Estimation of Ethanol/Water Solubility Profiles
Abstract (Summary)The goal of this study was to develop a simple means of estimating the cosolvent/water solubility profile using just the available properties (logKow, dielectric constant etc.) of the solute, cosolvent and water. Ethanol was used as the model cosolvent. One of the most commonly used polarity indicators is the octanol/water partition coefficient (logKow). Numerous programs are used to predict the logKow. The calculated values of logKow from three of the most commonly used programs ClogP®, ACD/logPdb® and KowWin® were compared to experimental values. It was found that all three programs have a user friendly interface but ClogP appears to be more accurate. 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 (fmax) between zero and one. A new empirical function that describes this deviation from linearity was applied to the experimental data for fifty-one compounds. The proposed model was a more accurate predictor of the co-solvent solubility profile than a general third order polynomial with the same number of parameters. The fmax value was also accurately predicted from the first derivative of the model. A sigmoidal relationship was observed between the value of fmax and logKow of the solute. Combining this sigmoidal relationship with the previously reported linear relationship between logKow and the initial slope of the plot of log 12 solubility vs. ethanol composition enables the estimation of the total ethanol/water solubility profiles of semi-polar compounds from just logKow. A new bilinear function was also introduced to address the deviation from linearity. This model accounts for both the initial and terminal slopes in the ethanol/water solubility profiles of semi-polar solutes. The proposed model is dependent only on logKow and an empirical constant that is cosolvent specific. It is also more accurate than the log-linear model and a general parabolic model. A solubility case study using Antalarmin, a novel stress inhibitor was performed. This study illustrates the use of cosolvents as solubility enhancers as well as pH, surfactants, complexants and lipid based systems.
School:The University of Arizona
School Location:USA - Arizona
Source Type:Master's Thesis
Date of Publication: