Department of Chemistry, Syracuse University, Syracuse, New York 13244, United States.
Hitachi High-Tech Corp., Ichige, Hitachinaka 312-8504, Japan.
J Phys Chem A. 2020 Nov 25;124(47):9793-9800. doi: 10.1021/acs.jpca.0c08093. Epub 2020 Nov 13.
The identification of crystalline drug polymorphs using terahertz vibrational spectroscopy is a powerful approach for the nondestructive and noninvasive characterization of solid-state pharmaceuticals. However, a complete understanding of the terahertz spectra of molecular solids is challenging to obtain because of the complex nature of the low-frequency vibrational motions found in the sub-3 THz (sub-100 cm) range. Unambiguous assignments of the observed spectral features can be achieved through quantum mechanical solid-state simulations of crystal structures and lattice vibrations utilizing the periodic boundary condition approach. The terahertz spectra of two polymorphs of enalapril maleate are presented here to demonstrate that even large pharmaceuticals can be successfully modeled using solid-state density functional theory, including cocrystalline solids comprised of multiple distinct species. These simulations enable spectral assignments to be made, but also provide insights into the conformational and cohesion energies that contribute to the polymorph stabilities. The results reveal that the Form II polymorph of enalapril maleate is the more stable of the two under ambient conditions, and that this stability is driven by a greater intermolecular cohesion energy as compared to Form I.
使用太赫兹振动光谱鉴定晶体药物多晶型体是一种用于非破坏性、非侵入性表征固态药物的有力方法。然而，由于在亚 3 太赫兹（亚 100 厘米）范围内发现的低频振动运动的复杂性，要完全理解分子固体的太赫兹光谱具有挑战性。通过利用周期性边界条件方法对晶体结构和晶格振动进行量子力学固态模拟，可以实现对观察到的光谱特征的明确分配。本文介绍了马来酸依那普利的两种多晶型体的太赫兹光谱，以证明即使是大型药物也可以成功地使用固态密度泛函理论进行建模，包括由多个不同物种组成的共晶固体。这些模拟不仅能够进行光谱分配，还可以深入了解构象和内聚能，这些因素有助于多晶型体的稳定性。结果表明，马来酸依那普利的 II 型多晶型体在环境条件下比 I 型更稳定，与 I 型相比，这种稳定性是由更大的分子间内聚能驱动的。
