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Revisiting the Thermodynamic Stability of Indomethacin Polymorphs with Low-Frequency Vibrational Spectroscopy and Quantum Mechanical Simulations
journal contribution
posted on 2018-10-08, 00:00 authored by Michael T. Ruggiero, Joshua J. Sutton, Sara J. Fraser-Miller, Adam J. Zaczek, Timothy M. Korter, Keith C. Gordon, J. Axel ZeitlerThe 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.