Interactions of alpha-tocopherol with biomembrane models: binding to dry lecithin reversed micelles

The state of alpha-tocopherol (Vitamin E) in solutions of dry lecithin reversed micelles dispersed in an apolar medium has been investigated as a function of the Vitamin E to surfactant molar ratio (RVE) at fixed surfactant concentration by FT-IR, 1H NMR and SAXS with the aim to emphasize the role played by anisotropic intermolecular interactions and confinement effects as driving forces of its partitioning between apolar bulk solvent and polar nanodomains and of mutual Vitamin E/reversed micelle effects. It has been found that its binding strength to reversed micelles, triggered by steric and orientational constrains, is mainly regulated by specific interactions between the hydrophilic groups both of Vitamin E and surfactant. Moreover, the RVE dependence of the Vitamin E distribution constant and of the micellar size suggest that the inclusion of increasing amounts of Vitamin E in reversed micelles involves substantial changes in the structural and dynamical properties of the micellar aggregates. The occurrence of mutual effects and the partitioning of Vitamin E between hydrophilic/hydrophobic interfaces and apolar domains allow to infer some important biological implications concerning the capacity of Vitamin E to scavenge free radicals arising from hydrophilic and/or hydrophobic domains, possible variations of its local reactivity respect to that observed in bulk as well as its significant influence on the stability of biomembranes.     

The spectrophotometric study of the binding of vitamin E to water + dimethyl sulfoxide and water + diethyl sulfoxide containing reversed micelles

The effect of dimethyl sulfoxide (DMSO) and its nearest homologue diethyl sulfoxide (DESO) as a polar cosolvents on the binding of vitamin E to water + DMSO (DESO) containing reversed micelles of sodium bis(2-ethylhexyl) sulfosuccinate (AOT) has been investigated by a spectrophotometric method. The results suggest that compare with water without organic cosolvent-containing reversed micelles in this case an increase of binding constant of vitamin E in reversed micelles takes place. The results obtained shown that with the addition of DMSO and DESO it will be possible to monitoring a penetration of vitamin E into micellar core.     

Spectral Studies on the Molecular Interaction of Anticancer Drug Mitoxantrone with CTAB Micelles

The interaction of anticancer drug mitoxantrone with cationic surfactant cetyltrimethylammonium bromide (CTAB) has been investigated by absorption spectroscopy as a function of surfactant concentration ranging from the premicellar to postmicellar region at pH 7.4 and 10. Interaction of mitoxantrone with CTAB micelles induces a bathochromic shift of both absorption maxima and spectral data showed that the micellization reduces the dimerization process and mitoxantrone is bound into micelles in the monomeric form. Binding constant and partition coefficient were estimated using the red shifts of the absorption maxima in the presence of surfactant. From the resulting binding constants for mitoxantrone–surfactant interactions, it was concluded that the hydrophobic interactions have a great effect on the binding of mitoxantrone to CTAB micelles. Also, by comparing the partition coefficients obtained using pseudo-phase model, the hydrophobic interactions have a major role in the distribution of mitoxantrone between micelle–water phases. Gibbs free energy of binding and distribution of mitoxantrone between the bulk aqueous medium and surfactant micelles were calculated.     

反胶束体系的组成对胆甾醇酯酶催化水解维生素E醋酸酯活性的影响

目的考察反胶束体系的组成对胆甾醇酯酶催化水解维生素E醋酸酯活性的影响。方法以卵磷脂、聚乙二醇对辛基苯基醚为表面活性剂 ,以溶有维生素E醋酸酯的不同有机溶剂为油相制备不同反胶束溶液 ,将胆甾醇酯酶溶入制得的反胶束体系使维生素E醋酸酯水解 ,采用HPLC法测定水解产物维生素E的生成量。结果有机溶剂、体系含水量、表面活性剂和助表面活性剂及其配比对反胶束体系中酶的活性影响较大。结论 14mmol·L-1卵磷脂 6mmol·L-1胆固醇 环已烷反胶束体系 (W0 =10 5 )是胆甾醇酯酶催化水解维生素E醋酸酯的最佳反应介质     

Preservation of solubilized and emulsified systems I: Correlation of mathematically predicted preservative availability with antimicrobial activity.

