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

Abstract

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  <b>III</b> and <b>IV</b>  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 <b>III</b>, which transforms into a novel hydrated form <b>IIIh</b> 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, <b>IIIh</b> transforms into the parent anhydrous form <b>III</b> within an hour. Form <b>IIIh</b> 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 <b>III</b> ↔ <b>IIIh</b> depending on the relative humidity is proposed