Formulation scientists are tasked with transforming an active pharmaceutical ingredient (API) into a stable, bioavailable and commercially viable dosage form, a journey which rarely proves straightforward. During formulation development and manufacturing, common issues such as polymorphic conversions, excipient incompatibilities, API degradation and real-time process drifts can all threaten product safety, efficacy and regulatory compliance.

The core challenge lies in balancing chemical, physical and performance characteristics while ensuring batch consistency and alignment with industry regulations. Spectroscopy has long supported the detailed analytical insights required to navigate these challenges, but its strategic importance has grown following the FDA’s Process Analytical Technology (PAT) initiative1 and the ICH Quality Guidelines, which emphasise Quality by Design (QbD) principles for robust pharmaceutical product and process design.2,3

These interlinked demands highlight the importance of rapid, flexible and practicable analytical tools across the product life cycle. Fourier transform infrared (FTIR) spectroscopy addresses these needs through sensitive, rapid and non-destructive molecular fingerprinting of solid, semi-solid and liquid formulations without extensive sample preparation. It offers inline, at-line or offline material characterisation in both R&D and manufacturing environments, providing actionable insights into critical quality attributes (CQAs), accelerating process optimisation, and supporting every phase of pharmaceutical formulation development.

This article introduces FTIR for pharmaceutical analysis and explains how it supports factors critical to formulation success, highlighting a range of spectroscopy accessories and experimental approaches that could benefit R&D leads, QC managers and researchers working in the field.

FTIR spectroscopy – versatile and accessible for formulation needs

Essentially, FTIR spectroscopy characterises molecules based on how they absorb infrared (IR) light. Spectra are typically recorded in the mid-IR range (4,000–400 cm−1), but some pharmaceutical applications also cover the near-IR (NIR) region (12,800–4,000 cm−1).4

A spectral ‘fingerprint’ is produced that reflects the vibrational modes of chemical bonds in the sample (as we explain in a previous article). These modes are highly sensitive to the molecular environment,5 making FTIR ideal for monitoring polymorphic forms and other subtle changes, and offering formulation scientists rapid access to detailed chemical insights without destroying the sample. The broad applicability of FTIR – from powders and tablets to gels, suspensions and even multicomponent blends (e.g., for excipient compatibility testing) – makes it a valuable tool for iterative formulation design and optimisation.

Accessories for real-world formulation analysis

In pharmaceutical settings, practicable FTIR analysis relies on accessories that adapt the spectrometer to required sample types. Dedicated accessories support the three main FTIR sampling modes: transmission/absorbance, attenuated total reflectance (ATR) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). If unfamiliar with these terms, refer to our introductory guides on transmission vs ATR spectroscopy and DRIFTS for more information.

For teams working across solid, semi-solid and liquid formats, flexibility in sampling mode is essential to streamline workflows, as well as ensuring robust analytical sensitivity and reproducibility across a variety of formulation tasks. The Specac range offers several accessories to support these workflows.

Simplifying liquid analysis

For solution-based formulations, the Specac Pearl™ Accessory simplifies a traditionally preparation-heavy process. The sample cell enables fast and easy loading and cleaning, while ensuring a precise path length to greatly simplify transmission FTIR analysis.

This Application Note shows how the Pearl™ was used to analyse two over-the-counter simeticone products with different dosage forms (tablet and liquid). The API content was determined according to the European Pharmacopoeia standard of toluene extraction followed by FTIR analysis, with comparison to reference solutions (see Figure 1). Both test samples closely matched the dosage stated on the label, demonstrating that the Pearl is an excellent choice for QC labs.

Figure 1. Overlay of FTIR spectra obtained using the Pearl™ for three different simeticone formulations. This spectral region corresponds to the methyl deformation vibration of the API.

Formulation and QC of peptide drugs

Also designed for low-volume liquid samples, the Harrick ConcentratIR2™ Multiple Reflection ATR Accessory incorporates a multi-bounce ATR crystal to significantly enhance signal-to-noise ratio, even at low analyte concentration.

A recent Application Note demonstrates high-quality spectra of two peptide drugs (ziconotide and calcitonin) in the µg/mL range, directly from injectable formulations, using simple buffer subtraction. This highlights ConcentratIR2™ as an ideal QC and formulation development tool for therapeutic peptides and proteins at low concentrations.

