Calculated Partition Coefficients Research Articles

Sorption kinetics and stability of conventional adsorbents for mercury remediation

In-situ remediation of mercury at numerous contaminated sites worldwide is a challenging and costly endeavor due to the persistency of this contaminant. In this study, we evaluated eight commercially available sorbent media ranging from carbon-, clays- and silica-based materials (PBC– Biochar, eSorb – Sorbster, nsPAC – Powdered Activated Carbon, fsPAC – Powdered Activated Carbon with Mackinawite, F300 – Filtrasorb 300, Si-SH – Silica Thiol, eBind – RemBind, Q-Clay – Organoclay PM-199), for their effectiveness in sorbing mercury (Hg2+) and mercury complexed with dissolved organic matter (Hg-DOM). Under the chosen experimental conditions of this study, results showed that in the absence of DOM, the kinetic rates of Hg2+ sorption onto the evaluated sorbents were in the order of 0.31 min−1(Si-SH) to 2.98 min−1 (nsPAC), whereas in the presence of DOM, the rates varied from 0.16 min−1 (F300) to 0.95 min−1 (nsPAC). The measured sorption capacity for Hg2+ in the absence of DOM varied from 3.02 mg/g (Q-Clay) to 35.15 mg/g (Si-SH), whereas in the presence of DOM, calculated partition coefficient (KD) ranged from 69.7 mL/g (Q-Clay) to 41,510 mL/g (Si-SH). Furthermore, kinetic data suggest liquid film diffusion was the rate-limiting steps governing mercury sorption onto the studied media. Overall, the obtained study parameters (kinetics/isotherm) are particularly important in informing robust engineering designs for deployment of the vast majority of evaluated sorbents. Thus, sorbent-based strategies offer viable solutions for cost-effective cleanup of mercury at industrially contaminated sites.

Benzoylation of Iota Carrageenan: Development of a Stable, Conductive, and Hydrophobic Drug Carrier with Reduced Toxicity and Improved Gel‐Forming Ability

AbstractIota carrageenan is characterized as a hydrocolloid, with the limitations of hygroscopicity and hydrophilicity. Here, each of these factors is addressed to enhance the stability, and hydrophobicity through the protection of highly reactive primary alcohol and the formation of stable, improved hydrophobic, and conductive gel for the loading of lipophilic drugs. The functionalized polymer is evaluated through the microscopic and scanning electron microscopy (SEM) image of the compounds, which confirm the confined nature of the functionalized polymer. Moreover, the values changed from compound 1 (iota carrageenan) to compound 2 (benzoyl liked iota carrageenan) included Log P (partition coefficient) from −0.97 to 0.90, calculated partition coefficient (cLog P) from −2.50 to 0.12, and total polar surface area (TPSA) from 214.1 to 208.57, which strongly suggest the enhanced hydrophobic character of functionalized polymers. The enhancement is further concluded by the loading of the lipophilic drug inside the core of functionalized polymer‐based gel. The enhanced loading of the drug clearly shows the improved hydrophobicity (56–86%) of the gel core of the functionalized compounds. In summary, a polymer with enhanced stability, hydrophobicity, conductivity, and capacity to make a more stable gel, with enhanced drug‐loading capability of water‐insoluble drugs, will be the best way to resolve the low bioavailability issue of the water‐insoluble drug.

Heterocycles 52: The Drug-Likeness Analysis of Anti-Inflammatory Thiazolo[3,2-b][1,2,4]triazole and Imidazo[2,1-b][1,3,4]thiadiazole Derivatives.

Lipophilicity, a significant physicochemical parameter of bioactive molecules, along with absorption, distribution, metabolism, excretion parameters and toxicity risk, was investigated for 32 thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives with anti-inflammatory potential. The experimental lipophilicity study was carried out by reversed-phase thin-layer chromatography in a binary isopropanol-water mobile phase, and the obtained results were compared with the theoretical lipophilicity parameters estimated by various computational methods. Strong correlations were found between the experimental retention factors and calculated partition coefficients. A modified Petra/Osiris/Molinspiration analysis was performed on the previously synthesized compounds, using SwissADME, Osiris and Molinspiration web tools. The predicted in silico parameters highlighted the most promising compounds as potential drug candidates. The compounds showed good gastrointestinal absorption, moderate activity according to the bioactivity score (values situated between -1.25 and -0.06), and a safe toxicity profile. The results obtained in this study will contribute to lipophilicity studies and other future studies focused on modulating new drug candidates starting from thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives, which are important heterocycles in medicinal chemistry.

