Abstract
Performance of COSMO-RS method as a tool for partition and distribution modeling in 20 solvent pairs—composed of neutral or acidic aqueous solution and organic solvents of different polarity, ranging from alcohols to toluene and hexane—was evaluated. Experimental partition/distribution data of lignin-related and drug-like compounds (neutral, acidic, moderately basic) were used as reference. Several aspects of partition modeling were addressed: accounting for mutual saturation of aqueous and organic phases, variability of systematic prediction errors across solvent pairs, taking solute ionization into account. COSMO-RS was found to predict extraction outcome for both ligneous and drug-like compounds in various solvent pairs fairly well without any additional empirical input. The solvent-specific systematic errors were found to be moderate, despite being statistically significant, and related to the solvent hydrophobicity. Accounting for mutual solubilities of the two liquids was proven crucial in cases where water was considerably soluble in the organic solvent. The root mean square error of a priori logP prediction varied, depending mainly on the solvent pair, from 0.2 to 0.7, overall value being 0.6 log units. The accuracy was higher in case of hydrophilic than hydrophobic solvents. The logD predictions were less accurate, due to pKa prediction being an additional source of error, and also because of the complexity of modeling the behaviour of ionic species in the two-phase system. A simple correction for partitioning of free ions was found to notably improve logD prediction accuracy in case of the most hydrophilic organic phase (butanol/water).
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Notes
One imaginary frequency was discovered in one of the conformers of compound B17. However, considering the low numerical value of the frequency and extremely low relative abundance of the conformer, it was deemed unlikely to influence the results and was ignored.
Both literature data and computations show that the effect of small (few degrees) temperature variations on solubility is comparable with or lower than the expected error of solubility determinations (mismatch of the values from different literature sources). Therefore the difference between the mutual solubilities of liquids at 25 and ca 23 °C (conditions of logP/logD determinations) was assumed to be negligible. Therefore experimental data from Table 1 was used in logP calculations at 23 °C without alterations.
It was observed earlier [50] that in case of compounds with strongly lipophilic ionized forms the concentration of ions (in the form of ion associates) even in relatively hydrophobic organic phases (octanol, toluene) may be comparable to or exceed the concentration of the neutral species. In such cases Eq. 4 is not adequate and some form of Eq. 5 must be used.
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Acknowledgements
This work was supported by the Institutional Funding IUT20-14 from the Estonian Research Council and by the EU through the European Regional Development Fund (TK141 “Advanced materials and high-technology devices for energy recuperation systems”). Authors thank Dr. Jens Reinisch for helpful discussions. Authors also thank Dr. Joel Hawkins and Pfizer Inc. for helpful discussions and help in obtaining chemicals.
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Tshepelevitsh, S., Hernits, K. & Leito, I. Prediction of partition and distribution coefficients in various solvent pairs with COSMO-RS. J Comput Aided Mol Des 32, 711–722 (2018). https://doi.org/10.1007/s10822-018-0125-y
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DOI: https://doi.org/10.1007/s10822-018-0125-y