Correlations of Crystal Structure and Solubility in Organic Salts: The Case of the Antiplasmodial Drug Piperaquine

Five organic salts of the antiplasmodial drug piperaquine (PQ, C29H32Cl2N6) were synthesized and characterized by X-ray diffraction methods. The corresponding solubilities in water and acetic acid solutions were evaluated in the 20-50 °C (293-323 K) T range by UV-vis spectroscopy, with the aim of elucidating how they depend on chemical, structural, and thermodynamic factors. Experiments were complemented by DFT calculations, both in vacuo and in the solid state, to estimate changes in thermodynamic state functions related to the solvation process. It is demonstrated that solubility is mainly governed by the electronic and chemical properties of the anion, while lattice energies and packing effects, including in-crystal conformational changes of the drug, play a less important role. PQ salts generally conform to the predictions of hard and soft acid and bases (HSAB) theory, as less soluble compounds bear ions of comparable hardness, and vice versa. A remarkable exception is the PQ hydrogen sulfate salt, whose poor solubility can be ascribed to an exceptionally stable crystal lattice. Other factors, such as entropic effects related to solid-state disorder, can influence the response of solubility to temperature.