Transmission electron microscopy of pharmaceutical materials

Area of Science:

• Materials Science
• Pharmaceutical Science
• Analytical Chemistry

Background:

• Transmission electron microscopy (TEM) is a powerful materials science technique.
• Its application in pharmaceutical analysis has been limited due to sample preparation and beam damage challenges.
• Overcoming these limitations enables detailed characterization of pharmaceutical compounds.

Purpose of the Study:

• To present straightforward methods for preparing and analyzing pharmaceutical samples using TEM.
• To demonstrate the utility of TEM for characterizing morphology, polymorphism, and defects in drug crystals.
• To highlight TEM's potential in addressing pharmaceutical form development challenges.

Main Methods:

• Development of simplified sample preparation techniques for pharmaceutical compounds.
• Application of TEM and electron diffraction for crystal structure and defect analysis.
• Characterization of various pharmaceutical compounds, including theophylline, paracetamol, aspirin, salts, and cocrystals.

Main Results:

• Successful characterization of pharmaceutical compounds' morphology, polymorphs, and crystal habit.
• Identification of impurity polymorphic phases in seemingly monophasic samples (e.g., theophylline).
• Observation of distinct crystal growth behaviors based on solvent (nitromethane vs. methanol) and identification of crystal defects like dislocations.

Conclusions:

• TEM is a valuable and accessible technique for pharmaceutical analysis, overcoming previous limitations.
• TEM provides critical information for pharmaceutical form development, including polymorph control and defect analysis.
• The described methods facilitate the use of TEM for routine characterization of drug substances and formulations.