Single Crystal Structure of Terfenadine Form I

• Published in: Journal of chemical crystallography 2022-03, Vol.52 (1), p.81-88
• Main Authors: Bookwala, Mustafa, Gumireddy, Ashwini, Aitken, Jennifer A., Wildfong, Peter L. D.
• Format: Article
• Language: English
• Subjects: Acetonitrile; Analysis; Antihistamines; Bonding strength; Chemistry; Chemistry and Materials Science; Crystal growth; Crystal structure; Crystallography and Scattering Methods; Crystals; Differential scanning calorimetry; Diffraction; Ethanol; Health aspects; Heat measurement; Hydrogen; Hydrogen bonds; Inorganic Chemistry; Material properties; Molecular conformation; Organometallic Chemistry; Original Paper; Physical Chemistry; Piperidine; Single crystals; Structure; Surface analysis (chemical); Terfenadine; Thermodynamics; X ray powder diffraction; X-rays
• ISSN: 1074-1542; 1572-8854
• DOI: 10.1007/s10870-021-00892-3

Terfenadine, C 32 H 41 NO 2 , 1 , contains an α,α-diphenyl-4-piperidinomethanol moiety, which is related to the H 1 -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 P 2 1 / 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). Graphic Abstract 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).