Precision for solids and high-stress conditions

The Specac Golden Gate™ Diamond ATR Accessory is widely used in formulation studies. Its monolithic diamond crystal offers excellent durability and optical clarity, making it ideal for routine analysis of solid and semi-solid dosage forms. The range also includes variants for specialised applications:

Applying FTIR in pharmaceutical formulation and control

FTIR provides fast, non-destructive molecular insights that support formulation development and manufacturing throughout the product life cycle. Notable application areas include:

Product formulation design

Drug–excipient compatibility studies track shifts in key spectral bands to screen for unwanted molecular interactions.6 For instance, ATR-FTIR and complementary techniques were used to reveal that levodopa, an essential Parkinson’s disease medication, is incompatible with many common excipients.7

Polymorph monitoring

Different polymorphs affect stability and bioavailability, potentially impacting safety and efficacy,8 but subtle IR shifts can track these forms. Using the Golden Gate High Temperature ATR Accessory, researchers unambiguously profiled paracetamol polymorphs via variable temperature ATR-FTIR.9 These phase changes are important for commercial manufacturing but are challenging to monitor by other techniques, due to similar transition temperatures.

Quality control in pharmaceutical manufacturing

Once a formulation is selected, ensuring batch consistency is essential. Blend uniformity is critical for all solid oral formulations, especially for APIs with a narrow therapeutic window.10 Moisture content is a vital CQA for solid dosage forms, while API identity and concentration also require accurate assessment.

  • Several studies have developed inline NIR-based monitoring methods for real-time analysis of homogeneity in blending processes, spanning R&D to manufacturing scales.11–13
  • Following QbD principles, other researchers developed and validated an analytical method for moisture content from 2–20% in pharmaceutical tablets, based on DRIFTS measurements from a handheld NIR spectrometer.14
  • DRIFTS also offers a rapid, non-destructive alternative to traditional Karl Fischer titration for moisture analysis in the chemotherapy drug 5-fluorouracil.15
  • A similar approach proved successful for measuring pimavanserin, a Parkinson’s disease psychosis treatment, which had previously lacked a spectroscopic quantitation method.16 Many other APIs may be quantified using FTIR.4

These examples illustrate why FTIR-enabled analyses are increasingly embedded into PATframeworks and continuous manufacturing strategies. The speed of FTIR data acquisition and flexibility of chemometric models support real-time monitoring of CQAs and implementation of QbD principles, such as detecting process drifts due to raw material variability.17

Product integrity: Ensuring consistency and compliance

Impurity and identity profiling are essential for product safety. Beyond batch variability and release testing, notable applications of FTIR in this area include:

  • Rapid ATR-FTIR screening to distinguish expired versus compliant tablets of a common antibiotic, co-amoxiclav. This is thought to reflect slow formation of degradation products from the less stable clavulanic acid component.18
  • Discriminating between authentic and counterfeit medicinal products. One study used ATR-FTIR fingerprinting (1,800–525 cm−1) to accurately differentiate adulterated and genuine tablets of tadalafil and sildenafil, based on differences in composition.19

Emerging applications

Looking forward, two exciting frontiers in pharmaceutical formulation deserve mention:

1. Point-of-care analysis of 3D printed dosage forms

Although levetiracetam remains the only commercial example, increased adoption of 3D printed dosage forms in personalised medicine is anticipated in the near future.20,21

  • FTIR may enable QC of 3D printed dosage forms produced in point-of-care clinical settings,20 based on existing results with griseofulvin, indomethacin and nifedipine formulations.22

2. Potential application in RNA therapeutics

Many RNA therapeutics are in clinical trials,23 and the field needs suitable analytical methods for these new medicines.24

  • FTIR is sensitive to RNA structure25 and supports fundamental RNA biology research.5 It may add value for pharmaceutical RNA formulation, and this remains to be explored.

Enabling smarter, safer formulation through FTIR

In an industry where product quality, regulatory compliance and patient safety are non-negotiable, rapid and reliable analytical tools are indispensable. For formulation scientists, FTIR spectroscopy offers speed and versatility to support better decisions and enhance optimisation efforts across the development life cycle. Its importance is set to grow as the industry moves towards a modern, data-driven approach to pharmaceutical R&D and manufacturing, under PAT and QbD frameworks where risk mitigation is tied to real-time data.

Inline FTIR analysis shows particular promise in monitoring blend uniformity in powder mixers, to avoid detrimental excessive blending without interrupting the process.10,26 Real-time data integrations allow immediate feedback to manufacturing systems, enhancing compliance and minimising failures.

Purpose-built accessories like the Pearl™ and ConcentratIR2™ for liquids, and the Golden Gate range for diverse sample types, further enhance the flexibility of FTIR across multiple formulation applications.

To see how these accessories can transform your workflows, from the lab bench to QC and commercial production, watch our expert-led webinar for more information.

