Imaging of Hygroscopic Ultrafine Pharmaceutical Powders Using Low Temperature and Environmental Scanning Electron Microscopy

Conventional scanning electron microscopy (SEM) is used successfully to image dry, mechanically stable pharmaceutical powders. However, problems occur when highly hydrated powders are exposed to the low pressures and high electron energies within the SEM chamber. Evaporation of adsorbed surface moisture or loosely-bound water of crystallization damages the conducting gold coat, leading to accumulation of negative charge on the imaged portion of the specimen sample surface. SEM characterization of nedocromil sodium, a hydrated hygroscopic drug powder, resulted in extensive charge build-up and image distortion. Therefore, alternative techniques have been adopted to image the drug powder in its fully hydrated state. Low temperature scanning electron microscopy (LTSEM) and environmental scanning electron microscopy (ESEM) have been used to determine the particle size and shape of nedocromil sodium trihydrate. The distribution of drug particles within carrier-based formulations for dry powder inhalation were also imaged. LTSEM and ESEM electron micrographs of samples taken from these dry powder systems illustrate how the drug forms as multi-particulate layers adhered to the lactose carrier surface or as self-agglomerates existing separately from the carrier component. Information regarding the interparticulate forces dictating the aerosol performance of the powder blends was inferred from the images and alternative formulation strategies were devised.