Membrane Partition Coefficients Research Articles

Computational Fluid Dynamics Modeling of the Filtration of 2D Materials Using Hollow Fiber Membranes

The current study presents a computational fluid dynamics (CFDs) model designed to simulate the microfiltration of 2D materials using hollow fiber membranes from their dispersion. Microfiltration has recently been proposed as a cost-effective strategy for 2D material production, involving a dispersion containing a permeating solute (graphene), a fouling material (non-exfoliated graphite), and the solvent. The objective of the model is to investigate the effects of fouling of flat layered structure material (graphite) on the transmembrane pressure (TMP) of the system and the filtration of the permeating solute. COMSOL Multiphysics software was used to numerically solve the coupled Navier–Stokes and mass conservation equations to simulate the flow and mass transfer in the two-dimensional domain. For the TMP calculations, we used the resistance-in-series approach to link the fouling of the foulants to the TMP behavior. The foulant particles were assumed to form a polarization layer and cake on the membrane surface, leading to the increment of the TMP of the system. We also assumed the wettability of the polymeric membrane’s inner wall increases upon fouling due to the flat layered structure of the foulant, which results in the reduction in the TMP. This approach accurately reproduced the experimental TMP behavior with a Mean Absolute Error (MAE) of 0.007 psi. Furthermore, the permeation of the permeating solute was computed by incorporating a fouling-dependent membrane partition coefficient for these particles. The effects of the concentration polarization and cake formation fouling stages on the membrane partition coefficient were encapsulated into our defined model parameters, denoted as α and β, respectively. This formulation of the partition coefficient yielded permeate concentration profiles, which are in excellent agreement with the experiments. For three feed concentrations of 0.05, 0.1, and 0.3 g/L, our model reproduced the experimental permeate concentration profiles with MAEs of 0.0002, 0.0003, and 0.0022 g/L, respectively. The flexibility of this model enables the users to utilize the size and concentration-dependent α and β parameters and optimize their experimental microfiltration setups effectively.

Abstract 16947: Sotagliflozin, a Dual SGLT 1 and 2 Inhibitor, Has High Membrane Affinity and Hydrocarbon Core Location Compared With Empagliflozin

Background: The dual SGLT-1 and 2 inhibitor sotagliflozin (sota) reduced atherothrombotic events and hospitalization for worsening heart failure in patients with diabetes in clinical trials (SCORED, SOLOIST). Unlike selective SGLT2 inhibitors such as empagliflozin (empa), sota binds with higher affinity to SGLT1, which is located in the intestine, kidney, heart, brain, and vascular endothelial cells. To elucidate the physico-chemical basis for differences in tissue distribution and receptor affinity, we compared the effects of these drugs on membrane binding and molecular location. Methods: Membranes reconstituted from cardiac phospholipid and cholesterol were used to measure drug partitioning across a range of cholesterol concentrations. Multilamellar vesicles were prepared as mixtures of cardiac phospholipid (CPL), cholesterol, and each agent at 30 μM or vehicle. Drug-membrane partitioning was determined by rapid centrifugation and UV/Vis spectrophotometry. In parallel experiments, we used small angle x-ray scattering (SAXS) to identify drug location in model membranes containing phosphatidylcholine and cholesterol. Results: Sota had a membrane partition coefficient (8590 ± 2078) that was 16-fold higher than empa (519 ± 195, p<0.001) in CPL membranes. This high membrane affinity was preserved over a range of cholesterol levels compared to empa (p<0.001). Consistent with high membrane affinity, SAXS analysis showed that sota had a location evidenced by a broad increase in electron density in the hydrocarbon core extending to approximately 20 Å from the membrane center. By contrast, empa had a location limited to the polar headgroup region, consistent with its lower lipophilicity and tissue penetration. Conclusions: Sota had high membrane affinity and distinct location in the hydrocarbon core compared to empa. This may contribute to the effect of its dual SGLT-1 and 2 inhibition in vivo across various tissues including the heart. These distinct membrane interactions may also partially explain the reduced atherothrombotic risk as demonstrated in outcome trials with sota but not selective SGLT-2 inhibitors.

Exploring the kinetic selectivity of drugs targeting the β1 -adrenoceptor.

