Contemporary Techniques and Prospects in Pharmaceutical Tablet Surface Analysis

Abstract

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.

Introduction

Tablets are a widely used dosage form, but their critical quality attributes, such as active pharmaceutical ingredient (API) content, distribution, hardness, and dissolution, are typically assessed by time-consuming and labor-intensive methods that often lack spatial information. (1) Current solid-dose tablet analysis increasingly combines vibrational spectroscopies with imaging to quantify composition and map the distribution of APIs. In practice, Raman and Fourier transform infrared (FTIR) spectroscopies are the primary techniques used. Both provide rich, molecularly selective or molecularly specific spectra, and both can discriminate between crystal forms (polymorphs) when the full spectrum is considered rather than a single peak, typically via multivariate statistical analysis (MVSA) methods to handle overlap and matrix effects. (2) For the spatial mapping of APIs and excipients, Raman spectroscopy chemical imaging offers (sub)micron-scale lateral detail and is routinely used by acquiring a spectrum at each pixel and comparing such against spectral libraries. FTIR spectroscopy imaging achieves lower spatial detail (several to tens of micrometers) but remains valuable for chemically specific mapping over larger areas. (2b) Confocal Raman spectroscopy can provide depth-resolved 3D maps, but is fundamentally limited by optical transparency and scattering, which restricts the practical depths in turbid tablets. (3) Moreover, coupling Raman and FTIR spectroscopies to the topography of the sample improves interpretation. Thus, atomic force microscopy (AFM) coupled with Raman spectroscopy enables the correlation of nanoscale topography with chemical identity, thereby mitigating topography-induced spectral artifacts during mapping. Furthermore, X-ray-based techniques can complement Raman and FTIR spectroscopies in such studies. Scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDXS) can generate element-specific maps, which can be useful for locating certain excipients (for example, the distribution of Mg from Mg stearate (4)).

However, the use of such a technique is limited because elements like Mg may originate from multiple sources. For instance, both Mg stearate and talc are common excipients, making it impossible to assign the signal unambiguously. Other X-ray-based techniques, such as microcomputed tomography, provide complementary insight by probing internal structure and porosity but do not yield detailed chemical information. (5)

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) offer complementary surface analysis capabilities for tablet characterization, which remain largely underutilized in routine practice. ToF-SIMS, although still rarely applied to map APIs in tablets, probes only the upper few nanometers of the surface. It can localize molecular fragments and molecular ions with a lateral resolution of approximately 100 nm (a routinely achievable lateral resolution in organic matrices). In applying ToF-SIMS, one must balance mass resolution, lateral resolution, and acquisition time according to the analytical objective. XPS also probes the outer few nanometers and yields (semi)quantitative elemental composition and short-range chemical-state information. Complementary to the latter, ToF-SIMS contributes to molecular specificity and molecular selective imaging. Both techniques can access subsurface regions using gas cluster ion beam (GCIB) sputtering, enabling the chemically nondestructive depth profiling of organic components. (6) The results obtained from GCIB sputtering, combined with ToF-SIMS and XPS, can help assess surface segregation, interfacial layers, and the heterogeneity of APIs and excipients. Additionally, they can detect the presence of trace contaminants and support development, reverse engineering, and quality control. AFM provides topographical and nanomechanical context, including roughness, phase contrast, and local heterogeneity, which enhances region selection and the interpretation of XPS and ToF-SIMS data.

Paracetamol (PAR) is a widely used analgesic and antipyretic. In contrast, indapamide (IND), amlodipine (AMLO), and perindopril (PER) are antihypertensive drugs classified as a thiazide-like diuretic, a dihydropyridine calcium channel blocker, and an angiotensin-converting enzyme inhibitor, respectively.

In order to illustrate the challenges of employing surface analysis techniques for the characterization of analytically complex samples, two extremes of API loading were examined: (i) single-API PAR tablets containing 500 mg PAR, representative of high-dose formulations; and (ii) combination (COMB) tablets containing a low dose of IND, AMLO, and PER in the 0.625–10 mg range, representative of low-level APIs dispersed within a larger excipient matrix. This design enables the evaluation of how surface analysis techniques respond to high and low API content, as well as the assessment of API distribution and excipient interactions under both conditions.

The main objective of this work is to present the current state of applying ToF-SIMS and XPS in the analysis of pharmaceutical tablets. In addition, AFM and 3D profilometry are employed to provide complementary insights into the tablet surface topography and roughness at both micro- and nanoscale levels. Surface analysis methods are extremely rarely used in pharmaceutical tablet analysis. Yet, this study demonstrates how they can be employed to probe both the surface and subsurface regions, reveal formulation-dependent differences, and capture information inaccessible by conventional techniques, e.g., Raman spectroscopy. Moreover, the limitations of these approaches are addressed, highlighting the practical considerations needed for their broader application in pharmaceutical research and quality control.

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Table 1. Summary of the PAR and COMB Tablet Formulations as Declared by Manufacturers and Analyzed in This Study

Contemporary Techniques and Prospects in Pharmaceutical Tablet Surface Analysis, Matjaž Finšgar, ACS Measurement Science Au 0, 0, pp, DOI: 10.1021/acsmeasuresciau.5c00178

Read also our introduction article on Talc here: