Modelling, solubility and pK(a) of five sparingly soluble drugs

Abstract

Drug solubility is an important aspect of drug development. The objective of this investigation was to measure solubilities of five drugs (cimetidine, phenylbutazone, fenbufen, nitrofurantoin, triamterene) at constant pH in range of temperature from 270 to 340K in three solvents: water, ethanol and 1-octanol with the dynamic-visual method and the saturation shake-flask method using spectrophotometric analysis. The Barton group contribution method was used for the calculations of molar volumes of solutes. The thermodynamic description of the solubility curves was made using the thermophysical properties obtained with the differential scanning microcalorimetry technique (DSC). The DSC measurements have shown different than existing in the literature enthalpies of melting for phenylbutazone and fenbufen. The experimental solubility data also differ from the literature data, normally measured at one, or two temperatures only. The solubility data have been correlated by means of three commonly known excess Gibbs energy, G(E) equations. The activity coefficients of drugs at saturated solutions were calculated from the experimental data. Reexamination of the pK(a) values using diluted solutions was made with the Bates-Schwarzenbach method for the pK(a) measurements. The association constants and corresponding pK(a) values of drugs were close to the most of the literature data. We hope that our new solubility data, thermophysical data, and pK(a) values will improve all prediction-methods and their precision.