In this study, we report the β1‐adrenoceptor binding kinetics of several clinically relevant β1/2‐adrenoceptor (β1/2AR) agonists and antagonists. [3H]‐DHA was used to label CHO‐β1AR for binding studies. The kinetics of ligand binding was assessed using a competition association binding method. Ligand physicochemical properties, including logD7.4 and the immobilized artificial membrane partition coefficient (K IAM), were assessed using column‐based methods. Protein Data Bank (PDB) structures and hydrophobic and electrostatic surface maps were constructed in PyMOL. We demonstrate that the hydrophobic properties of a molecule directly affect its kinetic association rate (k on) and affinity for the β1AR. In contrast to our findings at the β2‐adrenoceptor, K IAM, reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as clogP or logD7.4, at predicting association rate. Bisoprolol proved kinetically selective for the β1AR subtype, dissociating 50 times slower and partly explaining its higher measured affinity for the β1AR. We speculate that the association of positively charged ligands at the β1AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand‐binding pocket dominate the kinetics of ligand binding. In comparison at the β2AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptor's surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on‐target and off‐target pharmacology of clinically used β‐blockers.

Eicosapentaenoic Acid (EPA) has High Affinity for Cardiac Phospholipid Membranes Compared to other Triglyceride-Lowering Agents

Background: The benefits of EPA reported in REDUCE-IT appear to extend beyond TG-lowering. EPA is known to have membrane effects, and since it is unknown if other TG-agents exhibit like qualities we compared the binding of EPA to other TG-lowering agents in membranes derived from model and cardiac phospholipids. Distinct membrane interactions may contribute to pleiotropic benefits of EPA. Methods: The membrane binding or partition coefficient (Kp ) for EPA, fenofibric and nicotinic acid was measured by rapid centrifugation methods. Membrane vesicles were reconstituted from phosphatidylcholine (PC) extracted from bovine heart tissue or 1-palmitoyl-2-oleoyl-sn-glycero-3-PC (POPC) and cholesterol. Following centrifugation, samples were analyzed for drug concentrations using UV/Vis spectrophotometry. The Kp values are expressed as the mean ± SEM. Results: The measured Kp value for EPA was 6047 ± 1520 and approximately 8-fold higher than nicotinic acid and fenofibric acid which were 737 ± 30 and 763 ± 480, respectively. The Kp values in the cardiac membranes were consistent with those measured in model membranes composed of POPC and cholesterol: the Kp value for EPA was 7829 ± 1210 and again higher than nicotinic acid and fenofibric acid which were 468 ± 27 and 51 ± 20, respectively. Conclusion: As expected, these data suggest that EPA, unlike other TG-lowering agents, is able to partition efficiently into membranes with high affinity where it may exert pleiotropic effects beyond TG-lowering such as membrane stability and inhibition of lipid oxidation. These strong membrane interactions of EPA may contribute to atheroprotective benefits beyond TG-lowering.

CFD simulation of copper(II) extraction with TFA in non-dispersive hollow fiber membrane contactors.

This study presents computational fluid dynamics (CFD) simulation of dispersion-free liquid-liquid extraction of copper(II) with trifluoroacetylacetone (TFA) in hollow fiber membrane contactor (HFMC). Mass and momentum balance Navier-Stokes equations were coupled to address the transport of copper(II) solute across membrane contactor. Model equations were simulated using COMSOL Multiphysics™. The simulation was run to study the detailed concentration distribution of copper(II) and to investigate the effects of various parameters like membrane characteristics, partition coefficient, and flow configuration on extraction efficiency. Once-through extraction was found to be increased from 10 to 100% when partition coefficient was raised from 1 to 10. Similarly, the extraction efficiency was almost doubled when porosity to tortuosity ratio of membrane was increased from 0.05 to 0.81. Furthermore, the study revealed that CFD can be used as an effective optimization tool for the development of economical membrane-based dispersion-free extraction processes.

