A High Energy X-ray Diffraction Study of Amorphous Indomethacin

Area of Science:

• Materials Science
• Pharmaceutical Science
• Solid-State Chemistry

Background:

• Amorphous pharmaceuticals exhibit diverse molecular conformations and packing.
• X-ray pair distribution function (PDF) analysis is crucial for characterizing these structures.
• Understanding structural nuances in amorphous drugs is vital for formulation and stability.

Purpose of the Study:

• To investigate the structural sensitivity of amorphous Indomethacin using x-ray PDF.
• To analyze the influence of chlorobenzyl ring orientation on amorphous structure.
• To examine the role of hydrogen bonding and water interactions in amorphous Indomethacin.

Main Methods:

• X-ray pair distribution function (PDF) analysis of amorphous Indomethacin.
• Investigation of intra-molecular and inter-molecular packing arrangements.
• Time-resolved PDF measurements under varying humidity conditions.

Main Results:

• Amorphous Indomethacin's PDF is sensitive to chlorobenzyl ring orientation, with some samples showing preferred torsional angles and others not.
• Absence of preferred torsion angles correlates with enhanced inter-molecular hydrogen bonding, affecting the first sharp diffraction peak.
• Water molecules at high humidity form hydrogen bonds with Indomethacin, exhibiting similar strengths to inter-molecular bonds in the dry state.

Conclusions:

• Amorphous Indomethacin exhibits significant structural variability, precluding its use as a standard for x-ray PDF measurements.
• Hydrogen bonding plays a key role in the structure of both dry and hydrated amorphous Indomethacin.
• X-ray PDF is a powerful tool for elucidating complex structural features in amorphous pharmaceutical systems.