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

Importance of the topic

Fourier transform infrared (FTIR) microscopy has become a critical analytical tool in pharmaceutical research, development and quality control. It uniquely combines high-resolution visible imaging with spatially resolved chemical information, enabling identification and localization of active pharmaceutical ingredients (API), excipients, polymorphs, particle agglomerates and foreign particulates. These capabilities support faster formulation optimization, root-cause analysis of failures, counterfeit detection and assessment of biologic stability—all of which directly impact product safety, efficacy and time-to-market.

Study objectives and overview

This application note demonstrates practical FTIR microscopy workflows and outcomes for three pharmaceutical use cases: mapping drug distribution from metered dose inhalers (MDIs), comparing API/excipient distribution in tablets for quality control, and characterizing biologics formulation components and protein secondary structure in dried drops. The examples illustrate speed, spatial resolution and software-driven data analysis (including multivariate curve resolution and library searches) to obtain actionable chemical imaging results for R&D and QC laboratories.

Methodology and workflow

• Sample preparation varied by application: MDI emissions were deposited onto a gold-plated slide by actuation; tablets were analyzed directly by mapping; an insulin formulation was deposited as µL droplets onto a barium fluoride window and dried.
• Data collection modes included reflectance/reflection imaging for sprayed deposits and dried films, and attenuated total reflectance (Ge ATR contact mapping) for high signal-to-noise tablet mapping.
• Spatial mapping parameters: a reported tablet mapping used a 25 µm step size across ~1200 × 950 µm areas; a dried insulin area of 10 × 10 mm was mapped in reflection mode. The system supports infrared spatial resolution below ~5 µm (without ATR) and submicron visual imaging.
• Software processing: OMNIC Paradigm software enabled automated multi-area acquisition, multivariate curve resolution (MCR) to decompose mixed spectra into component distributions, and multi-component library searching to identify formulation constituents.

Used instrumentation

• Nicolet RaptIR FTIR Microscope (Thermo Scientific) combining high-quality visible microscopy and FTIR chemical mapping.
• Ge ATR accessory for contact-mode ATR mapping (high signal-to-noise, small-area mapping).
• Gold-plated microscope slides for reflectance deposition of MDI sprays.
• Barium fluoride (BaF2) infrared-transparent window for dried biologic drops.
• OMNIC Paradigm software suite for automated acquisition, MCR, and multi-component spectral searching.

Main results and discussion

• MDI spray mapping: Wide-field visible images combined with reflectance FTIR maps revealed non-uniform drug deposition across the sprayed profile. MCR analysis identified the API (salbutamol sulfate) and revealed heterogeneity and agglomeration; crystallinity and particle morphology changes were observable—features relevant to aerosol performance and bioavailability.
• Tablet QC comparison: Two tablets with identical nominal composition produced different spatial distributions. Ge ATR chemical mapping with 25 µm steps and MCR decomposition yielded three modeled components identified as acetaminophen, sodium bicarbonate and starch. One tablet showed more homogeneous component distribution and larger domain sizes than the other, indicating likely differences in formulation processing or compression despite identical formulations.
• Biologics formulation mapping: Dried insulin spots were analyzed in reflection mode. Multicomponent spectral search identified insulin and excipients (glycerol, phenol, meta-cresol). Chemical maps showed heterogeneous drying patterns with partial separation of glycerol and insulin; single-point spectra matched library signatures, supporting formulation component verification. Infrared microspectroscopy can also probe protein secondary structure and detect misfolding or fibril formation via amide band analysis.

Benefits and practical applications

• Rapid, spatially resolved chemical identification supports formulation optimization, reverse engineering and troubleshooting without destructive bulk assays.
• Ability to detect and map agglomerates, large particles and foreign particulates helps meet USP recommendations for inhalation product inspection and supports complaint investigations and counterfeit detection.
• High spatial resolution IR mapping plus visual imaging aids QC release testing by exposing batch-to-batch variability not evident from bulk analyses.
• For biologics, IR microspectroscopy provides a complementary approach to assess protein secondary structure, excipient distribution and early indicators of instability (misfolding, fibrillation) in formulation development.

Future trends and applications

• Faster automated mapping and more powerful multivariate algorithms will further lower the barrier for non-expert users to obtain high-quality chemical images for QC and R&D workflows.
• Integration of higher spatial resolution detectors and advanced ATR optics will expand capability to characterize nanoparticles, thin films and subcellular biological features relevant to advanced therapeutics.
• Combining FTIR microscopy with orthogonal techniques (Raman imaging, SEM/EDX, mass spectrometry imaging) will improve identification confidence for complex samples and trace contaminants.
• Machine learning applied to spectral imaging datasets will enable predictive quality assessments, automated defect/contaminant classification and enhanced counterfeit detection at scale.

Conclusion

FTIR microscopy, exemplified by the Nicolet RaptIR system and supported by OMNIC Paradigm software, delivers rapid, spatially resolved chemical and visual information that is highly relevant across pharmaceutical development and quality control. The method identifies APIs and excipients, maps their distribution, highlights agglomeration and crystallinity issues, and supports biologics formulation assessment. These capabilities accelerate formulation optimization, improve QC sensitivity to manufacturing variability and provide robust evidence for investigations of performance or contamination.

References

1. Tiernan H., et al. ATR-FTIR spectroscopy and spectroscopic imaging for the analysis of biopharmaceuticals. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2020;241:118636.
2. Manufacturer application note: Thermo Fisher Scientific. Nicolet RaptIR FTIR Microscope application note (AN53482_E 02/22M). For research use only. Not for use in diagnostic procedures. © 2022 Thermo Fisher Scientific Inc.