Discriminating the Interaction Anisotropy in Polymorphs Using Powder Brillouin Light Scattering

Abstract

Drug product performance is polymorph specific, and it is imperative that solid phase stability be monitored throughout the manufacturing process to ensure final product quality and performance. PXRD remains the gold standard for polymorph identification, but due to a growing interest in continuous manufacturing, a need has emerged for alternative process analytical technologies (PATs) that can provide fast, reliable, and non-destructive polymorph discrimination amenable to in situ process monitoring. Herein we demonstrate an original application of powder Brillouin light scattering (p-BLS) for the discrimination of polymorphic molecular solids. We hypothesize that the anisotropic sound velocities directly reflect the strength and orientation of the intermolecular forces in molecular solids. Redistributing these forces upon polymorphic conversion should thus clearly be reflected in the sound frequency distributions obtained by p-BLS. To test this hypothesis, three model compounds - resorcinol, sulfamerazine and furosemide - were selected. Distinct, polymorph-specific, acoustic frequency distributions were observed, and these p-BLS spectra were interpreted using a hydrogen-bond analysis and energy frameworks calculated from CrystalExplorer. In conclusion, this study clearly demonstrates that the sound frequencies measured in p-BLS are sensitive to the interaction forces in molecular solids, and p-BLS is a novel optical technique capable of reliably discriminating polymorphs. Extending this study further, we fully expect that many pharmaceutically relevant processes – e.g., hydrate formation, co-crystallization, or amorphous instability – could potentially be monitored using p-BLS.