Understanding the Metastability of Theophylline FIII by Means of Low-Frequency Vibrational Spectroscopy

 Paiva, Eduardo Maia, Qi Li, Adam J. Zaczek, Claudete F. Pereira, Jarbas José Rodrigues Rohwedder, and J. Axel Zeitler. "Understanding the Metastability of Theophylline FIII by Means of Low-Frequency Vibrational Spectroscopy." Molecular Pharmaceutics (2021).

Abstract
While theophylline has been extensively studied with multiple polymorphs discovered, there is still currently no conclusive structure for the metastable theophylline form III. In this present work, by combining more widely used techniques such as X-ray diffraction and thermogravimetric analysis with more emerging techniques like low-frequency Raman and terahertz time-domain spectroscopy, to analyze the structure and dynamics of a crystalline system, it was possible to provide further evidence that the form III structure has a theophylline monohydrate structure with the water molecules removed. Solid-state density functional theory simulations were paramount in proving that this proposed structure is correct and explain how vibrational modes within the crystal structures feature and govern polymorphic transitions and the metastable form III. Through the insight provided by both simulated and experimental results, it was possible to decisively conclude the elusive crystal structure of theophylline form III. It was also shown that the correct space group for theophylline monohydrate is not P21/n but, in fact, Pc.

for full paper see https://pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.1c0047

.......THz-TDS experiments were used to track the entire dehydration process of FM by placing the sample pellet under vacuum or by purging the sample chamber that contained the sample with a dry nitrogen gas overnight, both of which achieved the same results. In these cases, the terahertz transmission spectra were acquired with the TeraPulse 4000 spectrometer (TeraView Ltd.) at a continuous measurement interval of 10 s per spectrum for measurements acquired during a dehydration under vacuum and 5 min.....

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