AbstractIn the search for a better model of the rate limiting processes in peptide transport we studied the partitioning of solutes between heptane and ethylene glycol. Methods for determining the log partition coefficient (logPH/G) in this solvent system were developed and the reproducibility and ruggedness of such determinations were assessed. The partition coefficients in this system were found to correlate (r2= 0.86, n = 11) with the permeability coefficients for a group of model peptides. To understand the physical forces governing this partitioning process, the influence of four solvatochromic parameters: hydrogen bond donor strength (α) hydrogen bond acceptor strength (β), polarity (π*), and molecular volume (V1), was evaluated for a set of 20 benzene derivatives. Multiple regression analysis revealed that the solute hydrogen bonding parameters, especially α, were the most important determinants. Molecular volume of the solute was about half as influential compared with partitioning systems in which water is the polar phase. These results suggest that the requirement for hydrogen bond breaking is the principal deterrent to peptide transport and that log PH/Gis useful in predicting permea