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Triclabendazole: An Intriguing Case of Co-existence of Conformational and Tautomeric Polymorphism

Tothadi, Srinu and Bhogala, Balakrishna R and Gorantla, Asha R and Thakur, Tejender S and Jetti, Ram KR and Desiraju, Gautam R (2012) Triclabendazole: An Intriguing Case of Co-existence of Conformational and Tautomeric Polymorphism. In: Chemistry - An Asian Journal, 7 (2). pp. 330-342.

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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 degrees C, Delta Hf=approximate to 105 +/- 4 Jg-1) and is the more stable form at room temperature. Form II is the lower melting polymorph (m.p.: 166 degrees C, Delta Hf=approximate to 86 +/- 3 Jg-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.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to John Wiley and Sons.
Keywords: anthelmintic;co-crystals;crystal engineering;hydrogen bonds; tautomerism
Department/Centre: Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited: 12 Mar 2012 11:53
Last Modified: 14 Mar 2012 06:27
URI: http://eprints.iisc.ernet.in/id/eprint/43702

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