Linear solvation energy relationships (LSERs) for robust prediction of partition coefficients between low density...

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, logK_i,O/W: -0.72 to 8.61 and logK_i,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:logK_i,LDPE/W=-0.529+1.098E_i-1.557S_i-2.991A_i-4.617B_i+3.886V_i. 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 logK_i,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: logK_i,LDPE/W=1.18logK_i,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.