The Potential Impact of Micro-Electron Diffraction on Small Molecule Drug Development

In the realm of research and development (RD), micro-electron diffraction (MicroED) is gradually being recognized for its unique advantages in the field of small molecule drug development. This article explores the potential impact of MicroED on both early-stage drug discovery and the development of drug polymorphs, highlighting its advantages and limitations.

MicroED and Crystal-Free Analysis

One of the main advantages of MicroED is its ability to analyze small molecules without the need for crystals, a feature it shares with nuclear magnetic resonance (NMR) spectroscopy. However, NMR, while lacking the requirement for crystalline samples, faces challenges in resolving enantiomers, particularly mirror-image enantiomers, without specialized techniques. In contrast, if the absolute configuration of at least one stereocenter is known, NMR can be used to deduce the stereochemistry of other stereocenters.

MicroED does have a speed advantage compared to NMR. Nevertheless, it currently suffers from a failure rate of about 50%, which poses a significant challenge for widespread adoption in drug development.

Electron Microscopes and Their Rarity

Another factor to consider is the rarity of electron microscopes. While NMR spectrometers are more widely available, the limited presence of electron microscopes means that MicroED may be more feasible in early-stage drug discovery rather than revolutionizing the entire process.

However, on the development side, MicroED can have a significant impact. Drug polymorphs, which are different forms of the same chemical compound, can lead to dramatic changes in the physical properties of pharmaceuticals. Even small changes in the manufacturing process can result in pills with the same chemical composition but different properties. For instance, the drug ritonavir was withdrawn from the market due to the manufacturing of a polymorph that did not dissolve, rendering it ineffective as a treatment.

Tracing Contamination and Analyzing Polymorphs

Tracing the source of contamination often requires obtaining the chemical structure of the drug. This is particularly challenging with amorphous solid pills, as they do not readily lend themselves to conventional X-ray analysis or NMR. Special solid-state NMR techniques are needed for this purpose. In this context, MicroED is expected to play a crucial role in analyzing and identifying drug polymorphs.

Examples of the impact of drug polymorphs include the case of ritonavir, where a small contaminant led to the production of a biologically inactive Form II of the drug. Similar issues can be found in other drugs where the manufacturing process can lead to undesirable polymorphic forms.

Concluding Remarks

While MicroED does not yet have the potential to revolutionize the entire field of small molecule drug development, it can significantly impact the analysis and management of drug polymorphs in the development phase. As the technology improves and becomes more accessible, its role in ensuring the consistency and efficacy of pharmaceuticals is likely to grow.