Modelling the water–plant cuticular polymer matrix membrane partitioning of diverse chemicals in multiple plant species using the support vector machine-based QSAR approach

In this study, a support vector machine (SVM) based multi-species QSAR (quantitative structure–activity relationship) model was developed for predicting the water–plant cuticular polymer matrix membrane (MX) partition coefficient, KMXw of diverse chemicals using two simple molecular descriptors derived from the chemical structures and following the OECD guidelines. Accordingly, the Lycopersicon esculentum Mill. data were used to construct the QSAR model that was externally validated using three other plant species data. The diversity in chemical structures and end-points were verified using the Tanimoto similarity index and Kruskal–Wallis statistics. The predictive power of the developed QSAR model was tested through rigorous validation, deriving a wide series of statistical checks. The MLOGP was the most influential descriptor identified by the model. The model yielded a correlation (r2) of 0.966 and 0.965 in the training and test data arrays. The developed QSAR model also performed well in another three plant species (r2 > 0.955). The results suggest the appropriateness of the developed model to reliably predict the plant chemical interactions in multiple plant species and it can be a useful tool in screening the new chemical for environmental risk assessment.

A computational study of the inhibition mechanisms of P-glycoprotein mediated paclitaxel efflux by kinase inhibitors

BackgroundDrug resistance mediated by P-glycoprotein (P-gp) renders many cancer therapies ineffective. One P-gp substrate is the widely used chemotherapy drug paclitaxel. Co-administration of paclitaxel and another drug that inhibits P-gp may enhance the therapeutic effectiveness of paclitaxel by preventing its efflux from tumor cells.ResultsHere we present a computational approach that combines docking studies with mass action kinetic modeling to investigate how kinase inhibitors may inhibit P-gp mediated paclitaxel efflux. The results show that the inhibition can be attributed to competition between paclitaxel and a tyrosine kinase inhibitor (TKI) for the substrate binding domain (SBD) as well as competition between the kinase inhibitor and ATP for the nuclear (ATP) binding domain (NBD). The relative scales of these two competitions are TKI dependent and determined by the relative affinities of paclitaxel and TKIs to the SBD and NBD of P-gp, and their membrane partition coefficients. Additional simulations suggested that there is no single strategy to further improve the ability of TKIs to inhibit paclitaxel efflux and the most efficient way likely depends on the properties of the TKIs.ConclusionsThe developed model fits existing experimental results well and thus detailed analyses of isolated parameters provide insight into the mechanisms of rather important drug efflux. It can be used to guide how to design better TKIs or develop feasible drug combination strategies for targeting P-gp induced drug resistance.

A Hybrid All-Atom/Coarse-Grained Approach to Problems in Chemistry and Biology

Molecular dynamics simulations offer a unique tool to study chemical and biological processes at the microscopic level. Usually one has to make a choice between an all-atom (AA) model that is accurate but limited in the spatial and temporal scales that can be affordably simulated, and a coarse-grained (CG) model that is less accurate but can be used to simulate large systems for longer times. Unfortunately, this dichotomy renders some problems currently intractable. Therefore, we developed a hybrid approach where an AA solute is coupled with a CG solvent model. This novel method is a unique and complementary biophysical technique and can be used to study important chemical and biological problems. The hybrid AA/CG model is straightforward to use and was benchmarked on the membrane transfer of amino acid analogs, membrane partition coefficients of small molecules and the stability of transmembrane helices. Here, we present the latest work with the AA/CG model on partition coefficient of small molecules and protein dynamics. We also present our results in the SAMPL5 blind challenge and outline future directions.

Quantitative structure–retention relationships of flavonoids unraveled by immobilized artificial membrane chromatography

The pharmacokinetic properties of flavonoids with differing degrees of lipophilicity were investigated using immobilized artificial membranes (IAMs) as the stationary phase in high performance liquid chromatography (HPLC). For each flavonoid compound, we investigated whether the type of column used affected the correlation between the retention factors and the calculated octanol/water partition (log Poct). Three-dimensional (3D) molecular descriptors were calculated from the molecular structure of each compound using i) VolSurf software, ii) the GRID method (computational procedure for determining energetically favorable binding sites in molecules of known structure using a probe for calculating the 3D molecular interaction fields, between the probe and the molecule), and iii) the relationship between partition and molecular structure, analyzed in terms of physicochemical descriptors. The VolSurf built-in Caco-2 model was used to estimate compound permeability. The extent to which the datasets obtained from different columns differ both from each other and from both the calculated log Poct and the predicted permeability in Caco-2 cells was examined by principal component analysis (PCA). The immobilized membrane partition coefficients (kIAM) were analyzed using molecular descriptors in partial least square regression (PLS) and a quantitative structure–retention relationship was generated for the chromatographic retention in the cholesterol column. The cholesterol column provided the best correlation with the permeability predicted by the Caco-2 cell model and a good fit model with great prediction power was obtained for its retention data (R2=0.96 and Q2=0.85 with four latent variables).

