Rapid infrared microscopy in pharmaceutical product development, quality control and biologics formulation

Significance of the topic

Fourier transform infrared (FTIR) microscopy has become a versatile tool in pharmaceutical research and quality control because it combines high-resolution visual imaging with spatially resolved chemical information. This capability addresses crucial needs across product development, batch release testing and investigation of complaints or contamination events. Rapid, micro-scale chemical mapping supports formulation optimization, detection of polymorphs, assessment of particle agglomeration and crystallinity, and the identification of foreign particulates—factors that directly affect drug performance, stability and patient safety.

Objectives and study overview

This application note illustrates how a modern FTIR microscope (the Nicolet RaptIR) and associated software workflows can be applied to typical pharmaceutical problems: (1) mapping aerosol deposition from metered dose inhalers (MDIs) to evaluate API distribution and agglomeration, (2) comparing API and excipient distribution in compressed tablets for QC and reverse engineering, and (3) assessing biotherapeutic formulations (insulin) to detect excipients and probe protein distribution and possible aggregation. The goal is to show practical sample preparation, data-collection modes and multivariate analysis approaches that deliver actionable chemical and morphological information rapidly.

Methodology and sample preparation

• MDI spray analysis: MDIs were actuated at a fixed distance onto a gold-plated microscope slide, then analyzed in reflectance mode to generate wide-field visual images and infrared chemical maps revealing deposited material distribution and particle characteristics.
• Tablet mapping: Two commercially representative tablets with identical ingredient lists were mapped using a Ge ATR contact approach with a 25 µm step size to cover ~1200 × 950 µm areas on each tablet; high-quality visual images were acquired in parallel to guide IR sampling.
• Biologics (insulin) evaluation: 1 µL aliquots of a commercial insulin formulation were deposited and dried onto a barium fluoride (BaF2) window; multiple depositions increased signal for reflection-mode mapping across a 10 mm × 10 mm area.
• Data processing: Multivariate Curve Resolution (MCR) and multi-component library search algorithms (OMNIC Paradigm software) were used to decompose mixed spectra into chemical components, produce color-coded distribution maps, and identify formulation constituents from spectral matches.

Instrumentation used

• Nicolet RaptIR FTIR Microscope (Thermo Scientific) providing combined high-resolution visual imaging (<1 µm) and spatially resolved IR mapping (reported <5 µm without ATR).
• Ge ATR accessory for high signal-to-noise contact-mode IR mapping (25 µm step size used in tablet studies).
• Barium fluoride (BaF2) infrared window for transmission/reflection analysis of dried biologic drops.
• Gold-plated microscope slide used as substrate for MDI deposition and reflectance measurements.
• OMNIC Paradigm software for automated area selection, MCR, and multi-component spectral searching.

Main results and discussion

• MDI spray mapping showed non-uniform deposition: chemigrams revealed regions of higher API density and areas indicating interaction between propellant and API. MCR helped confirm the API identity (salbutamol sulfate) and highlighted agglomeration and crystallinity differences that could influence aerosol performance.
• Tablet comparison: MCR decomposition of the mapped tablets produced three modeled components identified as acetaminophen, sodium bicarbonate and starch. Although ingredient concentrations were nominally identical, tablet 1 displayed a more homogeneous spatial distribution of components, whereas tablet 2 showed smaller domain sizes and greater heterogeneity—suggesting differences in manufacturing steps such as mixing, granulation or compression.
• Biologics formulation mapping: Infrared mapping of dried insulin deposits detected insulin and formulation excipients (glycerol, phenol, meta-cresol). Spatial maps showed segregation of glycerol from protein in the dried film, and spectral matching verified component identities. Such information supports assessment of drying-induced separation, potential local concentration gradients and early indicators of aggregation or misfolding.
• Practical analytical advantages: FTIR microscopy supplements classical tests (e.g., cascade impactor for MDIs) by providing direct chemical identification of particles, visualizing morphology and crystal growth, quantifying agglomeration, and detecting foreign particulates that otherwise require additional steps to identify.

Benefits and practical applications

• Rapid, spatially resolved chemical mapping accelerates decision-making in R&D and shortens time-to-market by enabling targeted formulation changes and failure-mode analysis.
• Non-destructive or minimally destructive sample handling supports forensic and complaint investigations, reverse engineering and counterfeit detection.
• High visual and spectral resolution allows simultaneous assessment of particle morphology, polymorphism/crystallinity and chemical composition—key parameters for inhalation products, solid dosage forms and biologics.
• Software automation (automated area selection, MCR, library searching) reduces operator dependency, making the technique accessible to non-expert users while preserving advanced analytical options for specialists.

Future trends and potential applications

• Integration with advanced chemometrics and machine learning to improve automated component recognition, anomaly detection and predictive links between micro-distribution patterns and macroscopic product performance.
• Higher-throughput mapping approaches and faster detectors to enable routine screening of larger sample sets in QC environments.
• Correlative multimodal imaging combining FTIR microscopy with Raman, SEM or X-ray mapping to link chemistry with high-resolution morphology and elemental composition.
• Three-dimensional and depth-profiling adaptations for layered dosage forms, coatings and complex biologic aggregates.
• Expanded regulatory acceptance of spatially resolved chemical imaging as supportive evidence for product release and stability assessments, particularly for inhalation products and parenterals.

Conclusion

FTIR microscopy, exemplified by the Nicolet RaptIR platform and associated software, offers a powerful and flexible analytical approach for pharmaceutical development and quality control. By producing high-resolution visual images and spatially resolved chemical maps in minutes, the technique supports formulation optimization, batch comparison, identification of contaminants and evaluation of biologic formulations. Its combination of speed, sensitivity and accessible software workflows makes FTIR microscopy a practical tool across R&D, QC and investigation laboratories.

References

Hannah Tiernan, et al. ATR-FTIR spectroscopy and spectroscopic imaging for the analysis of biopharmaceuticals. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 241, 2020, 118636.