Retention of structurally diverse drugs in human serum albumin chromatography and its potential to simulate plasma protein binding

The retention behavior of 39 structurally diverse neutral, basic and acidic drugs was investigated on an HSA stationary phase using PBS buffer (pH 7.0) and acetonitrile or 2-propanol as organic modifiers. Extrapolated or directly measured logkw values as well as isocratic retention factors were correlated with plasma protein binding data taken from the literature. Retention factors determined in the presence of 10% acetonitrile led to high quality 1:1 correlation with apparent logKHSA values. The derived reference equation was successfully validated using a secondary set of 24 drugs. Further analysis of HSA retention into more fundamental properties revealed the involvement of anionic species in solute-stationary phase interactions, expressed by the negatively charged fraction, besides the partitioning mechanism which was reflected by lipophilicity. Protonation of basic drugs, although less important, may also influence retention, leading to reduced partitioning into the HSA surface as a net effect, while it seems to have no effect on HSA binding. The above results were further confirmed by linear solvation energy relationships (LSER). © 2010 Elsevier B.V

Dynamics of photodeformations and space charge field in photorefractive Fe:LiNb O3 studied with synchrotron area diffractometry

The method of synchrotron area diffractometry has been used to map with a high spatial resolution in real time the distribution over the crystal surface of the lattice deformation tensor components induced by a macroscopic visible light beam on a z -cut iron-doped photorefractive LiNb O3 crystal. The xy planes exhibit a tensile strain, on the order of 10-4, in the center and long range, extending up to 780 μm, shear deformations at the borders of the illuminated region, respectively. Photodeformations evolve with illumination time with relaxation type, time dependence, and time constants of the order of minutes. The observed lateral distribution of deformation tensor components, as well as their temporal evolution, has been examined, considering the coupling of the converse piezoelectric effect with the strong space charge field generated by the damage inducing beam along the z axis due to the bulk photovoltaic effect. The observed strain in the center can be attributed to the bulk photovoltaic field of the order of 107 Vm, while the long range shear deformations are mainly associated with the lateral components of the electric field which are present at the borders of the space charge regions. Both photodeformations and space charge field evolve at the same time scale, the dependence of time constants on the incident light intensity following the predictions of the one-center model charge redistribution due to the bulk photovoltaic effect. This work demonstrates that the method of synchrotron area diffractometry is a very powerful tool to study in situ the dynamics and spatial variation of microstuctural changes (deformations) induced by an external field (electric, magnetic, or temperature). © 2007 American Institute of Physics

Investigation of the retention behavior of structurally diverse drugs on alpha1 acid glycoprotein column: Insight on the molecular factors involved and correlation with protein binding data

Retention of 49 structurally diverse drugs on alpha1 acid glycoprotein column was investigated under different chromatographic conditions. Acetonitrile and 2-propanol were used as organic modifiers at different percentages and the pH was adjusted at 7.0 using PBS. Analysis of extrapolated and isocratic retention in terms of lipophilicity and electrostatic interactions revealed significant effect of the nature and percentage of organic modifier, which was attributed to the different shielding degree of the charged sites on the stationary phase by the buffer constituents. AGP retention factors were compared to HSA retention factors analyzed previously. Application of LSER analysis, extended to incorporate fractions ionized, demonstrated hydrogen bond acidity, dipolarity/polarizability and excess molar refraction as the most significant parameters for all AGP chromatographic indices, elucidating the differentiation of AGP retention from octanol-water partitioning and HSA retention. An attempt to correlate AGP chromatographic indices to AGP association constants, available in literature, supported the importance of stationary shielding in retention mechanism. Thus, isocratic retention factors log k10(ACN)AGP show a moderate but still better performance than lipophilicity in the case of A variant and may be a useful tool for the estimation of relevant association constants. For F1/S binding simulation lower stationary phase shielding is needed to obtain a significant two term regression equation, where log k20(ACN)AGP exerts a secondary contribution next to the most important bulk effect expressed by molecular weight. © 2014 Elsevier Inc. All rights reserved

Combined x-ray imaging and diffraction study of light-induced distortions in Fe:LiNbO3

A real-time investigation of the light-induced deformation on Fe:LiNbO3 crystals was performed by taking advantage of both the high flux and the detector system (FRELON CCD camera) available at a modern synchrotron radiation source like the ESRF. The observed contrast and effective misorientation after illumination of a Z-cut crystal are mainly due to (00l) lattice planes tilts. Considering the coupling of the bulk photovoltaic field and the converse piezoelectric effect, we develop a 'parallel plate condenser'-like macroscopic model of the distortion generated by the visible light beam. Calculation of the effective misorientation at the edges of the illuminated region gives values of the order of ±20 arcsec which are consistent with our experimental data. © 2001 IOP Publishing Ltd

The efficiency of RP-TLC for lipophilicity assessment. A comparative study on a series of pyrrolyl-acetic acid derivatives, inhibitors of aldose reductase

