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

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.

Structural and Energetic Aspects of Entacapone-Theophylline-Water Cocrystal

“…ENT-THP-water cocrystal was produced by solvent evaporation method in environmental conditions, without prior grinding, independently of using hydrate or anhydrous components as starting materials. This production method can be less restrictive and take advantage of the preferred use of the more stable theophylline anhydrous in pharmaceutical production [99]. ENT-THP-water cocrystal comprises a cocrystallization case of particular interest, as it is only formed in the presence of water.…”

“…The dehydration process of the cocrystal and the physical mixture was monitored via variable temperature ATR-FTIR analysis (Figure S6, Supplementary Materials). During heating, characteristic FTIR peaks of THP anhydrous at 1049 cm −1 , 1186 cm −1 , 1278 cm −1 , 1485 cm −1 , 2825 cm −1 , and 3120 cm −1 were revealed after 45 • C, while the dehydration of THP monohydrate occurs via a metastable state showing additional characteristic bands [98,99]. The loss of water was evident by the disappearance of the peaks at 3369 cm −1 and 3232 cm −1 , attributed to asymmetrically and symmetrically O-H stretching vibrations of hydrogen-bonded water, respectively, while the rearrangement of the hydrogen bond network associated with N-H groups shifted the peaks at the area of 3360-3310 cm −1.…”

Low- versus Mid-frequency Raman Spectroscopy for in Situ Analysis of Crystallization in Slurries

“…These modes are intrinsically sensitive to the nature of the crystal state (the polymorph). 5 The LFR spectra are similar in their information content to that of THz spectroscopy, 6,7 which has found wide application in polymorph identification. 8 For example, quantitative solid-state analysis of pharmaceutical ternary powder mixtures gave better results in terms of lower errors of prediction of the models in the LFR region when compared to the MFR region.…”

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

“… 6 , 8 , 9 Mid- and low-frequency Raman spectroscopy is sensitive to the solid-state structure and applied to identify hydrates. 10 , 11 Since terahertz (THz) radiation is located at the far-infrared region, THz spectroscopy can directly probe the lattice phonon modes originating from the crystal structure contents and specific packing. Using THz time-domain spectroscopy (THz-TDS), the identification of hydrates and anhydrates has been reported.…”

“…PXRD is widely used to identify crystalline forms in the pharmaceutical field and determine crystal structures directly. The combination of PXRD and calorimetric techniques such as differential scanning calorimetry and thermogravimetric analyses are powerful tools for evaluating the formation of hydrates and dehydrates of APIs. ,, Mid- and low-frequency Raman spectroscopy is sensitive to the solid-state structure and applied to identify hydrates. , Since terahertz (THz) radiation is located at the far-infrared region, THz spectroscopy can directly probe the lattice phonon modes originating from the crystal structure contents and specific packing. Using THz time-domain spectroscopy (THz-TDS), the identification of hydrates and anhydrates has been reported. − Also, novel solid-state density functional theory (ss-DFT) calculations for hydrate and anhydrate organic crystals have been performed to assign the vibrational modes of their THz absorption spectra. , …”