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Revisiting the Thermodynamic Stability of Indomethacin Polymorphs with Low-Frequency Vibrational Spectroscopy and Quantum Mechanical Simulations

preprint
submitted on 18.04.2018, 15:58 and posted on 19.04.2018, 13:11 by Michael Ruggiero, Joshua J. Sutton, Sara J. Fraser-Miller, Adam J. Zaczek, Timothy M. Korter, Keith Gordon, J. Axel Zeitler
The two major polymorphs of the active pharmaceutical ingredient indomethacin were studied using a combination of experimental low-frequency vibrational spectroscopies, theoretical solid-state density functional theory and \textit{ab initio} molecular dynamics calculations. The results enable a complete spectral assignment of the low-frequency IR and Raman spectra, and yield new insight into the energetic and dynamical factors present within the solids to be understood. Ultimately, these results are used to rationalize the thermodynamic properties of the two crystals, which result in a contradiction to the long-held belief that the $\gamma$-form is the more stable polymorph at ambient conditions due to its predominant abundance. Overall, the study highlights the combined role that molecular conformation, bulk packing arrangement, and intermolecular forces have on the ultimate properties of pharmaceutical crystals, and the need for detailed analyses into all of these effects in order to predict the properties of materials. 

Funding

EP/N022769/1, EP/L000202

History

Email Address of Submitting Author

mtr34@cam.ac.uk

Institution

University of Cambridge

Country

United Kingdom

ORCID For Submitting Author

0000-0003-1848-2565

Declaration of Conflict of Interest

No conflicts to declare

Exports