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

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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.

Lightowler, MollyStockholms universitet,Institutionen för material- och miljökemi (MMK)(Swepub:su)moli1290 (author)
Ou, Xiao (author)
Huang, Siyong (author)
Jiang, Yifan (author)
Li, Xizhen (author)
Zou, XiaodongStockholms universitet,Institutionen för material- och miljökemi (MMK)(Swepub:su)xzou (author)
Xu, HongyiStockholms universitet,Institutionen för material- och miljökemi (MMK)(Swepub:su)hxu (author)
Lu, Ming (author)
Stockholms universitetInstitutionen för material- och miljökemi (MMK) (creator_code:org_t)

By the author/editor: Li, Shuting; Lightowler, Moll ...; Ou, Xiao; Huang, Siyong; Jiang, Yifan; Li, Xizhen; show more...; Zou, Xiaodong; Xu, Hongyi; Lu, Ming; show less...

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NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Physical Chemist ...

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