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

ABSTRACT: 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.

SUBMITTER: Li S

PROVIDER: S-EPMC9871043 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Li Shuting S Lightowler Molly M Ou Xiao X Huang Siyong S Jiang Yifan Y Li Xizhen X Zou Xiaodong X Xu Hongyi H Lu Ming M

Communications chemistry 20230123 1

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 structur ...[more]

PMID: 36697943

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Project description:Crystal and conformational polymorphisms play crucial roles in the physical and chemical properties of materials, impacting their stability, solubility, and bioavailability, which are essential for various applications in pharmaceuticals, materials science, and chemistry. Despite their significance, the structural analysis of these polymorphisms, particularly conformational polymorphisms, remains challenging due to the limited methodology that provides sufficient resolution for microcrystalline variants of polymorphs. Three-dimensional electron diffraction (3D ED) is an emerging technique with significant potential for elucidating the microcrystal structures of functional organic molecules, pharmaceuticals, and biomolecules. Despite this potential, there are limited instances of 3D ED structures for small molecules exhibiting the lowest crystallographic symmetry with a preferred orientation and possibly conformational variations of constituent molecules. A novel organic semiconductor, Ph-anti-benzothieno[5,6-b]benzothieno[3,2-b]thiophene-C10 (antiC10), is one of such examples. We successfully determined the 3D ED structure of this challenging molecule. The antiC10 crystal exhibited the lowest symmetry (space group P1), and the preferred orientations against the grid resulted in a missing cone. These challenges were surmounted by employing a sequential molecular replacement approach with an ab initio-generated search model. The resulting octameric antiC10 structure reveals a two-monolayer architecture and an antiparallel alkyl-interdigitated herringbone configuration in contrast to the all-parallel associations observed in its previously reported isomer. Concurrently, the alkyl chains are intricately interdigitated with each other and positioned between the adjacent π-core strata. Detailed analysis has elucidated the conformational polymorphism in herringbone packing between the two monolayers as well as in intramolecular conformations among monomers. The structure with conformational polymorphism is presumably in a metastable intermediate state, stabilized by twinning. These findings may provide critical insights into the crystallization mechanisms and rational design of organic semiconductors. This research demonstrates that advancements in 3D ED technology and sequential phasing methodologies have enabled the study of previously unreachable structures.

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

Publications

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

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