Mathematical models were investigated for the distribution and antimicrobial activity of chlorocresol in solubilized and emulsified systems stabilized with a nonionic surfactant. The concentration of free preservative in the solubilized systems was described adequately by an equation widely used to describe the binding of small molecules to macromolecules. For the emulsions, this equation was combined with an expression for the partitioning of the preservative between the oil and water phases. It was confirmed that short-term antimicrobial activity can be related to the free (unbound) preservative concentration in the aqueous phase and that preservative solubilized within the surfactant micelles or partitioned into the oil phase does not contribute to short-term preservation.     

Thermodynamics of distribution of para-substituted phenols between organic solvents and sodium chloride solution

The distribution of para-substituted phenols between 8 organic solvents and 0.15 mol · dm⁻³ NaCl solution has been determined at five different temperatures using the shake-flask technique and the thermodynamic parameters for the process (ΔH and ΔS) evaluated from the van't Hoff isochore. The free energy change for the transfer of the methylene group from water to organic solvent was entropically controlled. Logarithms of distribution constants of phenols for a given organic solvent—water system were linearly related to those for other solvent systems and also to the substituent constant of Hansch. The influence of the nature of the organic solvent upon the distribution constants of phenols and the incremental distribution constants per methene group could be evaluated by the Regular Solution theory.     

Spectroscopic investigations of the molecular interaction of anticancer drug mitoxantrone with non-ionic surfactant micelles

Objectives The aim of this study was to investigate the interaction of the anticancer drug mitoxantrone with non‐ionic micelles, as simple model systems of biological membranes. Methods UV‐VIS absorption spectroscopy was used to quantify the drug–surfactant micelle interactions in terms of the binding constant and the micelle–water partition coefficient of the drug. Key findings Interaction of mitoxantrone with non‐ionic micelles reduces the dimerization process of mitoxantrone, the drug molecules being encapsulated into micelles as monomer. The strength of the interaction between mitoxantrone and non‐ionic micelles is higher at pH 10 than at pH 7.4, and depends on the surfactant in the order Tween 80 > Tween 20 > Triton X‐100. The higher partition coefficient at pH 10 compared to pH 7.4 suggests that at basic pH the deprotonated mitoxantrone is incorporated more efficiently into the hydrophobic medium of non‐ionic micelles compared to physiological pH, when the protonated drug is predominant. Conclusions These results on simple model systems miming the drug–membrane interactions contribute to the elucidation of the behaviour of the drug in vivo, as well as the possible utilization of surfactant micelles as drug carriers.     

Partition coefficients of salicylic acid between water and the micelles of some non-ionic surfactants

Partition coefficients of ionized and unionized salicylic acid molecules between water and the micelles of several non-ionic surfactants have been determined. Those of unionized molecules decreased with decreasing length of the surfactant alkyl chain and with increasing length of the surfactant polyoxyethylene chain. Ionized salicylic acid partitioned to a significant extent only into those surfactants having more than approximately 44 oxyethylene units in their hydrophile. The findings are discussed in terms of their biopharmaceutical significance.     

Solvent effects on chemical processes. I: Solubility of aromatic and heterocyclic compounds in binary aqueous-organic solvents.

The standard free energy change (delta G0) for equilibrium dissolution in binary solvent mixtures is written as a sum of effects arising from solvent-solvent interactions (the general medium effect), solvent-solute interactions (the solvation effect), and solute-solute interactions (the intersolute effect). The general medium effect is given by gA gamma, where g is a curvature correction factor to the surface tension (gamma) and A is the molecular cavity surface area. A new feature is the definition of gamma to be that value appropriate to the equilibrium mean solvation shell composition. The solvation effect is modeled by stoichiometric stepwise competitive equilibria between the two solvent components for the solute. The intersolute effect includes the crystal energy and solution phase interactions. In this work, water was solvent component 1, and various miscible organic cosolvents served as solvent component 2. Relating all data to the fully aqueous solution gives an explicit expression for delta M delta G0, the solvent effect on the free energy change, as a function of the mole fractions x1 and x2. This function is a binding isotherm. Nonlinear regression leads (for a two-step solvation scheme) to estimates of the solvation exchange constants K1 and K2 and the parameter gA. This relationship was applied to 44 systems comprising combinations of 31 solutes and eight organic cosolvents. Curve fits were good to excellent, and most of the parameter estimates had physically reasonable magnitudes.     

Micellar distribution equilibria: ultracentrifugal study of apparent partition coefficients.