References

  1. US Food and Drug Administration, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, Docket Number FDA-2003-D-0032, Rockville, MD, 2004, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pat-framework-innovative-pharmaceutical-development-manufacturing-and-quality-assurance, (accessed July 2025).
  2. Understanding ICH guideline Q14, https://www.pharmaceutical-technology.com/sponsored/understanding-ich-guideline-q14/, (accessed July 2025).
  3. L. X. Yu, G. Amidon, M. A. Khan, S. W. Hoag, J. Polli, G. K. Raju and J. Woodcock, AAPS J., 2014, 16, 771–783.
  4. Y. Roggo, P. Chalus, L. Maurer, C. Lema-Martinez, A. Edmond and N. Jent, J. Pharm. Biomed. Anal., 2007, 44, 683–700.
  5. E. Balduzzi, F. Geinguenaud, D. Sordyl, S. Maiti, M. A. Farsani, G. Nikolaev, V. Arluison and J. M. Bujnicki, Nucleic Acids Res., 2025, 53, D157–D162.
  6. A. A. Bunaciu, V. D. Hoang and H. Y. Aboul-Enein, Appl. Spectrosc. Rev., 2025, 60, 385–403.
  7. I. Ledeti, S. Bolintineanu, G. Vlase, D. Circioban, A. Ledeti, T. Vlase, L.-M. Suta, A. Caunii and M. Murariu, J. Therm. Anal. Calorim., 2017, 130, 433–441.
  8. J. Lu and S. Rohani, Curr. Med. Chem., 2009, 16, 884–905.
  9. B. Zimmermann and G. Baranović, J. Pharm. Biomed. Anal., 2011, 54, 295–302.
  10. S. Talwar, P. Pawar, H. Wu, K. Sowrirajan, S. Wu, B. Igne, R. Friedman, F. J. Muzzio and J. K. Drennen III, AAPS J., 2022, 24, 103.
  11. A. Khanolkar, B. Patil, V. Thorat and G. Samanta, AAPS PharmSciTech, 2022, 23, 235.
  12. Y. Li, C. A. Anderson, J. K. Drennen III, C. Airiau and B. Igne, Appl. Spectrosc., 2019, 73, 1028–1040.
  13. Z. Shi, K. S. Rao, P. Thool, R. Kuhn, R. Thomas, S. Rich and C. Mao, AAPS J., 2023, 25, 9.
  14. A. Patel, C. Jin, B. Handzo and R. Kalyanaraman, J. Pharm. Biomed. Anal., 2023, 229, 115381.
  15. P. Singh, D. K. Jangir, R. Mehrotra and A. K. Bakhshi, Drug Test. Anal., 2009, 1, 275–278.
  16. S. S. Panda, R. K. V. V. Bera, J. Panda, Vib. Spectrosc., 2020, 107, 103039.
  17. B. Igne, Z. Shi, J. K. Drennen III and C. A. Anderson, J. Pharm. Sci., 2014, 103, 545–556.
  18. M. Foschi, M. Marziale and A. Biancolillo, Pharmaceuticals, 2022, 15, 763.
  19. R. S. Ortiz, K. de Cássia Mariotti, B. Fank, R. P. Limberger, M. J. Anzanello and P. Mayorga, Forensic Sci. Int., 2013, 226, 282–289.
  20. M. Lyousoufi, I. Lafeber, D. Kweekel, B. C. M. de Winter, J. J. Swen, P. P. H. Le Brun, E. C. M. Bijleveld-Olierook, T. van Gelder, H.-J. Guchelaar, D. J. A. R. Moes and K. J. M. Schimmel, Clin. Pharmacol. Ther., 2023, 113, 1125–1131.
  21. Entering new domains for 3D printing of drug products, https://www.pharmtech.com/view/entering-new-domains-3d-printing-drug-products, (accessed July 2025).
  22. M. Deon, J. dos Santos, D. F. de Andrade and R. C. R. Beck, Int. J. Pharm., 2022, 628, 122293.
  23. A. Curreri, D. Sankholkar, S. Mitragotri and Z. Zhao, Bioeng. Transl. Med., 2023, 8, e10374.
  24. A. Demelenne, A.-C. Servais, J. Crommen and M. Fillet, J. Chromatogr. A, 2021, 1651, 462283.
  25. F. Geinguenaud, V. Militello and V. Arluison, in RNA Spectroscopy, ed. V. Arluison and F. Wien, Humana, New York, 2020, ch. 10, pp. 119–133.
  26. Y. Hattori and M. Otsuka, Anal. Sci., 2017, 33, 65–68.

Get in touch

Related Posts