Structure and membrane interactions of chionodracine, a piscidin-like antimicrobial peptide from the icefish Chionodraco hamatus

Chionodracine (Cnd) is a 22-residue peptide of the piscidin family expressed in the gills of the Chionodraco hamatus as protection from bacterial infections. Here, we report the effects of synthetic Cnd on both Psychrobacter sp. TAD1 and Escherichia coli bacteria, as well as membrane models. We found that Cnd perforates the inner and outer membranes of Psychrobacter sp. TAD1, making discrete pores that cause the cellular content to leak out. Membrane disruption studies using intrinsic and extrinsic fluorescence spectroscopy revealed that Cnd behaves similarly to other piscidins, with comparable membrane partition coefficients. Membrane accessibility assays and structural studies using NMR in detergent micelles show that Cnd adopts a canonical topology of antimicrobial helical peptides, with the hydrophobic face toward the lipid environment and the hydrophilic face toward the bulk solvent. The analysis of Cnd free energy of binding to vesicles with different lipid contents indicates a preference for charged phospholipids and a more marked binding to native E. coli extracts. Taken with previous studies on piscidin-like peptides, we conclude that Cnd first adsorbs to the membrane, and then forms pores together with membrane fragmentation. Since Cnd has only marginal hemolytic activity, it constitutes a good template for developing new antimicrobial agents.

Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.

Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors.

Comparative study of the interaction of CHAPS and Triton X-100 with the erythrocyte membrane

The zwitterionic detergent CHAPS, a derivative of the bile salts, is widely used in membrane protein solubilization. It is a “facial” detergent, having a hydrophilic side and a hydrophobic back. The objective of this work is to characterize the interaction of CHAPS with a cell membrane. To this aim, erythrocytes were incubated with a wide range of detergent concentrations in order to determine CHAPS partition behavior, and its effects on membrane lipid order, hemolytic effects, and the solubilization of membrane phospholipids and cholesterol. The results were compared with those obtained with the nonionic detergent Triton X-100. It was found that CHAPS has a low affinity for the erythrocyte membrane (partition coefficient K=0.06mM−1), and at sub-hemolytic concentrations it causes little effect on membrane lipid order. CHAPS hemolysis and phospholipid solubilization are closely correlated. On the other side, binding of Triton X-100 disorders the membrane at all levels, and has independent mechanisms for hemolysis and solubilization. Differential behavior was observed in the solubilization of phospholipids and cholesterol. Thus, the detergent resistant membranes (DRM) obtained with the two detergents will have different composition. The behaviors of the two detergents are related to the differences in their molecular structures, suggesting that CHAPS does not penetrate the lipid bilayer but binds in a flat position on the erythrocyte surface, both in intact and cholesterol depleted erythrocytes. A relevant result for Triton X-100 is that hemolysis is not directly correlated with the solubilization of membrane lipids, as it is usually assumed.

By‐passing the refinery for production of high‐value BTX derivatives

By‐passing the refinery for production of high‐value BTX derivatives

1-Butanol pervaporation performance and intrinsic stability of phosphonium and ammonium ionic liquid-based supported liquid membranes

The intrinsic stabilities of simple supported liquid membranes and their pervaporative recoveries of 1-butanol from dilute aqueous solutions were investigated. Hydrophobic ammonium- and phosphonium-based room temperature ionic liquids were used as the liquid membranes. The membranes performed better than or comparably to other pervaporation membranes. 1-Butanol flux was highly positively correlated with the ionic liquid's partition coefficient for 1-butanol and was inversely correlated with the membrane's hydrophobicity and viscosity. Water flux was strongly influenced by the ionic liquid's water saturation capacity. Except at the highest temperature investigated (70°C), no trade-off was seen between separation factor and temperature. Diffusivity and activation energy results suggested the presence of water microenvironments in the membranes, which influenced permeant transport. Permeances and membrane selectivities indicated that transport was dominated by sorption rather than diffusion. Membranes' selectivities consistently increased with increasing feed concentration. Sustained pervaporation for ∼90h showed that the ionic liquid required a minimum level of hydrophobicity to produce a stable membrane. Diluting the ionic liquid with oleyl alcohol enhanced separation by increasing the membrane's partition coefficient for 1-butanol and decreasing its viscosity; albeit temporarily as the fatty alcohol was gradually leached during sustained testing.