Ultracentrifugation was used for the partial isolation of polysorbate 80 micelles in aqueous media to determine the apparent partition coefficients of various drug species between water and the micellar pseudophase. The ratio of solute concentration in the micelles to that in water was measured for procaine, salicylic acid, sulfapyridine, sulfisoxazole, and sodium 2-naphthalensulfonate over ranges of pH, surfactant concentration, drug concentration, and micelle sedimentation. Apparent partition coefficients for the systems investigated were independent of both drug concentration and surfactant concentration, indicating that the mode(s) of surfactant-drug interaction are essentially invariant over the ranges of systematic variables studied. The method provides a relatively simple and rapid means of quantitatively evaluating drug-surfactant interactions above the CMC, when surfactant and solute can be assayed in mixtures without interference.     

The study of the influence of surfactant charge on alkaline hydrolysis reactions of acetylsalicylic acid (ASA) and triflusal (TFL) using spectrophotometric methods.

In this research, the effects of micellar systems on alkaline hydrolysis reactions of acetylsalicylic acid (ASA) and triflusal (TFL) were found to be dependant upon the surfactant charge within the micelle. In cationic micelles, there is a catalytic effect at low concentrations of surfactant. However, this reaction is inhibited at higher surfactant concentrations. In anionic micelles, a catalytic effect occurs, while in zwitterionic and non-ionic micelles there is an inhibitory effect. Such reactions are attributable to changes in reactants on the micellar surface, or to the fact that both reactants are found in different microenvironments. The pseudophase (PS) and ion-exchange (PPIE) models were found to be consistent with the experimental result. Furthermore, the association constants for both drugs could be determined together with micellar rate constants in heterogeneous media.     

Coadsorption of the sodium salts of two steroid molecules at a silica/interface as induced by the adsorption of a cationic surfactant

The incorporation of two ionic steroids, namely the sodium salts of hydrocortisone 21-hemisuccinate (HNa) and prednisolone 21-succinate (PNa), at a silica/water interface in the presence of adsorbed cetyltrimethylammonium bromide has been investigated first at a constant pH value. It is shown that this coadsorption effect is qualitatively similar to the adsolubilization effect which is described for neutral molecules. The adsorption of the cationic surfactant induces the coadsorption of the anionic drug molecules although the silica surface is negatively charged. At surfactant equilibrium concentration above the critical micelle concentration the drug molecules are distributed between the adsorbed aggregates and the free micelles. At larger surfactant concentration, the drugs may be completely depleted from the silica/water interface. Based upon Langmuir-type isotherms, the equilibrium constants of the drug molecules with the adsorbed aggregates and the free micelles are calculated. The constants are about three times larger for the former than for the latter aggregates. The signification of such results is discussed. The coadsorption of HNa at low surfactant surface coverage was also investigated in the pH interval between 3 and 9. HNa is strongly coadsorbed at lower pH onto the silica surface. The coadsorption goes through a maximum at a pH value which may be considered as equal to the apparent pK of the drug and decreases to zero at higher pH values. A pK value equal to 4.2 is proposed for HNa. This behaviour is interpreted as the result of the interplay of the drug dissociation and that of the surface silanol groups upon the change of pH.     

Influence of the Polymer–Micelle Interaction on Micelle‐Substrate Binding

In an attempt to investigate how a nonionic polymer, hydroxypropyl methylcellulose (HPMC), interacts with a cationic surfactant, hexadecyltrimethylammonium bromide (CTAB), a dialysis method was employed for directly measuring the HPMC–CTAB interaction. The result showed that an interaction existed between CTAB and HPMC, and the higher the HPMC concentration the greater the fraction of CTAB bound. The shift in the UV spectra represents the change in the microenvironment. UV spectroscopy was employed to indicate the location of substrates, α‐NA, IBA, and oil red O, in the CTAB micelles. The study of solubility as a function of CTAB concentration was the method used for determining the binding constants of the substrates. The addition of HPMC decreased the binding constants of the substrates to the micelles. It implied that the HPMC‐CTAB interaction influenced the substrate binding regions. The IBA binding constant was also determined using a potentiometric titration method. The results agreed well between the two methods. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1440–1451, 2010     

The effect of solvent polarity on the accumulation of leachables from pharmaceutical product containers.