An in-situ experimental HP/HT study on bromine release from a natural basalt

We present the first in-situ partitioning data for bromine between a natural basaltic melt and a coexisting fluid. For this study hydrothermal diamond anvil cell experiments at pressures up to 1.7 GPa were conducted. We combined laser heating to melt the basalt glass with external heating to lower the temperature gradient in the cell and to initiate circulation for the aqueous fluid. Bromine concentrations were measured in-situ with X-ray fluorescence in the basaltic melts, glasses, and in the fluid. From the results we calculated partition coefficients of DBrfluid/melt = 1.19 to 3.92 in the range of 0.4 to 1 GPa for aqueous fluids. Experiments with neon as the surrounding fluid (DBrfluid/melt = 0.38 ± 0.01 at 1.1 GPa) suggest that Br-release from a basalt into volatiles that have no bonding affinity with Br is weak. This should be the case for dry intra-plate volcanic eruptions. From the experimentally gained partition coefficients and from global Br concentration values in melt inclusions of arc magmas, we calculated an annual global Br flux of 23.5–72.9 × 109 g/y.

Lipophilic Studies and In Silico ADME Profiling of Biologically Active 2-Aminothiazol-4(5H)-one Derivatives.

Pseudothiohydantoin derivatives have a wide range of biological activities and are widely used in the development of new pharmaceuticals. Lipophilicity is a basic, but very important parameter in the design of potential drugs, as it determines solubility in lipids, nonpolar solvents, and makes it possible to predict the ADME profile. The aim of this study was to evaluate the lipophilicity of 28 pseudothiohydantoin derivatives showing the inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) using chromatographic methods. Experimentally, lipophilicity was determined by reverse phase thin layer chromatography (RP-TLC) and reverse phase high-performance liquid chromatography (RP-HPLC). In both methods, methanol was used as the organic modifier of the mobile phase. For each 2-aminothiazol-4(5H)-one derivative, a relationship was observed between the structure of the compound and the values of the lipophilicity parameters (log kw, RM0). Experimental lipophilicity values were compared with computer calculated partition coefficient (logP) values. A total of 27 of the 28 tested compounds had a lipophilicity value < 5, which therefore met the condition of Lipinski's rule. In addition, the in silico ADME assay showed favorable absorption, distribution, metabolism, and excretion parameters for most of the pseudothiohydantoin derivatives tested. The study of lipophilicity and the ADME analysis indicate that the tested compounds are good potential drug candidates.

Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration

Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (− logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24 µM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7 ± 0.5 µM, which exceeds its glioblastoma IC50 (1.17 µM) by over threefold.

Understanding Drug Skin Permeation Enhancers Using Molecular Dynamics Simulations.

Our skin constitutes an effective permeability barrier that protects the body from exogenous substances but concomitantly severely limits the number of pharmaceutical drugs that can be delivered transdermally. In topical formulation design, chemical permeation enhancers (PEs) are used to increase drug skin permeability. In vitro skin permeability experiments can measure net effects of PEs on transdermal drug transport, but they cannot explain the molecular mechanisms of interactions between drugs, permeation enhancers, and skin structure, which limits the possibility to rationally design better new drug formulations. Here we investigate the effect of the PEs water, lauric acid, geraniol, stearic acid, thymol, ethanol, oleic acid, and eucalyptol on the transdermal transport of metronidazole, caffeine, and naproxen. We use atomistic molecular dynamics (MD) simulations in combination with developed molecular models to calculate the free energy difference between 11 PE-containing formulations and the skin's barrier structure. We then utilize the results to calculate the final concentration of PEs in skin. We obtain an RMSE of 0.58 log units for calculated partition coefficients from water into the barrier structure. We then use the modified PE-containing barrier structure to calculate the PEs' permeability enhancement ratios (ERs) on transdermal metronidazole, caffeine, and naproxen transport and compare with the results obtained from in vitro experiments. We show that MD simulations are able to reproduce rankings based on ERs. However, strict quantitative correlation with experimental data needs further refinement, which is complicated by significant deviations between different measurements. Finally, we propose a model for how to use calculations of the potential of mean force of drugs across the skin's barrier structure in a topical formulation design.

