Towards Pharmaceutical Particle Imaging in Ultrathick Organic Films: 3D Visualization and Image Distortions Using Gas Cluster Bombardment Secondary Ion Mass Spectrometry

ABSTRACT Polystyrene spheres ranging in diameter from 2, 5, 10, to 20 μm were embedded in five different types of thick organic films (> 50 μm) to serve as model systems to evaluate the use of time‐of‐flight secondary ion mass spectrometry for the localization and particle sizing of pharmaceuticals in orodispersible drug delivery films. It was found that certain films, such as gelatin and ethyl cellulose, are prone to developing micron‐scale topography which can affect the linearity of the sputter yield, which can ultimately affect the maximum analyzable depth. Surprisingly, the sputter yield of the film was more of a determining factor for affecting the measurement of spheres. It was possible to more accurately extract the true dimensions of the buried spheres in faster sputtering films, while slower sputtering films were associated with matrix effects and sputtering artifacts that degraded the quality of the reconstructed image. Signal attenuation was also found to be problematic and quite significant for certain film chemistries, which placed a limit on the size of the particles that could be visualized. Overall, visualization of particles embedded in thick organic films is possible, but the extraction of quantitative data such as size and the amount of material is difficult given the influence of sample dependent sputtering artifacts.