Fourier Transform Infrared Spectroscopy and Vibrational Circular Dichroism Assisted Elucidation of the Solution-State Supramolecular Speciation in Racemic and Enantiopure Ketoprofen

Abstract

The molecular structure and solution-state molecular interactions in the popular non-steroidal anti-inflammatory drug, ketoprofen, are extensively studied with the aim of gaining a better understanding of the chemical behavior of its solution state and its connection to its nucleation pathway and crystallization outcome. Using as reference solid-state X-ray structures of enantiomeric and racemic forms of ketoprofen, a set of self-assembly models underpinned by density functional theory calculations has been considered for the analysis of spectroscopic data, infrared (IR) and vibrational circular dichroism (VCD), obtained for solutions of the samples as a function of composition and solvent. From our results it can be concluded that, contrary to the general belief for generic carboxylic acids, there are no cyclic dimeric structures of ketoprofen present in solution, but rather linear arrays made up of two (in high polar or diluted media) or more units (in low polar or low dilution media). This observation is in line with the idea that the weak contacts (other than H-bonding) would hold the key to molecular self-assembly, in agreement with recent studies on other aromatic carboxylic acids.

Chiral Monitoring Across Both Enantiomeric Excess and Concentration Space: Leveraging Quantum Cascade Lasers for Sensitive Vibrational Circular Dichroism Spectroscopy

“…6,12 In contrast, the MIR region contains bands specific to vibrations in chemical bonds, making it broadly applicable to organic molecules. 13,14 In contrast to ECD, VCD is plagued by low intensities, 10 –4 –10 –5 relative to the classical absorbance, making the measurement time-consuming, ranging from 1 h to up to 12 h depending on the sample–solvent system (but still quicker than X-ray crystallography and NMR) and restricted to highly concentrated solutions. 10,14,15 As a consequence, Fourier transform IR spectroscopy (FT-IR) VCD has mostly been routinely applied for AC determination of finished products, where concentration and time resolution restrictions are not a problem.…”

“…13,14 In contrast to ECD, VCD is plagued by low intensities, 10 –4 –10 –5 relative to the classical absorbance, making the measurement time-consuming, ranging from 1 h to up to 12 h depending on the sample–solvent system (but still quicker than X-ray crystallography and NMR) and restricted to highly concentrated solutions. 10,14,15 As a consequence, Fourier transform IR spectroscopy (FT-IR) VCD has mostly been routinely applied for AC determination of finished products, where concentration and time resolution restrictions are not a problem. 4,16 However, further applications, e.g., chiral monitoring of chemical reactions are not feasible with those restrictions in place.…”