Introduction of constrained Trp analogs in RW9 modulates structure and partition in membrane models

Over the past decades, many cell-penetrating peptides (CPP) have been studied for their capacity to cross cellular membranes, mostly in order to improve cellular uptake of therapeutic agents. Even though hydrophobic and anionic CPPs have been described, many of them are polycationic, due to the presence of several arginine (Arg) residues. Noteworthy, however, the presence of aromatic amino acids such as tryptophan (Trp) within CPPs seems to play an important role to reach high membranotropic activity. RW9 (RRWWRRWRR) is a designed CPP derived from the polyarginine R9 presenting both features. In general, when interacting with membranes, CPPs adopt an optimal conformation for membrane interactions – an amphipathic helical secondary structure in the case of RW9. Herein, we assumed that the incorporation of a locally constrained amino acid in the peptide sequence could improve the membranotropic activity of RW9, by facilitating its structuration upon contact with a membrane, while leaving a certain plasticity. Therefore, two cyclized Trp derivatives (Tcc and Aia) were synthesized to be incorporated in RW9 as surrogates of Trp residues. Thus, a series of peptides containing these building blocks has been synthesized by varying the type, position, and number of modifications. The membranotropic activity of the RW9 analogs was studied by spectrofluorescence titration of the peptides in presence of liposomes (DMPG), allowing to calculate partition coefficients (Kp). Our results indicate that the partitioning of the modified peptides depends on the type, the number and the position of the modification, with the best sequence being [Aia4]RW9. Interestingly, both NMR analysis and molecular dynamic (MD) simulations indicate that this analog presents an extended conformation similar to the native RW9, but with a much-reduced structural flexibility. Finally, cell internalization properties were also confirmed by confocal microscopy.

Evaluating performance of the approximate 3D-RISM-KH molecular solvation theory for solvation free energies in alkanes and alkane-water partition coefficients

The performance of the 3D-reference interaction site model (3D-RISM) with the Kovalenko-Hirata (KH) closure is benchmarked for liquid alkanes. The liquids are modelled using the united atom formalism. The intermolecular distribution functions obtained from the computations are in good agreement with the experimental reports. The solvation free energy (SFE) computed in the alkanes for a large set of solutes also agrees well with the experimental data. The molecular partition coefficients for alkane-water partition of the compounds were calculated for cyclohexane-water, alkane-water, and hexadecane-water partitions of a total of eight hundred and forty-three organic compounds with reliable accuracy. A calibration scale is proposed for alkane-water partition coefficient calculations based on the 3D-RISM-KH theory.

Continuous extraction of 2-chloroethyl isocyanate for 1-(2-chloroethyl)-3-cyclohexylurea purification

This study details the development of simulation-aided design, development, and successful operation of a continuous liquid-liquid extraction platform made with 1.5 mm tubing for the extraction of 2-chloroethyl isocyanate, an important reagent in the synthesis of cancer drugs. Preliminary solvent screening was carried out with partition coefficient calculations to determine solvents of interest. Next, batch and flow extraction experiments of 2-chloroethyl isocyanate in 2-methyl tetrahydrofuran and water were conducted to estimate extraction parameters. Following parameter estimation, experimental and model values for KLa were determined in the range of 1.13 × 10−3 to 36.0 × 10−3 s−1. Simulations of the extraction of 2-chloroethyl isocyanate were found to agree with experimental data resulting in a maximum efficiency of 77% and percent extraction of 69% for the continuous platform. Finally, model selection and discrimination was implemented for design space generation with experimental and model determined KLa values to guide lab-scale operation.

CO2‐Rich Rejuvenated Stage Lavas on Hawaiian Islands

AbstractSedimentary carbonates are sent to the deep mantle if they are not completely destroyed at subduction zones, and subducted carbonates may contribute to plume volcanism. To better constrain the role of recycled carbonates in Hawaiian volcanism, we report high‐precision olivine and whole‐rock geochemical compositions of shield and rejuvenated stage lavas from Kauai, Oahu and Maui Islands. The studied rejuvenated stage whole‐rocks have low SiO2 and high CaO concentrations, and are depleted in high field strength elements, such as, Nb and Zr, consistent with a role of carbonated melt. Rejuvenated stage olivines have Ni abundance lower than and CaO and MnO contents similar to those of shield stage at a given Fo. The calculated partition coefficients of Ca () and Mn () between olivine and shield melts are consistent with those of a dry melt system. However, the low and for rejuvenated lavas can only be explained by a volatile‐rich melt system. Based on the observed and in rejuvenated lavas, and considering the effect of H2O, our modeling calculation shows that rejuvenated primary magmas contain up to ∼10 wt% CO2, indicating a CO2‐rich mantle source. Using olivine‐spinel aluminum exchange thermometry, we show that the rejuvenated primary magma temperatures are similar to those of shield stage. We posit that the CO2‐rich rejuvenated stage lavas with lower olivine Ni than those of shield stage lavas were originated from melting of carbonated peridotites in the plume. The carbonated melts that metasomatized the peridotites were likely derived from subducted ancient carbonate‐bearing lithospheric mantle.

