International Journal of Pharmaceutics 286 (2004) 111–115 Estimation of the ethanol/water solubility profile from the octanol/water partition coefficient Stephen G. Machatha ∗ , Samuel H. Yalkowsky College of Pharmacy, The University of Arizona, 1703 E. Mabel Street, Rm# 441, Tucson, AZ 85721-0207, USA Received 19 March 2004; received in revised form 7 July 2004; accepted 10 August 2004 Available online 1 October 2004 Abstract While the ethanol/water solubility profiles of very polar and very non-polar drugs are monotonic, many semi-polar drugs show a maximum solubility at an ethanol volume fraction (f max ) between 0 and 1. A sigmoidal relationship was observed between the value of f max and the log of the octanol/water partition coefficient (log K ow ) of the solute. This re- lationship reasonably predicts the value of the volume fraction of ethanol that gives maximum solubility (f max ). Com- bining this sigmoidal relationship with the previously reported linear relationship between the log K ow and the initial slope of the plot of log solubility versus ethanol composition [Li, A., Yalkowsky, S.H., 1994. Solubility of organic so- lutes in ethanol/water mixtures. J. Pharm. Sci. 83, 1735–1740] enables the estimation of the total ethanol/water solubility profile. © 2004 Elsevier B.V. All rights reserved. Keywords: Ethanol/water solubility profile; Log-linear; Sigmoidal; Prediction of maximum solubility 1. Introduction Various theories and models of cosolvency includ- ing linear and parabolic models have been proposed to predict drug solubility profiles. Paruta et al. (1964) ∗ Corresponding author. Tel.: +1 520 626 4308; fax: +1 520 626 4063. E-mail address: machatha@pharmacy.arizona.edu (S.G. Machatha). estimated solubility using a parabolic function of the dielectric constant of the solvent mixture, and Martin et al. (1979, 1981) proposed a parabolic relationship between solute solubility and the solubility parame- ter of a solvent mixture. Recently, Ruckenstein and Shulgin (2003) applied fluctuation theory to generate a new parabolic model to predict solubility in aqueous mixed solvents. Yalkowsky and Roseman (1981) and Rubino and Yalkowsky (1984) first demonstrated a log-linear rela- 0378-5173/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2004.08.005