Beyond spectral similarity: conventional electronic circular dichroism (ECD) struggles to distinguish chiral compounds with similar spectra. It is shown that solid-state circular dichroism anisotropy (CDA) probed by ECD imaging (ECDi) technique reveals key differences between two polymorphs of finasteride. Supported by TDDFT simulations, this proof-of-concept offers a new approach to resolve subtle solid-state chiral variations of any chiral compounds.

Conventional electronic circular dichroism (ECD) spectroscopy fails when it comes to distinguishing chiral compounds with identical or nearly similar spectra. But what if we could harness solid-state anisotropy to break this limitation? In this article, it is demonstrated how CD anisotropy (CDA) uncovers critical differences between two well-known packing polymorphs of finasteride despite their nearly similar pellet ECD spectra. Using ECD imaging (ECDi) and TDDFT-simulated spectra from X-ray structures, it is shown that the second polymorphic form exhibits a unique CDA signature, setting it apart from the first polymorphic form. This proof-of-concept study paves the way for a new strategy to differentiate chiral solid-state systems that conventional methods might struggle to resolve.