Solubility analysis of 18 active pharmaceutical ingredients and intermediates in the non-polar solvents dioxane, toluene and cyclopentyl methyl ether

The temperature dependent solubility of 18 organic compounds, of which some are active pharmaceutical ingredients, was measured in 1,4-dioxane, toluene and cyclopentyl methyl ether over a temperature range between 0 and 70 °C using a turbidity method. The solubility of the studied compounds in the three solvents increases with temperature in all binary solute-solvent systems, and all compounds exhibit a higher solubility in 1,4-dioxane than in toluene and cyclopentyl methyl ether. The non-ideal behaviour of the binary systems was evaluated in terms of the activity coefficient. All the compounds in toluene presented a positive deviation from ideal solution, while both positive and negative deviations were observed for the model compounds in the other two apolar solvents. From the solubility and the activity coefficient, a number of thermodynamic models including van't Hoff, Apelblat, λh, Margules, van Laar, Wilson, and the Non-Randomness Two Liquids (NRTL) were used for the correlation of the experimental data. The NRTL and the van't Hoff equations present closer overall correlations, while the Margules and the λh models show deviations >5 % for several compounds in the three solvent systems. The mixing thermodynamic properties of the several solute-solvent systems were further analyzed by the van ‘t Hoff and Wilson equations for a better understanding of the solution behaviour. The analysis revealed systems with apparent ideal behaviour where counteracting non-ideality effects cancel each other's.