Multimodal Characterization of Enteric-Coated Pharmaceutical Beads Using Raman Chemical Mapping and SEM–EDX

Understanding the distribution and integrity of coating layers within enteric-coated pharmaceutical beads is essential for ensuring reliable performance during manufacturing scale-up, downstream processing, and ultimately the quality and safety of the drug product. Here, we apply confocal Raman microspectroscopy with chemical imaging capability, in tandem with scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM–EDX), to visualize structure–composition relationships in multilayer beads consisting of a sugar core, drug layer, seal coats, and delayed-release coatings. Beads produced at bench scale and at manufacturing scale, as well as beads extracted after tablet compression, were cross-sectioned near the midline and examined to assess coating continuity, component distributions, and potential impurities across lots (Figure 1).

Raman chemical imaging was performed using a 785 nm excitation laser and line-focus acquisition to collect more than 180,000 spectra per map at ∼3 cm⁻¹ spectral resolution over the 610–1724 cm⁻¹ range. Reference spectra were acquired for individual components (Table 1) to enable non-negative least-squares (NNLS) processing of the hyperspectral images. Because hydroxypropyl methylcellulose (HPMC) and a commercial film-coat exhibited highly similar spectra, chemical images labeled as HPMC encompass both materials. The resulting chemical images resolved the expected radial layer order from core to periphery and showed largely homogeneous distributions for most components (Figure 2). Magnesium stearate was not detected in the maps, likely due to its low concentration.

In addition to detecting the major components, a distinct Raman-active species, not present in the component library, was also detected across all lots. Its spectrum was extracted from regions of highest intensity but could not be matched to internal references, indicating a previously unassigned component present at low levels (Figure 3). Notably, beads extracted after compression lacked the outer enteric overcoat, likely due to mechanical loss during tableting. Layers containing talc exhibited high, sloping fluorescence baselines that suppressed Raman signal-to-noise; this effect was substantially stronger in manufacturing-scale material than in bench-scale material. A fourth-order polynomial baseline correction was applied to talc reference and sample spectra prior to NNLS processing to mitigate fluorescence and improve component contrast, as recommended for Raman workflows encountering impurity-induced fluorescence [1]. The comparatively stronger fluorescence in talc-bearing layers from the manufacturing-scale lots suggests minor differences in excipient purity.

Complementary SEM–EDX mapping on the same or matched beads corroborated the Raman-derived spatial organization. Elemental maps of carbon and oxygen highlighted organic layers (core, film-formers, and drug), nitrogen and sulfur were consistent with the drug distribution, and silicon localized to talc-rich layers. Magnesium signals arose from both the drug salt and talc. In addition to the major elements, small aluminum-containing particulates were consistently observed within talc-bearing regions, and a minor amount of calcium was detected in one manufacturing-scale, compression-extracted lot. The presence of aluminum and calcium is consistent with known mineral impurities associated with talc sources (Figure 4) [2].

Collectively, these multimodal datasets provide a coherent picture of pellet architecture, chemical composition, impurity signatures, and processing effects. Chemical images confirm the designed layer sequence and reveal that the enteric overcoat can be removed by compression, which can alter dissolution performance and increase the risk of dose dumping, underscoring the need to optimize compression force and ensure adequate coating thickness robustness. Differences in fluorescence behavior suggest that excipient variability contributes to analytical contrast and, potentially, to performance variability. The identification of trace aluminum and calcium by SEM–EDX, together with an unknown Raman-active component common to all lots, motivates targeted raw-material screening and supply-chain controls. While the present analysis focused on a single representative pellet per lot, extending the workflow to larger sample counts would strengthen statistical confidence and enable correlations with dissolution or release testing.

In summary, the combination of confocal Raman chemical imaging and SEM–EDX yields a high-resolution, layer-by-layer view of enteric-coated beads that supports troubleshooting of coating integrity, assessment of scale-up consistency, and refinement of manufacturing control strategies for pharmaceuticals. The approach is broadly applicable to complex solid-dose drug product systems that require non-destructive visualization of composition and structure at the microscale.

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Sarah Miller, Levi Litwiller, Multimodal Characterization of Enteric-Coated Pharmaceutical Beads Using Raman Chemical Mapping and SEM–EDX, Microscopy and Microanalysis, Volume 32, Issue Supplement_1, July 2026, ozag053.174, https://doi.org/10.1093/mam/ozag053.174