The solubilities of many pharmaceutical solids are affected by the molecules crystalizing into different three-dimensional packing arrangements or polymorphs. Since multiple (and often unintended) polymorphs may form during drug manufacturing, it is critical to rapidly and accurately verify polymorph content. The two known crystalline polymorphs of ribavirin (C₈H₁₂N₄O₅), a widely applicable antiviral, are investigated in this work using low-frequency vibrational spectroscopy experiments and solid-state density functional theory (ss-DFT) simulations. Previous research has established that mechanical processes found in manufacturing can lead to the simultaneous production of both polymorphs. Distinct terahertz (far-infrared) and low-frequency Raman vibrational spectra with numerous peaks in the sub-200 cm^-1 region were obtained of the more common polymorph of ribavirin (R-II). Quantum mechanical simulations were then used to optimize the solid-state structure of R-II and calculate the frequencies and spectral intensities of the lattice vibrations in the low-frequency region. PBE-D3 with def2-TZVP was augmented with three-body repulsion and provided excellent agreement with observed structure and spectra, permitting peak assignments to be made to specific atomic motions. Experimental attempts at growing R-I, the less common metastable polymorph, yielded polymorph mixtures with a heavy R-II majority. However, the successes with R-II validated the applied computational approach for predicting the vibrational spectra of R-I, and these simulations were important for identifying the weak spectral features originating from R-I. The ss-DFT analyses also provided insights into the factors governing the relative stabilities of the two polymorphs, revealing that R-II is more stable under ambient conditions due to a stronger cohesion energy than R-I. Overall, these results demonstrate that ss-DFT can be used to accurately simulate and assign the low-frequency vibrational spectra of complex pharmaceutical solids, and predict the spectral profiles of unstable or difficult to isolate polymorphs.

Margaret Davis

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