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

By neglecting the kinetics of leaching, accumulation of leachables in a clinically relevant medium in contact with plastics is principally driven by the equilibrium partition coefficient between the polymer and the medium phase. Based on experimental partition coefficients for a wide set of chemically diverse compounds between low density polyethylene (LDPE) and water, a linear solvation energy relationship (LSER) model was obtained in part I of this study, reading: 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). In this part II of the study, for further evaluation and benchmarking of the LSER model ∼ 33% (n = 52) of the total observations were ascribed to an independent validation set. Calculation of partition coefficients logK_i,LDPE/W for this validation set was based on experimental LSER solute descriptors. Linear regression against the corresponding experimental values yielded R² = 0.985 and RMSE = 0.352. When using LSER solute descriptors predicted from the compound's chemical structure by means of a QSPR prediction tool, instead, R² = 0.984 and RMSE = 0.511 were obtained. These statistics are considered indicative for extractables with no experimental LSER solute descriptors available. By comparison to LSER models from the literature, a strong correlation between the quality of experimental partition coefficients and the chemical diversity of the training set to the model's predictability was observed, the latter of particular relevance for the application domain of the model. Further, to tentatively match partitioning into LDPE to partitioning into a liquid phase, partition coefficients logK_i,LDPE/W were converted into logK_{i,LDPEamorph/W} by considering the amorphous fraction of the polymer as effective phase volume only. A LSER model now recalibrated based on the observations for logK_{i,LDPEamorph/W} exhibited the constant in the equation above to now read -0.079 instead of -0.529 which rendered the model more similar to a corresponding LSER-model for n-hexadencane/water. Based on LSER system parameters available, the sorption behavior of LDPE could be efficiently compared to the one of polydimethylsiloxane (PDMS), polyacrylate (PA) and polyoxymethylene (POM). The latter, by offering capabilities for polar interactions due to their heteroatomic building blocks, exhibit stronger sorption than LDPE to the more polar, non-hydrophobic domain of sorbates up to an logK_i,LDPE/W range of 3 to 4. Above that range, all four polymers exhibited a roughly similar sorption behavior. Overall, LSERs were found to represent an accurate and user-friendly approach for the estimation of equilibrium partition coefficients involving a polymeric phase. All intrinsic input parameters can be retrieved from a free, web-based and curated database along with the outright calculation of the partition coefficient for any given neutral compound with a known structure for a given two-phased system.