Solid-State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India.
Chem Asian J. 2012 Feb 6;7(2):330-42. doi: 10.1002/asia.201100638. Epub 2011 Dec 6.
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.
本文描述了驱虫药三氯苯达唑（TCB）的晶型多态性。先前已经提到了两种无水物（形式 I 和 II）、三种溶剂化物和一种无定形形式。本研究报告了形式 I（1）和 II（2）的晶体结构。这些结构说明了互变异构多态性的罕见现象。TCB 存在两种互变异构体 A 和 B。形式 I（Z'=2）由两个 A 型分子组成，而形式 II（Z'=1）包含 A 和 B 的 1:1 混合物。还使用其他固态技术（差示扫描量热法（DSC）、热重分析（TGA）、粉末 X 射线衍射（PXRD）、傅里叶变换红外光谱（FT-IR）和 NMR 光谱）对多晶型物进行了表征。形式 I 是熔点较高的形式（熔点：177°C，ΔH(f)≈105±4 J g(-1)），在室温下是更稳定的形式。形式 II 是熔点较低的多晶型物（熔点：166°C，ΔH(f)≈86±3 J g(-1)），与无定形形式相比，在储存时表现出较高的动力学稳定性，但它在溶液介导的过程中容易转化为形式 I。共晶 3-11 的晶体结构分析进一步证实了 TCB 中互变异构多态性的存在。在 3 和 11 中存在互变异构体 A，而在 4-10 中，TCB 分子完全以互变异构体 B 存在。DFT 计算表明，优化后的互变异构体 A 和 B 具有几乎相同的能量。单点能量计算表明，互变异构体 A（在形式 I 中）存在两种低能量构象，而在形式 II 中，互变异构体 A 和 B 都存在于不利的高能构象中，由五重二聚体合成子稳定。详细讨论了 1-11 的结构和热力学特征。三氯苯达唑是一个有趣的例子，其中互变异构和构象变化在多晶型物中共存。
