New Solid Forms: Structural, Supramolecular, and Dehydration-Induced Phase Transitions of Three Hydrated 17α-Alkylated Testosterone Derivatives

Synthetic derivatives of testosterone known as 17α-alkylated anabolic–androgenic steroids have been developed to retain anabolic effects while enabling oral administration. Here, we present newly identified hydrated solid forms of three agents: oxandrolone hemihydrate (C19H30O3·0.5H2O), fluoxymesterone hydrate (C20H29FO3·H2O), and methandienone hemihydrate (C20H28O2·0.5H2O). Their crystal structures were determined using single-crystal X-ray diffraction, supplemented by powder X-ray diffraction and thermal analyses. Computational methods were employed to investigate molecular interactions and crystal packing. Lattice energy evaluations revealed that the hydrated forms are energetically less stable than their anhydrous counterparts, with significantly less negative values (e.g., −113.4 kJ/mol for oxandrolone hemihydrate vs. −164.4 kJ/mol for the anhydrous form). Energy decomposition analysis indicates that while water molecules participate mostly in electrostatic-driven hydrogen bonding, they disrupt the dispersive packing efficiency found in the anhydrous phases. Specifically, intermolecular interaction energies show that host–host hydrogen bonds (up to −62.2 kJ/mol in oxandrolone) dominate over weaker host–water couplings (−8.9 to −34.9 kJ/mol). The newly reported crystal structures contribute to the expanding catalog of solid-state forms for 17α-alkylated steroids and provide important details regarding their metastable nature and the dehydration-driven phase transformations observed under climatic stress conditions.