Atomic-level structure determination of amorphous molecular solids by NMR

Area of Science:

• Materials Science
• Solid-State Chemistry
• Pharmaceutical Science

Background:

• Determining the atomic-level structure of amorphous materials is inherently challenging due to inherent disorder.
• Nuclear Magnetic Resonance (NMR) powder crystallography is a key technique for molecular solid structure determination.
• Disorder in amorphous materials causes signal overlap, hindering the identification of a single representative periodic structure.

Purpose of the Study:

• To determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625.
• To investigate the preferred conformations and intermolecular interactions stabilizing the amorphous drug form.

Main Methods:

• Combining solid-state Nuclear Magnetic Resonance (NMR) experiments with molecular dynamics (MD) simulations.
• Utilizing machine-learned chemical shifts for 1H and 13C atomic sites.
• Analyzing the ensemble of local molecular environments consistent with experimental data.

Main Results:

• Successfully determined the atomic-level ensemble structure of amorphous AZD4625.
• Identified an ensemble of local molecular environments that accurately reflect experimental NMR data.
• Extracted and analyzed preferred molecular conformations and intermolecular interactions.

Conclusions:

• The integrated NMR and simulation approach enables atomic-level structure determination of amorphous materials.
• Understanding molecular conformations and interactions is crucial for stabilizing amorphous drug forms.
• This methodology advances the structural characterization of disordered pharmaceutical compounds.