Low-Frequency Vibrational Spectroscopy and Quantum Mechanical Simulations of the Crystalline Polymorphs of the Antiviral Drug Ribavirin

Abstract

Crystal polymorphism is a common phenomenon in pharmaceutical solids and a critical issue when considering the formulation of therapeutics since multiple polymorphs may form during drug manufacturing. Low-frequency vibrational spectroscopy is sensitive to polymorphic content, and in this work, terahertz time-domain spectroscopy and low-frequency Raman spectroscopy were utilized in the study of crystalline ribavirin, a widely applicable antiviral. Characteristic spectra with numerous peaks in the sub-200 cm –1 region were obtained of the more common polymorph of ribavirin (Form II). Solid-state density functional theory (ss-DFT) simulations were then used to optimize the crystal structure of this polymorph and calculate the frequencies and spectral intensities of the lattice vibrations in the low-frequency region. The near-harmonic thermal behavior of the sample with cooling enabled excellent agreement between experiment and theory to be achieved, emphasizing the quality of the applied model, and the observed spectral peaks could be assigned to specific atomic motions in the solid. Form I and Form II polymorphs of ribavirin were both investigated with ss-DFT to understand the different aspects governing the relative stabilities of these solids. The ss-DFT simulations of the polymorph energies revealed that Form II is more stable at all temperatures due to a stronger cohesive energy than Form I; however, ribavirin in Form I has a significantly lower conformational energy. The finding of monotropism appears to conflict with the reported enantiotropism of the ribavirin polymorphs but ultimately confirms that crystal defects in the real samples greatly affect the thermodynamic relationship of the crystals.

Where do the Fluorine Atoms Go in Inorganic‐Oxide Fluorinations? A Fluorooxoborate Illustration under Terahertz Light

“…THz spectroscopy probes optical phonon modes generated by intermolecular interactions. [25][26][27][28][29][30] Different substitutions of the fluorine and hydroxyl groups typically result in significant alterations in intermolecular interactions, exhibiting distinct fingerprint peaks in THz spectroscopy. In a prior study, we employed THz spectroscopy to elucidate the fluorine substitution sites within the anion group of the hydroxyfluoroborate compound C(NH 2 ) 3 B 3 O 3 F 2 (OH) 2 (GBF1).…”

Where do the Fluorine Atoms Go in Inorganic‐Oxide Fluorinations? A Fluorooxoborate Illustration under Terahertz Light

“…THz spectroscopy probes optical phonon modes generated by intermolecular interactions. [25][26][27][28][29][30] Different substitutions of the fluorine and hydroxyl groups typically result in significant alterations in intermolecular interactions, exhibiting distinct fingerprint peaks in THz spectroscopy. In a prior study, we employed THz spectroscopy to elucidate the fluorine substitution sites within the anion group of the hydroxyfluoroborate compound C(NH 2 ) 3 B 3 O 3 F 2 (OH) 2 (GBF1).…”

“…Terahertz (THz) spectroscopy emerges as a powerful tool in overcoming the F/OH identification challenge. THz spectroscopy probes optical phonon modes generated by intermolecular interactions [25–30] . Different substitutions of the fluorine and hydroxyl groups typically result in significant alterations in intermolecular interactions, exhibiting distinct fingerprint peaks in THz spectroscopy.…”

Low Energy Vibrations and Crystalline Structure of Ambroxol Hydrochloride by THz Spectroscopy and DFT Calculations

“…During the past few decades, the THz spectroscopy technique has been used to analyze wide range of substancesfrom DNA, [19] over explosive materials to several active pharmaceutical ingredients (API). [20][21][22][23][24] The spectrum in THz region of electromagnetic radiation (sub 200 cm À 1 ) provides information about low energy vibrational modes, which arise from interactions based on both intra-and inter-molecular characters. [25] Despite the fact that covalent intramolecular interactions are much stronger than hydrogen bonds or any other dispersion forces, intermolecular interactions characterize overall three-dimensional structure of a system.…”