Direct structure determination of vemurafenib polymorphism from compact spherulites using 3D electron diffraction.

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Li S, Lightowler M, Ou X, Huang S, Jiang Y, Li X, Zou X, Xu H, Lu M

Commun Chem 6 (1) 18 [2023-01-23; online 2023-01-23]

The spherulitic morphology is considered to be the most common morphology of crystalline materials and is particularly apparent in melt-crystallized products. Yet, historically, the polycrystalline nature of spherulites has hindered successful crystal structure determination. Here, we report the direct structure determination of a clinical drug, vemurafenib (VMN), in compact spherulite form using 3D electron diffraction (3D ED). VMN has four known polymorphs. We first solved the crystal structures of α-, β-, and γ-VMN from compact spherulites using 3D ED, and the resulting structures were highly consistent with those obtained by single-crystal X-ray diffraction. We then determined the crystal structure of δ-VMN-the least stable polymorph which cannot be cultivated as a single crystal-directly from the compact spherulite sample. We unexpectedly discovered a new polymorph during our studies, denoted as ε-VMN. Single crystals of ε-VMN are extremely thin and not suitable for study by X-ray diffraction. Again, we determined the structure of ε-VMN in a compact spherulite form. This successful structure elucidation of all five VMN polymorphs demonstrates the possibility of directly determining structures from melt-grown compact spherulite samples. Thereby, this discovery will improve the efficiency and broaden the scope of polymorphism research, especially within the field of melt crystallization.

Cryo-EM [Service]

PubMed 36697943

DOI 10.1038/s42004-022-00804-2

Crossref 10.1038/s42004-022-00804-2

pmc: PMC9871043
pii: 10.1038/s42004-022-00804-2