Geometrical Isomerism in Guanabenz Free Base: Synthesis, Characterization, Crystal Structure, and Theoretical Studies

Abstract

Guanabenz is a drug used for the treatment of hypertension, and it exhibits isomerism and tautomerism. In this article, X-ray diffraction studies (single crystal and powder) as well as thermochemical analysis on the guanabenz have been reported. The results indicated that E/Z-isomerism in guanabenz is responsible for the identification of two solid forms, Form I (E-isomer) and Form II (Z-isomer). These two forms may be treated as geometrical polymorphs. Form I of guanabenz was already known. Identification of Form II and its X-ray structure are reported first time in this article. Quantum chemical analysis and two-dimensional fingerprint plots as Hirshfeld surfaces of these two forms highlight the differences in intermolecular hydrogen bonding, energy differences, and π-stacking interactions. The quantum chemical studies indicate that Form I (E-isomer) is more stable than Form II (Z-isomer) by 2.13 kcal/mol. The presence of Form II in the crystal structure has been rationalized by quantum chemical calculations on the basis of dimerization energies that suggest that the dimer of the Z-isomer is more stable than the dimer of the E-isomer by ∼7 kcal/mol.