Small Molecule Microcrystal Electron Diffraction for the Pharmaceutical Industry–Lessons Learned From Examining Over Fifty Samples

Abstract

The emerging field of microcrystal electron diffraction (MicroED) is of great interest to industrial researchers working in the drug discovery and drug development space. The promise of being able to routinely solve high-resolution crystal structures without the need to grow large crystals is very appealing. Despite MicroED’s exciting potential, adoption across the pharmaceutical industry has been slow, primarily owing to a lack of access to specialized equipment and expertise. Here we present our experience building a small molecule MicroED service pipeline for members of the pharmaceutical industry. In the past year, we have examined more than fifty small molecule samples submitted by our clients, the majority of which have yielded data suitable for structure solution. We also detail our experience determining small molecule MicroED structures of pharmaceutical interest and offer some insights into the typical experimental outcomes. This experience has led us to conclude that small molecule MicroED adoption will continue to grow within the pharmaceutical industry where it is able to rapidly provide structures inaccessible by other methods.

CELLOPT: improved unit-cell parameters for electron diffraction data of small-molecule crystals

“…3). Furthermore, we tested our program against several previously solved structures from the CSD ( van Genderen et al, 2016;Gruene et al, 2018;Jones et al, 2018;Clabbers et al, 2019;Bruhn et al, 2021). We summarize our results in Table 1.…”

“…S1-S10). We optimized the unit-cell parameters for a novel Vie-1 MOF, the pharmaceutical compound oseltamivir, and several previously determined structures ( van Genderen et al, 2016;Gruene et al, 2018;Jones et al, 2018;Clabbers et al, 2019;Bruhn et al, 2021). Our approach is not limited to MicroED data (Nannenga et al, 2014), but may also be applied in structure refinement using related 3D ED techniques (Dorset, 1995;Kolb et al, 2007;Zhang et al, 2010) or serial electron diffraction data (Smeets et al, 2018;Bu ¨cker et al, 2021).…”

“…We illustrate the use of CELLOPT with the structures of a previously unpublished Nd III -based metal-organic framework (MOF) we named Vie-1 and the antiviral medication oseltamivir, for which only an X-ray structure is available. Furthermore, we tested the cell optimization routine using various examples from the literature, including several microcrystal electron diffraction (MicroED) structures of organic pharmaceutical compounds ( van Genderen et al, 2016;Gruene et al, 2018;Jones et al, 2018;Clabbers et al, 2019;Bruhn et al, 2021). We provide an overview of the structures used in this work in Table 1.…”

Absolute configuration determination of pharmaceutical crystalline powders by MicroED via chiral salt formation

“…Practically speaking, to obtain a structural model from MicroED data, it is highly desirable to process the data using the kinematical theory of diffraction, as opposed to the dynamical theory, which enables the convenience of using well-established data reduction software packages written for scXRD familiar to most crystallographers. 21 In the absence of dynamical refinement, it is still possible to determine the absolute structure from MicroED data under certain conditions. For chiral crystals, two enantiomeric solutions are produced from diffraction data.…”

“…1A and B ). 21 The free base form of API 1 crystallized in the chiral space group P1. The unit cell contains two enantiomerically pure molecules in different conformations.…”