Contemporary Techniques and Prospects in Pharmaceutical Tablet Surface Analysis

This work demonstrates how surface analysis can be applied for the chemical characterization of solid pharmaceutical tablets using time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and 3D profilometry as complementary tools. Two formulation extremes were examined, i.e., high-dose single active pharmaceutical ingredient (API) tablets and low-dose three-API combination tablets, with five formulations assessed in each set. AFM and 3D profilometry were employed to characterize the micro- to nanoscale topography, assess roughness, and measure the crater depths formed after gas cluster ion beam (GCIB) sputtering. To define ToF-SIMS markers, API reference standards were analyzed using tandem (MS/MS) ToF-SIMS. Multivariate curve resolution was used to identify ions unique to each API. After marker definition, ToF-SIMS images were acquired in 2D and, by using GCIB, in 3D. Large-area maps were produced by image stitching. Delayed extraction and fast imaging modes enabled submicrometric imaging at high mass resolving power. XPS survey and high-resolution spectra, combined with GCIB sputtering, quantified the elemental composition and chemical states within the outer few nanometers and into the subsurface region. It was demonstrated that ToF-SIMS can provide molecularly specific maps and depth profiles that localize APIs and excipients, revealing surface segregation and interfacial layering. In contrast, XPS supplies quantitative elemental and chemical-state information on the surface and in the subsurface. Overall, the study demonstrates that these surface analytical techniques offer spatially resolved insights not accessible with conventional methods for solid dosage forms and that they complement practices in formulation development, troubleshooting, and quality control. These techniques can confirm API and excipient localization, assess surface segregation and interfacial layers, detect contaminants, and compare batches. Despite this utility, they have seen limited adoption, most likely because they require specialized instrumentation, method development, and data interpretation expertise not yet widespread in pharmaceutical laboratories.