Spironolactone: New Polymorphic Form III and Revisiting Form II at Low Temperatures

The steroidal drug spironolactone is known for its propensity to form many polymorphs and solvate forms that are governed by dispersive interactions and hence is a subject of interest for studies of weak intermolecular interactions in crystals. We herein report a new polymorphic form III of the unsolvated spironolactone, crystallizing in a monoclinic system with Z′ = 2. Furthermore, we revisit the most common form II at lower temperatures, revealing not only the presence of dynamic disorder on three different sites in the molecule but also an order–disorder transition occurring at 155 K changing from an orthorhombic crystal system into a monoclinic with Z′ = 2 as a consequence of freezing of the disorder. The intermolecular interactions present in the polymorphic forms were investigated by means of the Hirshfeld surface and noncovalent interaction (NCI) analysis. Both methods picture the overwhelmingly dispersive nature of the interactions and additionally some weak hydrogen bonds that show only subtle differences between the polymorphs. In the discussion, we put emphasis on the effects of disorder on the Hirshfeld surface maps and fingerprint plots, pointing out typical artifacts. Finally, lattice energy calculations were performed for spironolactones I, II, and III in an attempt to understand their relative thermodynamic stability.