Bromazepam distribution in a solid dosage form studied by time-of-flight secondary ion mass spectrometry

This work presents the surface and subsurface analysis of a bromazepam (BRZ) tablet using three-dimensional (3D) profilometry, atomic force microscopy, X-ray photoelectron spectroscopy, and time-of-flight secondary ion mass spectrometry. Profilometry and AFM showed that the tablet surface was heterogeneous, with an average mean surface roughness value of 66.98 ± 5.69 µm. XPS confirmed the expected elemental composition of the BRZ standard (a compressed powder of the reference standard). On the other hand, Br-related signals were not detected in the BRZ tablet due to its low BRZ content and the XPS technique's too high detection limit. Therefore, ToF-SIMS was the main technique for BRZ determination. Positive-ion spectra of the BRZ standard were used to assign characteristic BRZ-related ions. For imaging, negative-ion signals were more suitable. The ⁷⁹Br^- and ⁸¹Br^- ions were selected as BRZ markers and were verified by their spatial agreement with the deprotonated molecular ion C₁₄H₉BrN₃O^-. Two-dimensional (2D) imaging was performed using delayed-extraction analyzer mode combined with fast-imaging liquid-metal-ion-gun mode, yielding high-lateral-resolution images of localized BRZ-rich surface areas. 3D ToF-SIMS imaging was performed using a 10 keV Ar₂₀₀₀⁺ gas cluster ion beam for sputtering to a depth of approximately 13 µm. The 2D and 3D ToF-SIMS data showed that BRZ was not homogeneously distributed but was present in discrete BRZ-rich areas within the excipient-rich tablet matrix. These results demonstrate that ToF-SIMS is suitable for determining and imaging low-dose BRZ in solid pharmaceutical formulations where XPS lacks sufficient surface sensitivity.