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.
Terahertz time-domain spectroscopy in a transmission geometry combined with visual analysis was used to investigate the crystallization process of MgSO 4 solution. Careful spectral analysis of both a feature at 1.6 THz and the overall magnitude of absorption allowed the extraction of information about the liquid phase before and during crystallization, aiding the investigation of solvation dynamics and the behavior of molecular species at phase boundaries. The method was reproducibly applied to a number of measurements on a series of solutions of three chosen concentrations at different temperatures. When increasing temperature at the end of the measurement, the dissolution of crystals was observed as well. The temperature-dependent absorption data of the semicrystalline systems were converted to the solvent concentrations using a recently developed method. Solutions of a series of concentrations were also investigated in the temperature range of 4–25 °C. The results were compared to the theoretical calculated values, and the consistent differences proved the existence of a hydration shell around the salt ions whose behavior is different from bulk water. Future work will focus on triggering nucleation at specific positions in order to study the very beginning of the crystallization process. MgSO 4 heptahydrate is used as a model system in this study, while the concept and the setup can be applied to other systems.
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.
Cocrystallization can provide a potential route to usability for active pharmaceutical ingredients that are eliminated in the drug discovery process due to their low bioavailability. In this work, cocrystals of urea and thiourea with glutaric acid and tartaric acid were used as model systems to experimentally and computationally investigate the intermolecular energy factors within heterogeneous molecular crystals. The tools employed in this study were low-frequency Raman vibrational spectroscopy and solid-state density functional theory (ss-DFT). The sub-200 cm–1 Raman spectra give insights into vibrations that are characteristic of the crystal packing and the intermolecular forces within the samples. ss-DFT allows for the analysis of these vibrations and of the specific energies involved in the collective cocrystal. Moreover, ss-DFT permits the computational investigation of hypothetical cocrystals, utilized here to predict the properties of the unrealized thiourea:dl-tartaric acid cocrystal. These analyses demonstrated that it is both experimentally and computationally favorable for the urea and thiourea glutaric acid cocrystals to form, as well as the urea:dl-tartaric acid cocrystal, when compared to the crystallization of the pure component materials. However, changes in the hydrogen bonding network yield a thiourea:dl-tartaric acid cocrystal that corresponds to an energetic minimum on the potential energy surface but has a Gibbs free energy that prevents it from experimental formation under ambient conditions.
The underlying mechanism of the unusual emissive behavior of [Re(CO)3-1,1bisthiazole-(1,4)-diaminobutane)] bromide (4-BT) has been investigated. Synthesis and spectroscopic characterization of structurally similar isomers ([Re(CO)3-1,1-bis-2-thiazole-(1,4)diaminobutane)] bromide (2-BT) and , location of triplet states, solid state and low temperature spectroscopic measurements, and DFT calculations show that the photophysical properties are not due to photoisomerization as previously hypothesized. The results show that the unusual emissive behavior is not observed in structural isomers, is specific to the previously reported complex, 4-BT, and may arise from vibrational energy relaxation and vibrational cooling.
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