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.

Selective targeting of the conserved active site cysteine of Mycobacterium tuberculosis methionine aminopeptidase with electrophilic reagents

“…In this orientation, the disulfide exchange is not possible. On the other hand, the reaction between a thiol and the maleimide proceeds through the conjugation addition mechanism, also called Michael addition . In the current situation, the enone carbonyl of N ‐ethylmaleimide probably interacts with the metal center through a hydrogen bond with the bridging water, which not only stabilizes the configuration required for nucleophilic addition by the Cys105 thiol group, but also makes it more electrophilic (Fig.…”

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

“…Terada et al observed four conformational polymorphs of furosemide− nicotinamide 1:1 cocrystal [112]. A thermodynamic stability study of [116] Anthranilic acid (2) Packing Celecoxib [117] 4,4′-Bipyridine (BPY) (2) Packing Celecoxib [117] 1,2-Di(4-pyridyl) ethylene (DPE) (2) Packing Celecoxib [117] 1,2-Bis(4-pyridyl)ethane (BPE) (2) Packing Salicylic acid [118] N, N′-diacetylpiperazine (2) Packing Piroxicam [119] 4-Hydroxybenzoic acid (2) Tautomer Triclabendazole [120] 3,5-Dihydroxybenzoic acid (DHBA), 3,5-dinitrobenzoic acid (DNBA), oxalic acid, succinic acid, fumaric acid, 3,5-dinitrosalicylic acid (DNSA), maleic acid, adipic acid, glutaric acid, malonic acid (MA), salicylic acid (SA), and aspirin.…”

“…One of the polymorphs shows the piroxicam molecule as the zwitterionic form, whereas the other contains it as the non-ionized form [119]. Desiraju et al carried out several cocrystallization experiments on triclabendazole with several co-formers which included dihydroxybenzoic acid, dinitro benzoic acid, dinitro salicylic acid, oxalic acid, fumaric acid, succinic acid, glutaric acid, maleic acid, malonic acid, adipic acid, aspirin and salicylic acid [120]. This resulted in nine cocrystals of which two cocrystals were found to be tautomer A and the other seven cocrystals existed as tautomer B [120].…”

Mechanical property design of molecular solids

“…In other words, the different crystal structures show modulations at the molecular level within the same crystal packing. As the forms contain different amounts of tautomeric structures they can be classified as tautomeric polymorphs, a pair of polymorphs [67,68].…”