title: Triclabendazole: an intriguing case of co-existence of conformational and tautomeric polymorphism.
abstract: The crystal polymorphism of the anthelmintic drug, triclabendazole (TCB), is described. Two anhydrates (Forms I and II), three solvates, and an amorphous form have been previously mentioned. This study reports the crystal structures of Forms I (1) and II (2). These structures illustrate the uncommon phenomenon of tautomeric polymorphism. TCB exists as two tautomers A and B. Form I (Z'=2) is composed of two molecules of tautomer A while Form II (Z'=1) contains a 1:1 mixture of A and B. The polymorphs are also characterized by using other solid-state techniques (differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), PXRD, FT-IR, and NMR spectroscopy). Form I is the higher melting form (m.p.: 177 °C, ΔH(f) =≈105±4 J g(-1)) and is the more stable form at room temperature. Form II is the lower melting polymorph (m.p.:  166 °C, ΔH(f) =≈86±3 J g(-1)) and shows high kinetic stability on storage in comparison to the amorphous form but it transforms readily into Form I in a solution-mediated process. Crystal structure analysis of co-crystals 3-11 further confirms the existence of tautomeric polymorphism in TCB. In 3 and 11, tautomer A is present whereas in 4-10 the TCB molecule exists wholly as tautomer B. The DFT calculations suggest that the optimized tautomers A and B have nearly the same energies. Single point energy calculations reveal that tautomer A (in Form I) exists in two low-energy conformations, whereas in Form II both tautomers A and B exist in an unfavorable high-energy conformation, stabilized by a five-point dimer synthon. The structural and thermodynamic features of 1-11 are discussed in detail. Triclabendazole is an intriguing case in which tautomeric and conformational variations co-exist in the polymorphs.
authors.affiliation: Solid-State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Srinu
authors.initials: S
authors.lastname: Tothadi
authors.forename: Balakrishna R
authors.initials: BR
authors.lastname: Bhogala
authors.forename: Asha R
authors.initials: AR
authors.lastname: Gorantla
authors.forename: Tejender S
authors.initials: TS
authors.lastname: Thakur
authors.forename: Ram K R
authors.initials: RK
authors.lastname: Jetti
authors.forename: Gautam R
authors.initials: GR
authors.lastname: Desiraju
mesh_terms: D000871:Anthelmintics / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry*; D003460:Crystallization; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D000077682:Triclabendazole
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; D000077682:Triclabendazole