The lipophilicity of a series of pyrrolyl-acetic acid derivatives, inhibitors of the aldose reductase enzyme, was assessed by reversedphase thin layer chromatography (RP-TLC). The role of the carbon content of the stationary phase in reproducing the octanol-water partitioning was examined using RP-18 F254S and RP-8 F254S plates. Retention on RP-8 plates was found to be more uniform, while these plates exhibit some advantages for the lipophilicity assessment of acidic compounds, compared to the most commonly used RP-18 plates. However, in both cases, different energetics between octanol-water partitioning and RP-TLC retention seem to be involved. On both plates the influence of ionization of the acid functional group was found to be more pronounced on retention in comparison with previous findings for basic compounds. Both sets of R Mw values were compared with HPLC chromatographic indices, reported previously. They were found to correlate better with logk w values, if the latter have been determined in the presence of noctanol as mobile phase additive. In all cases, best relationships were obtained with R Mw(C18). The performance of R Mw indices in regression equations modeling the aldose reductase inhibitory activity was evaluated. Results were comparable with those previously generated using logP. Both R Mw(C8) and R Mw(C18) proved to perform equally well as lipophilicity indices in correlating biological activity, if combined with the ionization correction term Q and Abraham's basicity term B as additional parameters. © Akadémiai Kiadó, Budapest

HPLC-based lipophilicity of pyrrolyl-acetic acid ARIs: Relationships with biological activity

Reversed phase HPLC was used to assess the lipophilicity of a series pyrrolyl-acetic acid derivatives with aldose reductase inhibitory activity. The pH conditions were adjusted at 3.0 to investigate the behavior of the neutral species and at pH 7.4, at which the ionized form predominates, using phosphate and MOPS buffer. Retention was monitored in absence and in presence of different amounts of n-octanol in the mobile phase in order to explore the chromatographic conditions which best reproduce the octanol-water partition or distribution coefficients. The effect of n-octanol in retention was systematically studied and its role in lipophilicity assessment was evaluated. Nevertheless rather moderate regression equations were obtained, which deviated significantly from the ideal 1:1 correlation. No significant effect of buffer was observed. The appropriateness of retention factors to be used in correlation with aldose reductase inhibitory activity was further evaluated and compared to the efficiency of the corresponding octanol-water log P values. © 2009 Elsevier B.V. All rights reserved

Strain profiles in overcritical (001) ZnSe GaAs heteroepitaxial layers

ZnSe layers of various thicknesses have been grown epitaxially on (001)-oriented GaAs substrates by metalorganic vapor phase epitaxy and studied by x-ray diffraction and Raman scattering. Consistent results have been found for the in-plane strains of both, ZnSe layers below and above the critical value of plastic relaxation. The experimental results are well described by strain profiles which are evaluated by an energy model and a geometrical model including the effects of strain and work hardening. The thickness-dependent full widths at half maximum of the x-ray reflections and the Raman resonances are accounted for by assuming uncorrelated misfit dislocations in the layers. (C) 1999 American Institute of Physics. [S0021-8979(99)00813-0]

Microstructural differences of the two possible orientations of GaAs on vicinal (0 0 1) Si substrates

Two alternative orientations of a GaAs layer in respect to a vicinal (0 0 1) substrate, misoriented toward [1 1 0], are possible for most of the miscut angles; type A orientation having the GaAs [1 1 0] parallel to the [1 1 0] Si misorientation direction and type B with the GaAs [1 1̄ 0] parallel to the [1 1 0] Si direction. The dependence of the GaAs surface roughness and of the tilting between the GaAs and Si (0 0 1) planes on the GaAs/Si orientation and the miscut angle of the vicinal substrate, in the range of 0-9°, has been investigated. The GaAs/Si surface roughness was characteristic for preferential growth along [1 1̄ 0]. Thin GaAs films of approximately 2 μm thickness exhibited an almost constant rms roughness of 6.5-7.0 nm for the type A orientation, while the rms roughness varied in the range of 4.2-60 nm for the type B orientation, depending on the value of the miscut angle. The tilting angle between the GaAs and Si (0 0 1) planes exhibited different signs for the two types of orientation and much higher values for the type B orientation. A rather constant negative tilting was observed for type A samples, in the range of miscut angles of 1.5-7.5°. The results suggest that the GaAs/Si lattice tilting may be a sensitive index for the domain purity in the GaAs/Si films. © 2001 Elsevier Science B.V

Lipophilicity studies on pyrrolyl-acetic acid derivatives. Experimental versus predicted logP values in relationship with aldose reductase inhibitory activity

The lipophilicity of a series of pyrrolyl-acetic acid derivatives, inhibitors of the aldose reductase enzyme, was assessed by direct partitioning experiments in the n-octanol - water system. Distribution coefficients concerning both the neutral and the anionic species were compared to calculated values generated by commonly used software. The reliability of the predictions was evaluated considering the absolute differences, as well as the correlation between experimental and predicted logP or logD values. The inferior performance of the different algorithms for logD7.4 prediction should be attributed to additional sources of errors and in particular to the nonsystematic interference of ion pairing in partitioning. Although the traditional fragmental system of Rekker as modified in PrologP (logPCDR) was quite successful in logP estimation of the pyrrolyl-acetic acid derivatives, the nonlinear artificial neural network module ANN2005, implemented in the same software was found to be more consistent in reflecting the features involved in partitioning process. Plot of experimental logP versus aldose reductase inhibitory activity values revealed a definite trend in biological activity and adequate quantitative relationships were further established if, besides logP, Hammett electronic constant σ or Abraham's hydrogen bond acceptor term was included in the regression equation. Among the calculated logP, logPANN05 and ABlogP showed an analogous trend with biological activity, although leading to equations of inferior quality, whereas the other calculated logP values failed to show any regular pattern. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA