Improving Solubility and Avoiding Hygroscopicity of Tetrahydropalmatine by Forming a Pharmaceutical Salt Cocrystal via CAHBs

In order to improve the solubility of tetrahydropalmatine (THP), an unreported THP-sulfosalicylic acid (THP-SSA) pharmaceutical salt cocrystal is designed and synthesized. Structural analysis shows that the building unit of THP-SSA is composed of two THP cations, two SSA anions and one ethyl acetate molecule. Meanwhile, 1D chain, 2D layered structure, 3D hydrogen bond network, and Supramolecular motif R-10(11)(48) of THP-SSA are connected by stable charge-assisted hydrogen bonds (CAHBs) N+-H center dot center dot center dot O-, pi-pi packing, and hydrogen bond. As expected, the maximum solubility of THP-SSA in water is about 60 times that of THP, probably due to the protonation of the N atom on the piperidine ring in THP forms a pharmaceutical salt cocrystal, which greatly improves the solubility of THP. However, to the surprise, the hygroscopicity of THP-SSA is also effectively reduced compared with THP, probably because the hydrogen bonds between THP and SSA have been formed, preventing the entry of water molecules. In addition, THP-SSA also has higher antibacterial activity than THP. This suggests that forming a pharmaceutical salt cocrystal by cocrystal technology can not only improve the solubility of THP and avoid the hygroscopic property, but also improve the antibacterial activity of THP in vitro.