Determination of the absolute configuration of organic molecules is essential in drug development and the subsequent approval process. We show that this determination is possible through electron diffraction using nanocrystalline material. Ab initio structure determination by electron diffraction has so far been limited to compounds that maintain their crystallinity after a dose of one electron per square angstrom or more. We present a complete structure analysis of a pharmaceutical cocrystal of sofosbuvir and l-proline, which is about one order of magnitude less stable. Data collection on multiple positions of a crystal and an advanced-intensity extraction procedure enabled us to solve the structure ab initio. We further show that dynamical diffraction effects are strong enough to permit unambiguous determination of the absolute structure of material composed of light scatterers.

Institute of Physics of the Czech Academy of Sciences Na Slovance 2 18200 Prague 8 Czech Republic

University of Chemistry and Technology Technická 3 16628 Prague 6 Czech Republic

Zentiva U Kabelovny 130 10237 Prague 10 Czech Republic

Comment In

Science. 2019 May 17;364(6441):632-633. doi: 10.1126/science.aax5385. PubMed

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