Linking Crystal Structure to Solubility and Hygroscopicity in Oxytetracycline Hydrochloride Forms

The present study was motivated by the unusually large differences in solubility observed between two polymorphic forms of an antibiotic active pharmaceutical ingredient, oxytetracycline hydrochloride. These differences significantly exceed typical polymorphic solubility variations. Through detailed structural analysis, we demonstrate that forms I and II are not true polymorphs but pseudopolymorphs: anhydrous salt of oxytetracycline hydrochloride (OxyCl) and its hydrate (2OxyCl·3H2O). In the course of this work, we also crystallized and characterized three new structures of hydrates, as well as one methanol and one ethanol solvate of oxytetracycline hydrochloride. Having determined the crystal structures of all known forms and supplemented this data with XRPD measurements at different humidity levels, we provide new insight into structure–property relationships within this system. Our analysis reveals that solubility and hygroscopicity are closely related to specific features of crystal packing - particularly the thickness of alternating organic and inorganic layers formed through characteristic intermolecular interactions.