Isostructurality is a potential tool to design crystals with tailored arrangements, especially for multicomponent systems, but research into its formation mechanism is still limited to date. Herein, a family of spironolactone (SPI) isostructural and non-isostructural solvates was investigated to explore the selective formation of isostructural crystals. The SPI framework, dominated by van der Waals forces, is robust and flexible, with different solvent molecules in its channels playing the same structural role. The formation of the SPI isostructural solvate is a delicate energy balance between the energy loss caused by the expansion of the SPI framework and the addition of SPI···solvent interactions. Besides the size and functional groups of solvent molecules, the directionality of the SPI···solvent interactions should also be carefully considered in the isostructurality-based crystal design. In addition, weak interactions seem to be regarded as potential design elements for organic host architectures.