with E^N_T, π*, and β and decreases with α parameter. To predict accurately solvent effects on the rate constant, optimized artificial neural network with three inputs (including α, π*, and β parameters) was applied for prediction of the log k_A values in the prediction set. It was found that properly selected and trained neural network could fairly represent the dependence of the reaction rate constant on solvatochromic parameters. Mean percent deviation of 5.023 for the prediction set by the MLR model should be compared with the value of 0.343 by the artificial neural network model. These improvements are due to the fact that the reaction rate constant shows nonlinear correlations with the solvatochromic parameters. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 41: 153–159, 2009     

Hydro­gen‐bonded adducts of ferrocene‐1,1′‐diyl­bis­(di­phenyl­methanol): monomeric and polymeric adducts with 1,2‐bis(4‐pyridyl)­ethene and 1,6‐di­amino­hexane

In the adduct ferrocene‐1,1′‐diyl­bis­(di­phenyl­methanol)–1,2‐bis(4‐pyridyl)­ethene (1/1), [Fe(C₁₈H₁₅O)₂]·C₁₂H₁₀N₂, there is an intramolecular O—H?O hydrogen bond in the ferro­cene­diol component and a single O—H?N hydrogen bond linking the diol to the di­amine, which is disordered over two sets of sites, so forming a finite monomeric adduct. In the adduct ferrocene‐1,1′‐diyl­bis­(di­phenyl­methanol)–1,6‐di­amino­hexane (2/1), 2[Fe(C₁₈H₁₅O)₂]·C₆H₁₆N₂, the amine lies across a centre of inversion in space group P. There is an intramolecular O—H?O hydrogen bond in the ferrocenediol, and the molecular components are linked by O—H?N and N—H?O hydrogen bonds, one of each type, into a C(13)[R(12)] chain of rings.     

Polysulfonylamine. CLXXVIII Onium‐Salze des Benzol‐1,2‐di(sulfonyl)amins (HZ): Eine zweite Kristallform des Ammonium‐Salzes NH4Z·H2O und Kristallstruktur des Bis(triphenylphosphoranyliden)ammonium‐Salzes [Ph3PNPPh3]Z

Polysulfonylamines. CLXXVIII. Onium Salts of Benzene‐1,2‐di(sulfonyl)amine (HZ): A Second Crystal Form of the Ammonium Salt NH₄Z·H₂O and Crystal Structure of the Bis(triphenylphosphoranylidene)ammonium Salt [Ph₃PNPPh₃]Z A dimorphic form of NH₄Z·H₂O, where Z^? is N‐deprotonated ortho‐benzenedisulfonimide, has been obtained and structurally characterized (previously known form 1A : monoclinic, P2₁/c, Z′ = 1; new polymorph 1B : monoclinic, P2₁/n, Z′ = 1). Both structures are dominated by an abundance of classical hydrogen bonds N⁺–H/O–H···O=S/OH₂, whereby the anionic N^? function does not act as an acceptor. The major difference between the dimorphs arises from the topology of the hydrogen bond network, which is two‐dimensional in 1A , leading to a packing of discrete lamellar layers, but three‐dimensional in 1B . Moreover, the latter network is reinforced by a set of weak C–H··O/N hydrogen bonds, whereas the layered structure of 1A displays only one independent C–H···O bond, providing a link between adjacent layers. The compound [Ph₃PNPPh₃]Z ( 2 , monoclinic, P2₁/c, Z′ = 1) is the first structurally authenticated example of an ionic Z^? derivative in which the cation contains neither metal bonding sites nor strong hydrogen bond donors. This structure exhibits columns of anions, surrounded by four parallel columns of cations, giving a square array. The large cations are associated into a three‐dimensional framework via weak C–H···C(π) interactions and an offset face‐to‐face phenyl interaction, while the anions occupy tunnels in this framework and are extensively bonded to the surrounding cations by C–H···O/N^? hydrogen bonds and C–H···C(π) interactions.