Low-Frequency Raman Spectroscopy of Pure and Cocrystallized Mycophenolic Acid.

The aqueous solubility of solid-state pharmaceuticals can often be enhanced by cocrystallization with a coformer to create a binary cocrystal with preferred physical properties. Greater understanding of the internal and external forces that dictate molecular structure and intermolecular packing arrangements enables more efficient design of new cocrystals. Low-frequency (sub-200 cm-1) Raman spectroscopy experiments and solid-state density functional theory simulations have been utilized together to investigate the crystal lattice vibrations of mycophenolic acid, an immunosuppressive drug, in its pure form and as a cocrystal with 2,2'-dipyridylamine. The lattice vibrations primarily consist of large-amplitude translations and rotations of the crystal components, thereby providing insights into the critical intermolecular forces governing cohesion of the molecular solids. The simulations reveal that despite mycophenolic acid having a significantly unfavorable conformation in the cocrystal as compared to the pure solid, the cocrystal exhibits greater thermodynamic stability over a wide temperature range. The energetic penalty due to the conformational strain is more than compensated for by the strong intermolecular forces between the drug and 2,2'-dipyridylamine. Quantifying the balance of internal and external energy factors in cocrystal formation indicates a path forward in the development of future mycophenolic acid cocrystals.

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

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.

In Situ Observation of the Structure of Crystallizing Magnesium Sulfate Heptahydrate Solutions with Terahertz Transmission Spectroscopy.

Terahertz time-domain spectroscopy in a transmission geometry combined with visual analysis was used to investigate the crystallization process of MgSO4 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. MgSO4 heptahydrate is used as a model system in this study, while the concept and the setup can be applied to other systems.

Study on Hydration and Dehydration of Ezetimibe by Terahertz Spectroscopy with Humidity-Controlled Measurements and Theoretical Analysis.

Understanding the solid-state transitions of active pharmaceutical ingredients (APIs) is essential for quality control since differences in their forms affect the bioavailability of APIs. Terahertz (THz) frequency-domain spectroscopy is suitable for such an application since it can sensitively probe the lattice phonon modes originating in the crystal structures. THz absorption spectra were obtained for ezetimibe (EZT) and ezetimibe monohydrate (EZT-MH), which have similar crystalline structures and belong to the same space group. The observed absorption spectrum of EZT matched well with the solid-state density functional theory (ss-DFT)-simulated spectrum for the structures at 0 K and room temperature (modeled using constrained unit cell volumes). However for EZT-MH, the ss-DFT spectrum of the room-temperature structure showed better correlation with the experimental THz spectrum than that of the simulated spectrum of the 0 K structures, suggesting that the EZT-MH crystal has greater anharmonic character. Gibbs free-energy curves were calculated, and EZT-MH was found to be more stable than pure EZT and water in a broad temperature range. The hydrate stability may be influenced by the existence of more hydrogen bonds in EZT-MH. The hydration and dehydration of EZT in a pure API tablet and formulation tablets were monitored using a THz spectrometer with a humidity-controlled sample chamber. The effect of the excipient in the formulation tablet on hydration was successfully confirmed by showing that the solid-state transition of the API with excipients is significantly slower than that without it. Under a relative humidity of 60%, hydration of EZT in a pure EZT tablet occurred in 200 min, while the hydration of EZT in a formulation tablet was 50 times slower.

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.