The size, shape, and spatial distribution of active pharmaceutical ingredient (API) are important physical characteristics of drug delivery systems that can affect the performance, stability, appearance, and even bulk properties of the end product. This study explores the feasibility of using time-of-flight secondary ion mass spectrometry (ToF-SIMS) for the 3D characterization of API particles in two commercially available oral dissolvable drug delivery films. It was found that ToF-SIMS imaging with argon gas cluster ion beam (GCIB) sputtering allowed production of 3D chemical maps that could be utilized to obtain size distributions of buprenorphine particles whose effective diameters ranged from approximately 6 μm to 41 μm, with shapes that were generally spherical with a few nonspherical structures. The particles were heterogeneously distributed both laterally and as a function of depth in the film. In addition, ToF-SIMS was able to differentiate between different oral drug delivery films based on differences in the spatial distribution of buprenorphine; in one case, the particles were distributed throughout the depth of the film, whereas the particles in the other case were localized close to the surface. Preliminary studies suggest that ToF-SIMS with argon GCIB sputtering may also allow us to provide a very rough estimate of the concentration of the APIs (factors of 2 to 4), namely buprenorphine and naloxone, at pharmacologically relevant concentrations inside organic drug delivery systems with a thickness of hundreds of micrometers.

Argon cluster ions have enabled molecular depth profiling to unprecedented depths, with minimal loss of chemical information or changes in sputter rate. However, depth profiling of ultrathick films (>100 μm) using a commercial ion source oriented at 45°to the surface causes the crater bottom to shrink in size because of a combination of the crater wall angle, sputter rate differences along the trailing-edge crater wall, and undercutting on the leading-edge. The shrinking of the crater bottom has 2 immediate effects on dualbeam depth profiling: first is that the centering of the analysis beam inside the sputter crater will no longer ensure the best quality depth profile because the location of the flat crater bottom progressively shifts toward the leading-edge and second, the shifting of the crater bottom enforces a maximum thickness of the film that could be depth profiled. Experiments demonstrate that a time-of-flight secondary ion mass spectrometry instrument equipped with a 20 keV argon cluster source is limited to depth profiling a 180 μm-thick film when a 500 μm sputter raster is used and a 100 μm square crater bottom is to be left for analysis. In addition, depth profiling of a multilayer film revealed that the depth resolution degrades on trailing-edge side of the crater bottom presumably because of the redeposition of the sputtered flux from the crater wall onto the crater bottom.