Efficient calculation of the free energy for protein partitioning using restraining potentials

An approach for the efficient simulation of phase-separated lipid bilayers, for use in the calculation of equilibrium free energies of partitioning between lipid domains, is proposed. The methodology exploits restraint potentials and rectangular aspect ratios that enforce lipid phase separation, allowing for the simulation of smaller systems that approximately reproduce bulk behavior. The utility of this approach is demonstrated through the calculation of potentials of mean force for the translation of a transmembrane protein between lipid domains. The impact of the imposed restraints on lipid tail ordering and lipid packing are explored, providing insight into how restraints can best be employed to compute accurate free-energy surfaces. This approach should be useful in the accurate calculation of equilibrium partition coefficients for transmembrane protein partitioning in heterogeneous membranes, providing insight into the thermodynamic driving forces that control this fundamental biophysical phenomenon.

Calculation and application of partition coefficients of light hydrocarbons in oil-based mud system

To find out the relationship between the oil-based mud, the formation fluid and the extracted gas, we use a thermodynamic approach based on static headspace gas chromatography technique to calculate the partition coefficients of 47 kinds of light hydrocarbons compounds between nC5 and nC8 in two kinds of oil-based mud-air systems, and reconstruct the original formation fluid composition under thermodynamic equilibrium. The oil-based drilling mud has little effect on the formation fluid compositions in the range of nC5–nC8 (less than 1% for low-toxicity oil-based mud and less than 10% for oil-based mud). For most light hydrocarbon compositions, the partition coefficients obtained by vapor phase calibration and the direct quantitative methods have errors of less than 10%, and the partition coefficients obtained by direct quantitative method are more accurate. The reconstructed compositions of the two kinds of crude oil have match degrees of 91% and 89% with their real compositions, proving the feasibility and accuracy of reconstructing the composition of original formation fluid by using partition coefficients of light hydrocarbon compositions between nC5 and nC8.

Occurrence, spatial distribution, and partitioning behavior of marine lipophilic phycotoxins in the Pearl River Estuary, South China

The occurrence, spatial distribution, and partitioning behavior of 17 marine lipophilic phycotoxins (MLPs) in surface and bottom seawater, particulate organic matter (POM), and surface sediment from the Pearl River Estuary (PRE) were investigated to understand current contamination and the potential risks to marine ecosystems in this region. Nine MLPs were detected, including azaspiracid1−3, gymnodimine, okadaic acid, dinophysistoxin 1−2, pectenotoxin2 (PTX2), and homoyessotoxin, with Σ17MLP concentrations ranging 545–12,600 pg L−1 and 619−8,800 pg L−1 in surface and bottom seawater, respectively; 0–294 ng g−1 and 0.307–300 ng g−1 dry weight (dw) in surface and bottom POM, respectively; and 3.90–982 pg g−1 dw in surface sediment. Lower Σ17MLP levels in the seawater were found at the mouth of the PRE, and gradually increased with increasing distance offshore. According to the calculated partition coefficient, the affinity of MLPs for the aquatic environment components was as follows (from highest to lowest): POM > seawater > sediment. Overall, the distribution and migration of MLPs in the PRE may depend on partition coefficients, the organic carbon fraction, and environmental factors.

Particle-based characterization and classification to evaluate the behavior of iron ores in drum-type wet low-intensity magnetic separation

Magnetic separation is a versatile technique widely used in the mining industry. Drum-type wet low-intensity magnetic separation (WLIMS) represents the backbone of the iron ore upgrading circuits since the mid 19th century. However, it has been traditionally applied through guidelines that commonly disregard the ore properties and their interaction with the operating conditions to influence the final process selectivity. This work describes a three-stage methodology to achieve the comprehensive characterization and classification of an iron ore, seeking to recognize links between the ore properties and operating conditions, and their influence upon the process performance. This methodology integrates 1) laboratory testing, 2) particle-scale characterization of the ore and products from separation trials, and 3) data analysis to identify and categorize the particle attributes that control their behavior in a laboratory-scale magnetic separator. Dry sieving, Saturation Magnetization Analyzer (SATMAGAN) and Mineral Liberation Analysis (MLA) represent the basis to collect quantitative particle-level information for clustering the ore into classes of unique nature. The further determination of the volumetric magnetic susceptibility by particle class, together with the relative probability of particle capture, provides valuable insight on the ore magnetic behavior. The calculation of particle-classed partition coefficients resulted practical to assess the process selectivity in terms of particle attributes and operating conditions. The methodology proposes guidelines to comprehend the behavior of an ore from a particle-scale perspective. Moreover, the acquired data can be used for geometallurgical and process modeling, which represent promising forecasting tools to support decision-making in plants.

