Discovery of oxyacanthine dihydrochloride monohydrate polymorphs from obfuscated samples by MicroED

Abstract

It is estimated that more than 50% of marketed pharmaceuticals are derived from natural products. Structural characterization of natural products and their drug formulations is essential for the pharmaceutical industry. Here we report the use of microcrystal electron diffraction (MicroED), to identify two polymorphic crystal structures of oxyacanthine dihydrochloride monohydrate from obfuscated samples that were mislabeled as "berbamine dihydrochloride". The two polymorphs display primary conformational differences in one of the tetrahydroisoquinoline rings: one polymorph exhibits an intermediate conformation between half-chair and half-boat, while the other adopts a distinct half-boat conformation. Analysis of their structures, energies and crystal packing diagrams indicates a thermodynamic preference for a transformation into the latter. This study highlights the value of integrating MicroED into pharmaceutical pipelines as an efficient tool for structural analysis and quality control.