Preparation, characterization, and crystal structures of novel sophocarpine salts with improvements on stability and solubility

Crystal engineering has proved to be an effective and reliable approach to tailor the physicochemical properties of active pharmaceutical ingredients. In this work, three novel sophocarpine salts were prepared and reported, named sophocarpine-hesperetin (SC-HES), sophocarpine-L-(-) malic acid monohydrate (SC-LMA MH), and sophocarpine-p-hydroxybenzoic acid monohydrate (SC-PHBA MH). The crystal structures of the salts were confirmed by infrared spectroscopy and single crystal X-ray diffraction. SC-HES exhibited a laminated molecular stacking structure, SC-LMA MH formed a wavy layered structure, while sophocarpine molecules filled in the voids of the reticular structure to form the 3D structure of the SC-PHBA MH. Thermal analysis shows that after salification, the melting point of the compound increased from 78°C to over 120°C, overcoming its low melting point. Lattice energy and Hirshfeld surface analysis indicated that lower lattice energy provides better thermal stability of the crystal and intermolecular hydrogen bonds (O–H···O and N→H···O) play a key role in the construction of the crystal structures. In addition, the water solubility and hygroscopicity of the three salts were characterized and discussed, with SC-HES exhibiting satisfying physical stabilities and hygroscopicity, and SC-LMA MH achieving 6.7 times solubility than the free base, which provides viable options for solid dosage form development of the drug.