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Three new pharmaceutical co-crystals: 1 PZA-MA (malonic acid), 2 PZA-SA (succinic acid, a new polymorph of a reported one), and 3 PZA-GA (glutaric acid) have been prepared and characterized by differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), and single-crystal X-ray diffraction. Wherein, PZA formed 1:1 co-crystals with MA and GA by acid–amide and acid–py heterosynthon, while it formed 2:1 co-crystal with SA by amide–amide homosynthon in addition to acid–amide and acid–py heterosynthon. Their melting points follow the order, PZA-GA < PZA-MA < PZA-SA, which are lower than the melting points of the individual components. Hirshfeld surface analysis revealed that N–H···O hydrogen bonding and π···π interactions for PZA in them follow the order: PZA-MA > PZA-SA > PZA-GA, while H–H and O–O interactions follow the order: PZA-MA < PZA-SA < PZA-GA. We also compared the Hirshfeld surfaces of the present co-crystals with the nine reported PZA co-crystals, which obtained important results. The studies of the solubility and dissolution showed a semiempirical inverse relationship with the melting point: the solubility follows the order, PZA-SA < PZA-GA < PZA-MA and dissolution rate follows the order, PZA-SA < PZA-MA < PZA-GA.

The protonation of different functional acidic and alkalic groups is of utmost importance for the crystal engineering field. By using hydrochloric acid, in this work, the amine group of 3-aminobenzoic acid (1, C7H7NO2) and the hydroxy group of (E)-4-hydroxy-3,5-dimethoxybenzaldehyde oxime (2, C9H11NO4) have been protonated, giving birth to the organic salts [C7H8NO2]+·[Cl]−([1H]+·[Cl]–) and [C9H12NO4]+·[Cl]−([2H]+·[Cl]–). Results revealed that both salts display similar 1D “stair-like” ribbon models via the formation of intermolecular hydrogen bonding contacts between chloride ion and the protonated groups into four-membered squares. Note that the protonated acidic groups have shown much closer and stronger intermolecular interactions than the alkalic groups. In addition, 3D Hirshfeld surfaces, 2D fingerprint plots, and crystal void calculations have been performed, which have suggested 21.4% and 17.5% interactions around the protonated acidic and alkalic groups, respectively. This work will provide a new insight into the rational design and control of molecular crystal with protonated functional groups.