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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Sutton, JJ 
Fraser-Miller, SJ 
Zaczek, AJ 

Abstract

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 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 γ-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.

Description

Keywords

34 Chemical Sciences, 3406 Physical Chemistry, 3407 Theoretical and Computational Chemistry, Bioengineering

Journal Title

Crystal Growth and Design

Conference Name

Journal ISSN

1528-7483
1528-7505

Volume Title

18

Publisher

American Chemical Society (ACS)
Sponsorship
EPSRC (1198)