Crystal engineering provides practical strategies to increase the aqueous solubility and enhance the palatability of anthelminthic medications cost-effectively. Through solvothermal and mechanochemical treatments, salts were readily formed by combining TBZ with H2FU, H2MA, SAC, and H2OX. As expected, all of the salts exhibited higher solubility compared to the molecular form of TBZ, with approximately 4-fold, 21-fold, 23-fold, and 60-fold increases in solubility observed for HTBZ-HFU, HTBZ-HOX, HTBZ-SAC, and HTBZ-HMA (LAG), respectively. Although the difference in acidity between molecular TBZ and each acid plays a significant role in salt formation, it alone cannot explain the increase in solubility. For instance, despite HSAC (pKa1 of 1.60) and H2OX (pKa1 of 1.23) both being more acidic than H2MA (pKa1 of 1.93), HTBZ-HMA was found to be the most soluble salt. The crystal structure and packing of the salts were found to be crucial in determining their physicochemical properties. First, there is a noteworthy aspect in the relationship between crystal structure and the potential for crystal growth. The more soluble salts (HTBZ-HOX, HTBZ-SAC, and HTBZ-HMA) yielded highquality single crystals suitable for single-crystal X-ray diffraction. In contrast, the least soluble salt (HTBZ-HFU) formed microcrystals, and its crystal structure was determined using powder diffraction. Understanding the crystal structures of both highly and less soluble formulations is equally essential for establishing structure-property relationships. Here we show that in the least soluble salt (HTBZ-HFU), HTBZ cations have the freedom to adjust their stacking distance, forming thermodynamically stable π-π stacked columns with the anion. In the moderately soluble salts (HTBZ-HOX and HTBZ-SAC), HTBZ cations also form stable π-π stacked columns, but the arrangement of the anions influences the HTBZ•••HTBZ distance. In these salts, the acids serve as a templating agent of the HTBZ cations and influence the structure of the π-π motif, hence the physicochemical properties. Lastly, in the most soluble salt (HTBZ-HMA), the π-π stacked columns are disrupted by anions between the HTBZ cations. This packing arrangement is thermodynamically less favorable, resulting in higher solubility. This knowledge can guide the design of new and improved formulations of TBZ and related compounds.