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.
Highlights
The three-dimensional structure of a molecule provides detailed information regarding relative atom positions, bonding and intra-molecular interactions, which informs stability, reactivity, solubility, and function
As part of our pipeline validation process, we determined the structures of three compounds, progesterone, biotin, and paracetamol (Figures 4A–C), that had already been solved by single crystal X-ray crystallography (Naumov et al, 1998; Shikii et al, 2004; Altaf and Stoeckli-Evans, 2013) and microcrystal electron diffraction (MicroED)
Since electron diffraction allows for data collection from crystals orders of magnitude smaller than those required for single-crystal X-ray diffraction (XRD), this technique can deliver structures of challenging targets for which large crystals are not available
Summary
The three-dimensional structure of a molecule provides detailed information regarding relative atom positions, bonding and intra-molecular interactions, which informs stability, reactivity, solubility, and function. In the development of small molecule pharmaceuticals, knowledge of the crystalline solid form is extremely important, beyond confirmation of the proposed 2D structure. The crystal form adopted by an active pharmaceutical ingredient (API) and the lattice interactions that hold it together can have important ramifications for stability, tableting properties, solubility and dissolution rates, affecting bioavailability, potency, and even toxicity (Lu and Rohani, 2009; Censi and Di Martino, 2015). It is critically important to understand the solid form(s) of APIs and the crystal lattice interactions that underly them. It is highly desirable to be able to determine the structure of the many crystal forms an API can adopt in order to understand the underlying lattice properties and better engineer the optimal crystal form for development
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