# Unveiling the Structure of Anhydrous Sodium Valproate with 3D Electron Diffraction and a Facile Sample Preparation Workflow

## TL;DR

Researchers determined the structure of anhydrous sodium valproate using a new method that handles sensitive crystals, revealing polyhedral chains.

## Contribution

A glovebox-assisted cryo-transfer workflow was developed to study air- and beam-sensitive crystals using 3D electron diffraction.

## Key findings

- The structure of anhydrous sodium valproate was successfully determined using 3D electron diffraction.
- Na-valproate polyhedral chains were revealed in the crystal structure.
- The workflow enables reliable 3D ED analysis of air-sensitive crystals.

## Abstract

Understanding the structure of an active pharmaceutical
ingredient
is essential for gaining insights into its physicochemical properties.
Sodium valproate, one of the most effective antiepileptic drugs, was
first approved for medical use in 1967. However, the structure of
its anhydrous form has remained unresolved. This is because it was
difficult to grow crystals of sufficient size for single-crystal X-ray
diffraction (SCXRD). Although 3D electron diffraction (3D ED) can
be used for studying crystals that are too small for SCXRD, the crystals
of anhydrous sodium valproate are extremely sensitive to both humidity
and electron beams. They degrade quickly both in air and under an
electron beam at room temperature. In this study, we developed a glovebox-assisted
cryo-transfer workflow for the preparation of EM grids in a protected
atmosphere to overcome the current challenges for studying air- and
beam-sensitive samples using 3D ED. Using this technique, we successfully
determined the structure of anhydrous sodium valproate, revealing
the formation of Na-valproate polyhedral chains. Our results provide
a robust framework for the 3D ED analysis of air-sensitive crystals,
greatly enhancing its utility across various scientific disciplines.