Disruption of phosphatidylcholine monolayers and bilayers by perfluorobutane sulfonate.

Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants resistant to biological and chemical degradation due to the presence of carbon-fluorine bonds. These compounds exhibit developmental toxicity in vitro and in vivo. The mechanisms of toxicity may involve partitioning into lipid bilayers. We investigated the interaction between perfluorobutane sulfonate (PFBS), an emerging PFAA, and model phosphatidylcholine (PC) lipid assemblies (i.e., dimyristoyl-, dipalmitoyl- and distearoylphosphatidylcholine) using fluorescence anisotropy and Langmuir monolayer techniques. PFBS decreased the transition temperature and transition width of PC bilayers. The apparent membrane partition coefficients ranged from 4.9 × 10(2) to 8.2 × 10(2). The effects on each PC were comparable. The limiting molecular area of PC monolayers increased, and the surface pressure at collapse decreased in a concentration-dependent manner. The compressibility of all three PCs was decreased by PFBS. In summary, PFBS disrupted different model lipid assemblies, indicating potential for PFBS to be a human toxicant. However, the effects of PFBS are not as pronounced as those seen with longer chain PFAAs.

Nonsteroidal Anti-inflammatory Drugs Alter the Spatiotemporal Organization of Ras Proteins on the Plasma Membrane

Ras proteins on the inner leaflet of the plasma membrane signal from transient nanoscale proteolipid assemblies called nanoclusters. Interactions between the Ras lipid anchors and plasma membrane phospholipids, cholesterol, and actin cytoskeleton contribute to the formation, stability, and dynamics of Ras nanoclusters. Many small biological molecules are amphiphilic and capable of intercalating into membranes and altering lipid immiscibility. In this study we systematically examined whether amphiphiles such as indomethacin influence Ras protein nanoclustering in intact plasma membrane. We found that indomethacin, a nonsteroidal anti-inflammatory drug, induced profound and complex effects on Ras spatial organization, all likely related to liquid-ordered domain stabilization. Indomethacin enhanced the clustering of H-Ras.GDP and N-Ras.GTP in cholesterol-dependent nanoclusters. Indomethacin also abrogated efficient GTP-dependent lateral segregation of H- and N-Ras between cholesterol-dependent and cholesterol-independent clusters, resulting in mixed heterotypic clusters of Ras proteins that normally are separated spatially. These heterotypic Ras nanoclusters showed impaired Raf recruitment and kinase activation resulting in significantly compromised MAPK signaling. All of the amphiphilic anti-inflammatory agents we tested had similar effects on Ras nanoclustering and signaling. The potency of these effects correlated with the membrane partition coefficients of the individual agents and was independent of COX inhibition. This study shows that biological amphiphiles have wide-ranging effects on plasma membrane heterogeneity and protein nanoclustering, revealing a novel mechanism of drug action that has important consequences for cell signaling.

Prediction of water-phosphatidylcholine membrane partition coefficient of some drugs from their molecular structures

In this work, the phosphatidylcholine membrane-water partition coefficients (MA) of some drugs were estimated from their theoretical derived molecular descriptors by applying quantitative structure-activity relationship (QSAR) methodology. The data set consisted of 46 drugs where their log MA were determined experimentally. Descriptors used in this work were calculated by DRAGON (version 1) package, on the basis of optimized molecular structures, and the most relevant descriptors were selected by stepwise multilinear regressions (MLRs). These descriptors were used to developing linear and nonlinear models by using MLR and artificial neural networks (ANNs), respectively. During this investigation, the best QSAR model was identified when using the ANN model that produced a reasonable level of correlation coefficients (Rtrain = 0.995, Rtest = 0.948) and low standard error (SEtrain = 0.099, SEtest = 0.326). The built model was fully assessed by various validation methods, including internal and external validation test, Y-randomization test, and cross-validation (Q2 = 0.805). The results of this investigation revealed the applicability of QSAR approaches in the estimation of phosphatidylcholine membrane-water partition coefficients.

