Enhancing the Solubility of 6‑Mercaptopurine by Formation of Ionic Cocrystal with Zinc Trifluoromethanesulfonate: Single-Crystal-to-Single-Crystal Transformation

An
antitumor drug, 6-mercaptopurine monohydrate (MP·H2O), has a low oral bioavailability due to its poor aqueous solubility.
In order to improve its solubility, two ionic cocrystals of 6-mercaptopurine
with zinc trifluoromethanesulfonate (Zn­(CF3SO3)2), [Zn­(MP)2­(H2O)2]­(CF3SO3)2­·2H2O (1) and [Zn­(MP)2]­(CF3SO3)2 (2), were prepared. Slow
evaporation of the methanol solution containing 1 gave
the crystals of [Zn­(MP)2(H2O)­(MeOH)]­(CF3SO3)2­·H2O (1a). Single-crystal-to-single-crystal transformation occurred
under certain conditions, in which 1a transformed to 1 in the open air around 10 °C, and 1 further
transformed to [Zn­(MP)2­(H2O)]­(CF3SO3)2 (1b) at room temperature
(∼25 °C) and low RH%. The structures of 1, 1a, and 1b were determined by single
crystal X-ray diffraction, in which MP and Zn­(CF3SO3)2 were assembled via coordination bonds and hydrogen
bonds, and the coordination geometry of Zn­(II) changed from octahedron
in 1 and 1a to square pyramid in 1b. After the formation of ionic cocrystals of 1 and 2, both the apparent solubility and dissolution rate were
increased.