Single Crystal Structure of Terfenadine Form I

Terfenadine, C32H41NO2, 1, contains an α,α-diphenyl-4-piperidinomethanol moiety, which is related to the H1-receptor blocking activity, facilitating its prior use as an antihistamine drug. In addition to its bioactivity, terfenadine is useful as a model, small-molecule crystalline solid for studying several material properties. Despite a history of therapeutic use, the absence of a crystal structure has limited current studies of the physicochemical behavior of this material. In the present manuscript, the elusive X-ray crystal structure of 1 was solved and refined at 296 K using single crystals grown from a co-solvent mixture of acetonitrile:methanol:ethanol (0.50:0.25:0.25). Terfenadine crystallizes in the monoclinic space group P21/n, and exhibits a chair conformation of the piperidine ring and a gauche conformation of the n-butyl chain. Hydrogen bonds between O–H⋯O and O–H⋯N, along with weak van der Waals interactions between C16–H16B⋯H16B’–C16’ and C2–H2⋯H16A–C16A were confirmed using Hirshfeld-Surface analysis. Differential scanning calorimetry and X-ray powder diffraction confirmed that the crystal structure reported herein was that of the most thermodynamically stable monotropic polymorph of terfenadine (form I). The elusive single crystal structure of terfenadine is solved and refined. Characterization using differential scanning calorimetry and powder X-ray diffraction confirms the structure to be the thermodynamically most stable polymorph (form I).