posted on 2019-01-09, 00:00authored byPietro Sacchi, Laura Loconte, Giovanni Macetti, Silvia Rizzato, Leonardo Lo Presti
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.