Chiral Purity of Crystals Using Low‐Frequency Raman Spectroscopy

Abstract

The pharmaceutical industry is in need of new techniques to identify the chirality of solids due to regulatory and safety concerns regarding the biological activity of enantiomers. In this study, we present for the first time the application of low-frequency Raman spectroscopy as a new and sensitive method for analyzing the chiral purity of crystals. Using this method, we were able to identify small amounts, as low as 1 % w/w, of an enantiomer in racemic crystals. To demonstrate the capabilities of the method, we used a model system based on chiral crystals of enantiopure, racemic crystals and their mixtures in various ratios. We found that the low-frequency Raman spectra of racemic and enantiopure crystals are significantly different, reflecting the different hydrogen bond networks. Moreover, a comparison of the sensitivity of enantiomeric excess in chiral crystals to that of circular dichroism and X-ray diffraction measurements showed that low-frequency Raman attains high sensitivity comparable to chiral optical methods used for solutions. Overall, our proposed approach of using Raman spectroscopy for determining enantiomeric excess in crystals is simple, fast, and offers a high degree of chiral sensitivity.

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.…”

Polydopamine/Silver Substrates Stemmed from Chiral Silica for SERS Differentiation of Amino Acid Enantiomers

“…Among these methods, circular dichroism (CD) spectroscopy is a typical method but CD is not effective in some cases. For instance, CD is a poorly sensitive assay to detect the chirality of systems with inherently weak absorption bands, weak chiroptical signals, a low enantiomeric excess, or locally microscopic chirality. − Vibrational circular dichroism and Raman optical activity have supplemented valuable chiral information . However, the related equipments with complex optical setups are currently less popular and accessible.…”

Polarization Dependence of Low-Frequency Vibrations from Multiple Faces in an Organic Single Crystal

“…To date, many different physical techniques have been used to characterize crystalline structures, such as X-ray diffraction (XRD) [4], thermal analysis [5], and electron microscopy [6]. Recently, low-frequency (LF) Raman was presented as a tool for chiral characterization of crystalline powders [7,8].…”

“…In general, this method is considered fast, as one Raman measurement requires a few seconds while a XRD measurement normally takes over 10 min. Furthermore, higher sensitivity was established for Raman compared to XRD in crystal purity investigations [8]. LF-Raman focuses on intermolecular interactions, including shear modes, breathing modes, and hydrogen bond stretching modes, which are lower in energy and provide LF shifts.…”