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 R1110(48) of THP‐SSA are connected by stable charge‐assisted hydrogen bonds (CAHBs) N+‐H···O‐, π–π 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.
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