Solid-state vibrational circular dichroism for pharmaceutical purposes

Abstract

X-ray diffraction is commonly used in the pharmaceutical industry to determine the atomic and molecular structure of crystals. However, it is costly, sometimes time-consuming, and it requires a considerable degree of expertise. Vibrational circular dichroism (VCD) spectroscopy overcomes these drawbacks while also being highly sensitive to small changes in conformation and molecular packing in the solid phase. Here, we investigate the ability of VCD to distinguish between different crystal forms of the same molecule (polymorphs) and, thereby, identify those with the greatest pharmaceutical potential. First, we developed a universal experimental approach for obtaining reliable and reproducible solid-phase VCD spectra. Using three amino acids (serine, alanine, tyrosine) and one hydroxy acid (tartaric acid) as model pharmaceutical ingredients we investigated an effect of various experimental conditions on resulting VCD spectra. Solid samples were prepared using two techniques: (i) suspension of each model compound in oil (mulling agent); (ii) mixture of the model compound and crystalline powder (matrix) compressed into a pellet. Additionally, to achieve artifact-free results with a maximal signal-to-noise ratio, the following experimental conditions were optimized: time of spectral acquisition (0.5‒3h), mulling agent (Nujol, fluorolube), pellet size (0.7 and 20 mm in diameter) and pellet matrix (KBr, KCl, CsI). Then, the optimized approach was successfully applied to distinguish three polymorphs of the antiviral drug sofosbuvir. Our results suggest that solid-state VCD represents a relatively rapid, cost-effective, and easy-to-use structural probe for the identification of crystal structures, with potential use in pharmaceutics.

Vibrational Circular Dichroism Spectroscopy of Chiral Molecular Crystals: Insights from Theory

“…In the solid state, this can be achieved by thoroughly grinding the sample to obtain microcrystals that are dispersed in the matrix material (KBr, nujol, etc.). [3,10] In addition, spectral artefacts arise from scattering (Christiansen effect) as well as from linear birefringence and linear dichroism that have to be accounted for. [79,80] Hence, only an isotropic, artefact-free sample can deliver a VCD signal that can be calculated from the electric and magnetic transition dipole moments.…”

“…[3,5] In recent years, conducting VCD experiments on molecular solids has become increasingly important: Instead of dissolving the chiral substrate in a solvent, the sample is analysed in (micro-)crystalline form-as pellets, oil mulls or films. [10,11] IR-measurements in the solid state are an established technique, in particular using KBr pellets, but for a long time, they have not been very popular for VCD measurements, mainly due to peak artefacts and a poor signal-to-noise ratio. Yet, as Kaminsky et al pointed out, the experimental methods have improved and solid-state VCD is showing its potential for pharmaceutical purposes.…”

“…Yet, as Kaminsky et al pointed out, the experimental methods have improved and solid-state VCD is showing its potential for pharmaceutical purposes. [10] In fact, the route towards an artefact-free spectrum is well documented and while solid-state VCD has been recorded as early as 1979, [12] there have in the meantime appeared several reports indicating its capability to distinguish polymorphic forms. [13][14][15][16][17] However, the interpretation of solidstate VCD remains challenging, because it proves to be very susceptible to "crystal effects".…”