Application of acidic deep eutectic solvents in green extraction of 5-hydroxymethylfurfural

The extraction of the 5-hydroxymethylfurfural (5-HMF), as building block for many applications, from aqueous solutions has been became an indispensable challenge. Consequently, this study investigated the extraction ability of acidic deep eutectic solvent-based aqueous two-phase system (ATPS), choline chloride as hydrogen bond acceptor (HBA) and lactic acid, oxalic acid and citric acid as hydrogen bond donor (HBD), countering polypropylene glycol 400 at T = 298.15 K. Two semi-empirical Zafarani-Moattar et al. and Merchuk equations were used to fit the measured binodal data. Further, the NRTL and UNIQUAC models were used for correlating of tie-line data. The consistency of the experimental tie-line data was determined by utilizing the Bachman-Brown and Hand correlations. Also, the performance of these ATPSs to partitioning of 5-HMF, were investigated by calculation of extraction efficiencies, EE% and partition coefficients, K. This strategy indicates DES-based ATPSs have the acceptable extraction efficiency of the 5-HMF in a single-step extraction. A greenness assessment tool, Analytical GREEnness metric (AGREE), was tested to evaluate of greenness of analytical protocol.

Fractionation of trace and platinum-group elements during metamorphism of komatiitic chromites from the early Archean Gorumahishani greenstone belt, Singhbhum Craton (eastern India)

It is well established that the major and minor element contents of chromites are subject to change during greenschist to amphibolite facies metamorphism. During upper amphibolite facies metamorphism, chromite can be completely converted to chrome magnetite. However, not all elements are affected to the same degree, the concentrations of +2 ions (e.g. Zn, Co, Mn) being particularly vulnerable to modification. The degree to which trace elements, particularly the platinum-group elements (PGE), are affected has not been closely examined. The compositions and textures of chromites from komatiites of the Gorumahishani greenstone belt of the Singhbhum Craton (India) have experienced a range of metamorphic conditions from greenschist to amphibolite facies, providing the opportunity to study the changes of trace and platinum-group element composition with metamorphic grade. Five types of altered chromites are identified from the komatiitic suite of rocks in the ~120-km-long greenstone belt. The type-I chromites are non-porous and characterized by the least modified cores. These chromites are mostly present in the northern Maharajgunj-Tua Dungri section where rocks show metamorphism from greenschist to greenschist-amphibolite transition facies. The type-II and type-III chromites are porous and mostly found in the southern Kapili section of the greenstone belt where rocks show metamorphism up to the mid-amphibolite facies. Type-IV and type-V chromites are completely modified to ferritchromit and chrome magnetite, respectively, and are present in the komatiitic rocks from the entire greenstone belt. The central cores of the type-I and type-II grains have relatively higher concentrations of mobile trace elements (e.g. Zn, Co, and Mn) with higher Mg# [Mg/(Mg + Fe2+)], lower Cr# [Cr/(Cr + Al)], and lower Fe3+/R3+ (R3+ = Fe3+ + Cr3+ + Al3+) ratios than their respective rims. Significantly higher concentrations of the immobile trace elements (e.g. Ti and V) in the cores of the type-II grains relative to their chrome magnetite rims from the Kapili section and to the type-I varieties from other sections might be due to the metamorphism of the komatiitic rocks under higher-grade conditions (amphibolite facies). In situ LA-ICPMS analysis for PGE reveals a relatively higher concentration of Ru and Rh in the rims of the type-I chromites than in the cores which is due to the diffusion of these elements from the normal spinel structure of the cores towards the bivalent octahedral sites of the inverse spinel structure of the chrome magnetite rims during metamorphic processes. The lower concentrations of Os, Ir, Ru, and Rh in the cores of the type-II chromites from the Kapili section might be related to the metamorphism of the rocks under higher-grade conditions that facilitated the diffusion of these elements to associated sulphide or platinum-group mineral or alloy phases. The calculated partition coefficients of Sc, Ti, V, Mn, Ni, Ga, Os, Ir, Ru, and Rh from the least altered chromite cores assuming equilibrium with the parental komatiitic melt also suggest the variable effects of metamorphism when compared with global experimental and empirical values of the natural samples.

