The solubility of pharmaceutical and bioactive compounds in non-volatile ionic liquids can lead to their usage in pharmaceutical processing, competing directly with flammable chemicals used routinely in pharmaceutical development. The solubility of a variety of drugs and bioactive compounds, namely N-acetyl-l-cysteine, isoniazid, pyrazine-2-carboxamide (pyrazine-2-carboxamide), coumarin, 4-hydroxycoumarin, 4′-isobutylacetophenone, ibuprofen and thymoquinone, was tested in a hydrophobic ionic liquid (trihexyl(tetradecyl)phosphonium bis[(trifluoromethyl)sulfonyl]amide). The solid–liquid equilibrium (SLE) measurements have been performed using a dynamic (synthetic) method. Glass transition temperature, Tg and heat capacity at glass transition temperature, ΔCp,g, of 4′-isobutylacetophenone and (trihexyl(tetradecyl)phosphonium bis[(trifluoromethyl)sulfonyl]amide) were acquired using a differential scanning calorimetry (DSC). Dependence between hydrophobicity and melting point directs the solubility of the solutes studied in [P6,6,6,14][NTf2]. 4′-Isobutylacetophenone, thymoquinone, coumarin and ibuprofen exhibited the best solubility in the IL due to their hydrophobicity. Then, N-acetyl-l-cysteine was found to be less soluble, and later on isoniazid, 4-hydroxycoumarin and pyrazinecarboxamide showed limited solubility in IL. The solid–liquid phase equilibria of all investigated systems were described using the six different correlation equations. Considering the correlation of the phase equilibrium data, the satisfactory results which revealed a good description with an acceptable standard deviation temperature range were collected for systems with: N-acetyl-l-cysteine, coumarin, thymoquinone and ibuprofen.