Material/water equilibrium interaction constants (E(b)) were determined for 12 organic model solutes and a plastic material used in pharmaceutical product containers (non-PVC polyolefin). An excellent correlation was obtained between the measured interaction constants and the organic solute's octanol/water partition coefficient. The effect of solvent polarity on E(b) was assessed by examining the interaction between the plastic and selected model solutes in binary ethanol/water mixtures. In general, logE(b) could be linearily related to the polarity of the ethanol/water mixture. This information, coupled with the interaction model, was used to estimate the levels to which container leachables could accumulate in contacted solutions. Such estimates were made for six known leachables of the polyolefin material and compared to the leachable's measured accumulation levels in binary ethanol/water systems. In general, the accumulation level of the leachables increased with increasing solution polarity. For most of the leachables, the measured accumulation level was less than the calculated levels, suggesting that equilibrium was not achieved in the leaching portion of this study. This lack of equilibrium is attributable to the layered structure of the material studied, as such layering retards the migration of the leachables that are derived from the material's non-solution contact layers.     

Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: A co-surfactant study

The purpose of this study was to evaluate the effect of process (homogenization speed and evaporation time) and formulation (aqueous/organic phase ratio, surfactant concentration, polymer type and concentration, and drug amount) variables on the preparation of paclitaxel-loaded biodegradable polymeric nanoparticles using modified solvent evaporation technique. Thereafter, a formulation was selected and subjected to evaluation of inclusion of a co-surfactant for further reduction of particle size. Particle size, encapsulation efficiency and in-vitro drug release kinetics were evaluated. It was observed that the inclusion of vitamin E TPGS (0.01%), Poloxamer 188 (0.5%) or Tween 80 (0.25%) reduced the particle size of nanoparticles to 230, 244 or 301 nm from 438 nm, respectively. Encapsulation efficiency increased for both vitamin E TPGS and Poloxamer 188 up to concentration at 0.010% and 0.25%, respectively, while this was not the case for Tween 80. Comparison of drug release kinetics demonstrated that drug release accelerated from paclitaxel-loaded biodegradable nanoparticles prepared with the inclusion of Tween 80 but was delayed for Poloxamer 188 and vitamin E TPGS. Thus, it was concluded that the particle size of the nanoparticles could be reduced further and the paclitaxel release kinetics could easily be adjusted by taking advantage by the inclusion of a co-surfactant.     

Comparison of solute-binding properties of plastic materials used as pharmaceutical product containers

Material/water equilibrium binding constants (E(b)) were determined for 11 organic solutes and 2 plastic materials commonly used in pharmaceutical product containers (plasticized polyvinyl chloride and polyolefin). In general, solute binding by the plasticized polyvinyl chloride material was greater, by nearly an order of magnitude, than the binding by the polyolefin (on an equal weight basis). The utilization of the binding constants to facilitate container compatibility assessments (e.g., drug loss by container binding) for drug-containing products is discussed.     

Effect of chemical interactions in pentachlorophenol mixtures on skin and membrane transport.

Pentachlorophenol (PCP) has been widely used as a pesticide, and topical exposure to a chemical mixture can alter its dermal absorption. The purpose of this study was to evaluate the influence of single and binary solvent systems (ethanol, EtOH, and water), a surfactant (6% sodium lauryl sulfate, SLS), and a rubifacient/vasodilator (1.28% methyl nicotinate, MNA) on PCP membrane transport, and to correlate these effects with physiochemical characteristics of the PCP mixtures. Partitioning, diffusion, and absorption parameters of (14)C-PCP at low (4 microg/cm(2)) and high (40 microg/cm(2)) doses were assessed in porcine skin and silastic membranes in vitro. In these 8-h, flow-through diffusion studies, PCP was dosed with the following vehicles: 100% EtOH, 100% water, 40% EtOH + 60% water, 40% EtOH + 60% water + SLS, 40% EtOH + 60% water + MNA, and 40% EtOH + 60% water + SLS + MNA. PCP absorption ranged from 1.55-15.62% for the high dose and 0.43-7.20% for the low dose. PCP absorption, flux, and apparent permeability were influenced by PCP solubility, and PCP apparent permeability was correlated with log PC (r2 = 0.66). Although PCP was very soluble in pure ethanol (100%), this vehicle evaporated very rapidly, and PCP absorption in ethanol was the lowest with this vehicle when compared to pure water (100%) or aqueous ethanol mixtures in general. MNA had no significant effect on membrane absorption or relative permeability R(P) in aqueous ethanol solutions, but the presence of the surfactant, SLS, significantly reduced PCP absorption and R(P) in both membrane systems. In conclusion, these studies demonstrated that modification in mixture composition with either a solvent and/or a surfactant can influence PCP diffusion in skin. Physicochemical interactions between these mixture components on the skin surface and stratum corneum contributed significantly to PCP transport, and these interactions were identified by simultaneously assessing chemical diffusion in biological and inert membrane systems.     

