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

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 -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.

Capabilities of low‐wavenumber Raman spectroscopy for analyzing the mechanism of devitrification of molecular glasses

“…The development of a new generation of filters makes it possible to analyze the low‐wavenumber region with routine spectrometers . A quick look at the literature in the pharmaceutical domain reveals a recent development of low‐wavenumber investigations on pharmaceuticals for different applications This study shows the powerful and the capabilities of the LWRS and how LWRS can be used for analyzing phase transformations, disorder in polymorphism situations, atypical mechanisms of crystallizations, and stability conditions in molecular materials including pharmaceuticals.…”

The Necessity of Periodic Boundary Conditions for the Accurate Calculation of Crystalline Terahertz Spectra

“…This is of critical importance, as the correct modeling of terahertz spectra implies that the simulation is fully capturing all of the interatomic forces with a high-degree of accuracy. When this criterion is met, experimental terahertz spectra can be used to validate the simulation, enabling access to many related properties that might be difficult to measure experimentally, for example thermodynamic parameters, 28 or interatomic forces. 14 These conditions lead to a powerful methodology for describing dynamic processes with atomic-level precision.…”

Chasing the “Killer” Phonon Mode for the Rational Design of Low‐Disorder, High‐Mobility Molecular Semiconductors

“…Low‐frequency spectroscopy techniques have long been used to investigate phonon modes in molecular solids, for example, in the context of pharmaceutical drug development or for identifying polymorphism in OSCs . Quantum mechanical simulations provide powerful tools to interpret the modes observed in experiments; considerable emphasis has been spent over the last decade to achieve the necessary computational accuracy required to fully capture the very weak forces that are responsible for the low‐frequency motions in van der Waals bonded molecular crystals and are more challenging to model than in more strongly bonded systems . Here we use this state‐of‐the‐art methodology to compare the vibrational dynamics of several important classes of high‐mobility molecular semiconductors.…”