Simulation and Assignment of the Terahertz Vibrational Spectra of Enalapril Maleate Cocrystal Polymorphs

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–1) 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.