In order to improve the solubility of tetrahydropalmatine (THP), based on the summary of the relationship between cocrystal/salt synthesis and conformation of the protoberberine type compounds, we hypothesized that by introducing sulfamic acid (SA) with the sulfonic acid group may form cocrystal with THP and improve the solubility of THP. An unreported pharmaceutical salt (C21H26NO4 center dot SO3NH2, THP-SA) with supramolecular helical structure of THP and SA was designed and synthesized, and its structural characterization and properties were investigated. Structural analysis showed that the pharmaceutical salt with supramolecular helical structure were formed by introducing SA with THP. In THP-SA pharmaceutical salts, the protons of hydroxyl groups on the introduced SA were transferred to the nitrogen atom of the THP via charge-assisted hydrogen bonding (+) CAHBs (N+-H center dot center dot center dot O-) to form a stable crystal structure. Meanwhile, the S atom in the sulfamic acid forms an angle of 116.16 degrees with the O atom, so that the two THP and the two SA are connected sequentially by the 116.16 degrees angle formed between the S atom and the O atom under the action of C-H center dot center dot center dot O hydrogen bond to form the R-4(3)(17) supramolecular synthons. And THP and SA are alternately connected by C-H center dot center dot center dot O hydrogen bonds, forming a left-handed helical chain and a right-handed helical chain along the a-axis, and the left-handed helical chains and right-handed helical chains are connected by C-H center dot center dot center dot O hydrogen bonds formed between the O atoms in SA and the C atoms in THP to form a 3D supramolecular double helix structure. As expected, solubility studies showed that the solubility of THP-SA was significantly improved compared to that of THP. The reason may be that the introduction of SA makes THP and SA form a helical steric structure, and the intermolecular arrangement tightness is reduced, which is conducive to the entry of water molecules. And THP and SA depend on CAHBs to form pharmaceutical salts, which changes THP from neutral to ionized, resulting in increased solubility of THP. This work implies that THP can improve its physicochemical properties by introducing special coformers to form pharmaceutical salts with supramolecular helical structure, which provides a theoretical basis for the subsequent improvement of the physicochemical properties of the protoberberine type compounds.