Development of a mass transfer model for simulation of sulfur dioxide removal in ceramic membrane contactors

ABSTRACTThis paper presents mass transfer simulation of sulfur dioxide (SO2) removal in a ceramic membrane contactor by means of computational fluid dynamics techniques. The membrane contactor considered here is a tubular ceramic contactor. A two‐dimensional mass transfer model was developed to describe the absorption of SO2 in N,N‐dimethylaniline as absorbent. Physical absorption was considered in this work. Computational fluid dynamics techniques were applied to solve the model equations including continuity and momentum equations. The simulations were focused on the behavior of gas and liquid phases to obtain the distribution of SO2 concentration in the membrane contactor. The effect of the operating parameters on the performance of the ceramic contactor was investigated. The simulation results revealed that the gas flow rate has significant effect on the removal of SO2, whereas the liquid flow rate does not affect the SO2 removal significantly. It is indicated that the main mass transfer resistance is located in the membrane and gas phase because of high tortuosity of the ceramic membrane and high partition coefficient for SO2 between gas and liquid phases respectively. © 2011 Curtin University of Technology and John Wiley & Sons, Ltd.

Radiotracer properties determined by high performance liquid chromatography: a potential tool for brain radiotracer discovery

Previously, development of novel brain radiotracers has largely relied on simple screening tools. Improved selection methods at the early stages of radiotracer discovery and an increased understanding of the relationships between in vitro physicochemical and in vivo radiotracer properties are needed. We investigated if high performance liquid chromatography (HPLC) methodologies could provide criteria for lead candidate selection by comparing HPLC measurements with radiotracer properties in humans. Ten molecules, previously used as radiotracers in humans, were analysed to obtain the following measures: partition coefficient (Log P); permeability (P(m)); percentage of plasma protein binding (%PPB); and membrane partition coefficient (K(m)). Relationships between brain entry measurements (Log P, P(m) and %PPB) and in vivo brain percentage injected dose (%ID); and K(m) and specific binding in vivo (BP(ND)) were investigated. Log P values obtained using in silico packages and flask methods were compared with Log P values obtained using HPLC. The modelled associations with %ID were stronger for %PPB (r(2)=0.65) and P(m) (r(2)=0.77) than for Log P (r(2)=0.47) while 86% of BP(ND) variance was explained by K(m). Log P values were variable dependant on the methodology used. Log P should not be relied upon as a predictor of blood-brain barrier penetration during brain radiotracer discovery. HPLC measurements of permeability, %PPB and membrane interactions may be potentially useful in predicting in vivo performance and hence allow evaluation and ranking of compound libraries for the selection of lead radiotracer candidates at early stages of radiotracer discovery.

Alcohol enhanced permeation in model membranes. Part II. Thermodynamic analysis of membrane partitioning

The role of solvents in drug transport has not been properly addressed in the literature, despite its well known influence on drug permeation. Previously we have conducted thermodynamic and kinetic analyses to probe the molecular mechanisms of alcohol enhanced permeation. In the present study, the influence of temperature on the partitioning of methyl paraben into silicone membranes is investigated. In line with previous membrane transport studies of methyl paraben in silicone membranes, butanol and heptanol are used as representative alcohols. The results show higher amounts of methyl paraben extracted from the silicone membrane following equilibration with butanol, at all experimental temperatures. This was in line with alcohol uptake data. In fact, a linear correlation ( r 2 ∼0.97) was found between the amount of methyl paraben in the silicone membrane and the corresponding alcohol uptake. Calculated “specific” vehicle–membrane partition coefficients for both alcohols were approximately one, suggesting that the effective concentrations of methyl paraben inside and outside the membrane were the same. Thermodynamic analysis of the alcohol–membrane partition coefficients as a function of temperature showed no apparent trend for butanol, with an associated enthalpy change of approximately zero. Conversely, there was a positive trend in the van’t Hoff plot for methyl paraben in heptanol, indicative of an exothermic process. Moreover, the partitioning trends of methyl paraben in silicone membranes obtained from membrane transport and equilibrium experiments were not the same. This reflects the fundamental differences between the calculated vehicle–membrane partition coefficients in the two studies. Finally, the findings from membrane transport and equilibrium experiments support a model of alcohol enhanced permeation where high solvent sorption promotes high solute concentrations in the overall volume of the membrane (i.e. K), thus leading to modified solute transport (i.e. increased flux). The same model also accounts for changes in membrane diffusivity (i.e. D) related to the properties of the imbibed alcohol.