Surface and Subsurface Mass Spectrometric Analysis of Dexamethasone in Solid Pharmaceutical Dosage Forms

Abstract

This study presents an in-depth mass spectrometric investigation of dexamethasone (DEX) distribution within pharmaceutical tablets using time-of-flight secondary ion mass spectrometry (ToF-SIMS) combined with gas cluster ion beam (GCIB) sputtering. Fragmentation mechanism of DEX was identified, which enabled the determination of three-dimensional chemical imaging of the active ingredient in both surface and subsurface regions. The data reveal that a 4-mg DEX formulation exhibits a continuous and extended distribution of the drug into the tablet matrix, while a 0.5-mg formulation shows DEX localized in distinct, isolated domains. Topographical features and the overall composition of the surface were confirmed by complementary analyses employing atomic force microscopy (AFM) and x-ray photoelectron spectroscopy (XPS). These results demonstrate how molecule distribution patterns can be linked to formulation heterogeneity using advanced mass spectrometric techniques, opening new possibilities for pharmaceutical manufacturing quality control and optimization.

Keywords: AFM; ToF‐SIMS; XPS; active ingredient; dexamethasone; tablet analysis.

FIGURE 1

(a, b) 3D surface topography profiles measured over a 3 by 3 mm area and (c, d) AFM images acquired from six different spots over a 1 by 1 μm area. The images in (a, c) correspond to the 4‐mg DEX tablet, and the images in (b, d) correspond to 0.5‐mg DEX tablet, highlighting differences in surface topography, morphology, and roughness. The scale bar represents 200 nm.

FIGURE 2

XPS (a) survey and high‐resolution (b) C 1s, (c) O 1s, (d) Si 2p, (e) Mg 2p, (f) Ca 2p, and (g) F 1s spectra. The lowest spectra (solid lines) represent the surface before sputtering; sputtering is represented by the spectra from the bottom up. (h) The surface atomic concentration determined during depth profiling using 10‐keV Ar₁₀₀₀ ⁺. The depth after 10 800 s of GCIB sputtering was determined using 3D profilometry to be 15 μm. The lowest spectra represented by the dashed lines in (a–c, g) describe the measurement of the DEX standard.

FIGURE 3

Suggested fragmentation pattern for DEX with fragments whose signals were confirmed in the ToF‐SIMS spectra (Figure 4).

FIGURE 4

Wide‐range ToF‐SIMS spectra for (a) the 4‐mg DEX tablet and (b) the DEX standard; a detailed view of the ToF‐SIMS spectra measured for (c–m) the DEX standard and for (n) the 4‐mg DEX tablet showing the signals as predicted in Figure 3. The red arrows in (c–n) show the theoretical m/z position of the corresponding signals. Spectra were acquired after 600 s of sputtering on an area of 500 by 500 μm using a 10‐keV Ar₂₀₀₀ ⁺ to remove adventitious carbonaceous species.

FIGURE 5

3D ToF‐SIMS images showing the distribution of DEX (green, represented by C₈H₉O⁺), lactose and starch (orange, represented by C₆H₇O₃ ⁺), SiO₂ (blue, represented by Si⁺), and Mg stearate (red, represented by Mg⁺). 3D ToF‐SIMS images were measured for three different 4‐mg DEX tablets at two different locations. The depth after 10 800 s of sputtering was determined by using 3D profilometry to be 40 μm.