From Powders to Single Crystals: A Crystallographer’s Toolbox for Small-Molecule Structure Determination

Newman, Justin A.; Iuzzolino, Luca; Tan, Mélissa; Orth, Peter; Bruhn, Jessica F.; Lee, Alfred Y.

doi:10.1021/acs.molpharmaceut.2c00020

Cited by 11 publications

(12 citation statements)

References 68 publications

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“…30 Small-molecule crystals represent the most widely studied category, with constituents that include aromatic hydrocarbons, heterocycles, p-conjugated architectures, and pharmaceutical compounds. 31 While traditionally perceived as fragile materials, certain organic molecular crystals are now known to exhibit remarkable latent mechanical compliance and adaptability to external stimuli. [32][33][34][35][36][37]…”

Section: Fundamentals Of Organic Molecular Crystalsmentioning

confidence: 99%

Hybrid and composite materials of organic crystals

Yang,

Al-Handawi,

et al. 2024

Chem. Sci.

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Section: Fundamentals Of Organic Molecular Crystalsmentioning

confidence: 99%

Hybrid and composite materials of organic crystals

Yang,

Al-Handawi,

et al. 2024

Chem. Sci.

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“…It was ultimately the rapid project development timelines that prevented us from following these options to acquire additional structural data, and this shows how an integration of CSP with routine laboratory analytical data such as thermal analysis, NMR, and XRPD, combined with powder indexing, can quickly procure the crystal structure. This approach is being applied more frequently in drug development and, as computing power continues to increase and becomes less expensive, it may ultimately replace more traditional brute force experimental approaches. − …”

Section: Crystal Structure Prediction Of Hydroxy Epimer Formmentioning

confidence: 99%

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

Shultz,

Iuzzolino,

Codan

et al. 2023

Org. Process Res. Dev.

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This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel−Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a π−π stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications.

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“…Advancement of electron diffraction techniques led to the development of microcrystal electron diffraction (MicroED), or continuous rotation electron crystallography, for structure solution of small molecules [18][19][20][21][22][23][24][25] as well as macromolecules like proteins and peptides. 26 MicroED can solve crystal structures from fine powders, even when it is a mixture of multiple compounds.…”

Section: Introductionmentioning

confidence: 99%

Structure elucidation of olanzapine molecular salts by combining mechanochemistry and MicroED

Gogoi

Sasaki

Nakane

et al. 2023

Preprint

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Olanzapine (OLN), an anti-psychotic drug, is one of the most widely studied pharmaceutical materials. Although OLN and most of their multicomponent solids are highly crystalline, some of their molecular salts are difficult to crystallize and optimization takes long time. After several batches of failed crystallization, we applied mechanochemistry and microcrystal electron diffraction (MicroED) for structure elucidation. This combined approach was successful not only in structure determination of the drug molecule but also in characterizing traces of impurity present in a bulk solid. This study demonstrates that the combined approach is fast and efficient for structure elucidation of pharmaceutical materials when generation of suitable single crystals is challenging.

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From Powders to Single Crystals: A Crystallographer’s Toolbox for Small-Molecule Structure Determination

Cited by 11 publications

References 68 publications

Hybrid and composite materials of organic crystals

Hybrid and composite materials of organic crystals

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

Structure elucidation of olanzapine molecular salts by combining mechanochemistry and MicroED

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