Two Anhydrous and a Trihydrate Form of Tilorone Dihydrochloride: Hydrogen-Bonding Patterns and Reversible Hydration/Dehydration Solid-State Transformation

During the polymorph screening of an active pharmaceutical ingredient tilorone dihydrochloride (chemical name 2,7-bis[2-(diethylamino)ethoxy]-9-fluorenone dihydrochloride) two new polymorphic modifications  III and IV  were obtained. The crystal structures of both polymorphs were established from X-ray powder diffraction. An interesting phenomenon has been observed at ambient conditions for III, which transforms into a novel hydrated form IIIh during 2–3 h when the humidity in the storage room increases to 70% or more. As soon as the relative humidity falls to 30% or less, IIIh transforms into the parent anhydrous form III within an hour. Form IIIh has been identified as a trihydrate of tilorone dihydrochloride, and its crystal structure has been established from X-ray powder diffraction. On the basis of the crystal structures and hydrogen-bonding patterns, a mechanistic model of reversible hydration/dehydration solid-state transformation III ↔ IIIh depending on the relative humidity is proposed.