Comparison of UNIFAC and LSER Models for Calculating Partition Coefficients in the Hexane–Acetonitrile System Using Middle Distillate Petroleum Products as an Example

Comparison of UNIFAC and LSER Models for Calculating Partition Coefficients in the Hexane–Acetonitrile System Using Middle Distillate Petroleum Products as an Example

Molecular Modeling of Ionic Liquids: Force‐Field Validation and Thermodynamic Perspective from Large‐Scale Fast‐Growth Solvation Free Energy Calculations

AbstractIn molecular modelling of novel solvents such as ionic liquids, it is common to scale atomic charges to improve the experiment‐simulation agreement for some selected properties. As these liquids are designed to solvate solutes, whether the solvation thermodynamics could be correctly described is of utmost importance. Therefore, we present a comprehensive large‐scale calculation of solvation free energies via nonequilibrium fast‐switching simulations for a spectrum of molecules in ionic liquids, the atomic charges of which are scaled to maximize the prediction‐experiment correlation. Further, the density‐derived choice is compared with the solvation‐thermodynamics‐derived one. When the scaling factor is decreased, the density exhibits a monotonically decreasing behavior due to weaker inter‐molecular interactions produced by scaled atomic charges. However, solvation free energies do not show consistent monotonic behaviors, which are caused by competing electrostatic and vdW responses to the scaling‐parameter variation. More intriguingly, the solvation‐free‐energy‐derived scaling factor is generally slightly higher than the density‐derived one. We further calculate partition coefficients ortransfer free energies of solutes from water to ionic liquids to provide another thermodynamic perspective of charge scaling. Another central result is the detailed evaluation of the widely used force fields for bonded and vdW terms, i.e., the GAFF derivatives.

Linear solvation energy relationships (LSERs) for robust prediction of partition coefficients between low density polyethylene and water. Part I: Experimental partition coefficients and model calibration

When equilibrium of leaching is reached within a product's duty cycle, partition coefficients polymer/solution dictate the maximum accumulation of a leachable and thus, patient exposure by leachables. Yet, in the pharmaceutical and food industry, exposure estimates based on predictive modeling typically rely on coarse estimations of the partition coefficient, with accurate and robust models lacking. This first part of the study aimed to investigate linear solvation energy relationships (LSERs) as high performing models for the prediction of partition coefficients polymer/water. For this, partition coefficients between low density polyethylene (LDPE) and aqueous buffers for 159 compounds spanning a wide range of chemical diversity, molecular weight, vapor pressure, aqueous solubility and polarity (hydrophobicity) were determined and complimentary data collected from the literature (n=159, MW: 32 to 722, logKi,O/W: -0.72 to 8.61 and logKi,LDPE/W: -3.35 up to 8.36). The chemical space represented by this compounds set is considered indicative for the universe of compounds potentially leaching from plastics. Based on the dataset for the LDPE material purified by solvent extraction, a LSER model for partitioning between LDPE and water was calibrated to give:logKi,LDPE/W=−0.529+1.098Ei−1.557Si−2.991Ai−4.617Bi+3.886Vi. The model was proven accurate and precise (n = 156, R2 = 0.991, RMSE = 0.264). Further, it was demonstrated superior over a log-linear model fitted to the same data. Nonetheless, it could be shown that log-linear correlations against logKi,O/W can be of value for the estimation of partition coefficients for nonpolar compounds exhibiting low hydrogen-bonding donor and/or acceptor propensity. For nonpolar compounds, the log - linear model was found as: logKi,LDPE/W=1.18logKi,O/W−1.33 (n = 115, R2=0.985, RMSE=0.313). In contrast, with mono-/bipolar compounds included into the regression data set, an only weak correlation was observed (n= 156, R2 = 0.930, RMSE = 0.742) rendering the log-linear model of more limited value for polar compounds. Notably, sorption of polar compounds into pristine (non-purified) LDPE was found to be up to 0.3 log units lower than into purified LDPE. To identify maximum (i. e. worst-case) levels of leaching in support of chemical safety risk assessments on systems attaining equilibrium before end of shelf-life, it appears adequate to utilize LSER - calculated partition coefficients (in combination with solubility data) by ignoring any kinetical information.