Poly(acrylic acid) microgels (carbopol 934)/surfactant interactions in aqueous media. Part I: nonionic surfactants

The interaction between Tween 80 and Pluronic F-127 with carbopol in water was studied as a function of surfactant concentration. 0.25% carbopol microgels dispersions showed a continuous decrease in transmittance, viscosity and conductivity when surfactant concentration ranged from 0.01-0.02% to 0.50% Tween 80 or from 0.03-0.06% to 0.30% Pluronic F-127. These limit values can be considered as the critical association concentration and the saturation binding concentration, respectively. In this concentration range, a strong rise in pH (from 3.18 to 3.50) suggested that surfactant-polymer binding occurred mainly through a stoichiometric hydrogen-bonding interaction between the oxyethylene and carboxylic groups. In the presence of carbopol, the concentration of Tween 80 at the air/water interface decreases as the surfactant is adsorbed onto the polymer and drawn into the bulk solution. In contrast, the interaction with the polymer seems to change the conformation of the expanded chains of Pluronic F-127, making it easier for more molecules of surfactant to be at the interface and increasing the thickness of the interfacial surfactant layer. Fluorescence probes indicated that the carbopol network presents a more apolar medium than pure water, and the differences in the hydrophile-lipophile balance (HLB) of each surfactant were responsible for the lower I(I)/I(III) values obtained with Tween 80/carbopol systems. Microcalorimetry titration data made it possible to conclude that Tween 80/carbopol interaction, at 298K, is an enthalpy-driven process due to stabilization of Tween 80 units inside the polymer network. In contrast, Pluronic F-127/carbopol association (endothermic process) occurs owing to a gain in entropy when polymer-surfactant interaction allows the restoration of free water hydrogen-bonding structure, resembling the micellization process.     

Excess free energy approach to the estimation of solubility in mixed solvent systems I: Theory

An approach is developed by which the solubility of an organic compound in mixed solvents may be estimated. In this approach, an expression for the excess Gibbs free energy of mixing for multicomponent solvent systems was used to obtain parameters characteristic of the interaction between the solvents. A fairly simple equation which predicts the solubility of a solute in a binary solvent system over the entire solvent composition range was then derived. The equation may be partitioned into terms that contain (a) pure solvent solubilities, (b) solvent-solvent interaction contributions, and (c) contributions from the solute-mixed solvent interactions. The required data are the molar volume of the solute, the pure solvent solubilities, and, theoretically, one experimentally determined solubility in a solvent mixture. The equation can be easily extended for systems with three or more solvents.     

Photodynamic effect in lysozyme: a kinetic study in different micellar media

Abstract: The influence of medium heterogeneity on the kinetics of the photodynamic effect on native protein lysozyme (Lyso), as well as the interaction of protein and the medium, anionic (SDS) micelles, neutral (Triton X‐100) micelles and reversed micelles of AOT, were investigated at pH 8. The interaction between Lyso, Triton X‐100 and SDS micelles was quantified by determining the respective associations constant (K_Lyso). Values were 37 m ^–1 for Triton X‐100 and 514 m ^–1 for SDS, indicating that the Lyso molecule binds Triton X‐100 micelles effectively and SDS micelles even more strongly. Time‐resolved phosphorescence detection (TRPD) indicates that the protein interacts with O₂ (¹Δ_g), with overall rate constants of the order of 10⁸ m ^–1/s in direct micelles and 10⁷ m ^–1/s in reverse micelles. Apparent reactive rate constants for eosin‐sensitized photo‐oxidation (singlet molecular oxygen [O₂ (¹Δ_g)]‐mediated) of the protein were determined through oxygen uptake experiments for the direct micelles, while the fade in the protein fluorescence spectrum upon sensitized irradiation was used in AOT. The results indicate that the O₂ (¹Δ_g) attack on the interior of Lyso on amino acid residues, was more effective in leading to a photo‐oxidative reaction in SDS and in Triton X‐100 at surfactant concentrations < 1 × 10^–2 M than in a homogeneous solution. However, Lyso reactivity reached a maximum when the concentration of micelles was ≈ 1 × 10^–5, the same as the protein concentration In AOT reverse micelles, the quenching rate constants decreased > 75% with respect to water. This effect can be attributed to the decrease in accessibility of the amino acid residues to O₂ (¹Δ_g).