Chemical Imaging for Pharmaceutical Process Analytical Technology

Mid-infrared (mid-IR) spectroscopy is an established imaging method for characterizing a broad range of materials and advancements in the technique have rendered it cost-effective, rapid, and non-destructive. Mid-IR imaging can be applied in the identification of materials and for the quantification of the distinctive elements contained in mixtures.

The size of mid-IR spectrometers has been reduced by technological advancements, and the need for liquid nitrogen cooling has been eliminated, making it more applicable for industrial uses. Besides, at present, new instrumentation is completely automated and supported with data analysis tools that are user-friendly, thus allowing even non-skilled operators to perform IR spectroscopy and interpret results.

Hence, the use of mid-IR spectroscopy in industry has largely increased in the recent years. It has been largely used in industrial process management in several different types of industries, such as synthetic and chemical polymers, semiconductors, and so on.

Yet, until recent times, mid-IR spectroscopy did not find wide applications in the pharmaceutical industry for at-line, real-time, or online analysis. This transition toward mid-IR analysis was mostly coaxed by an FDA directive requiring phase-by-phase monitoring of pharmaceutical processes, that is, process analytical technology. Only now has the prospective value of IR spectroscopy been appreciated, and there is an increase in the extent of distinctive applications of the technology in the pharmaceutical industry.1

What Information Does Mid-Infrared Provide?

Mid-IR spectroscopy involves the analysis of interactions between the molecules within a sample and infrared light. It is one of the standard and widely used spectroscopic methods. When IR light is used for exciting molecules, they tend to vibrate. The vibration frequency differs according to the functional groups existing in the molecules and the molecular bond strength. The response is unique for every chemical compound. Each component has a distinctive “fingerprint” region in its infrared absorption spectrum.

Among the three infrared light regions, the region most suitable for identifying compounds for process monitoring is mid-IR, which extends from a wavelenth of 2.5 to 25 μm.2 Low-energy far IR is mainly used for the measurement of inorganic molecules. In contrast, near-IR region is used for food applications, for example, determining fat or moisture content.

Basic absorption bands providing a molecular fingerprint fall within the mid-IR region. Absorption bands in the near-IR region emerge as a result of combination bands and overtones of the fundamental bands in the mid-IR region. Hence, only less clear spectra can be obtained from the near-IR region; yet, it is advantageous as it allows the contents to be analyzed without removing them from the container.

The Advantages of Spectroscopy over Other Techniques

IR spectroscopy offers several intrinsic advantages; hence, it is now commonly regarded as an alternative for conventional chemical analysis. The method can be largely applied to a broad range of samples without any need for extraction, which usually leads to degradation of components and can result in contamination. Besides, since the need for laborious sample preparation is eliminated, the analysis time is substantially reduced, enabling precise data to be rapidly obtained.

Moreover, a sample’s chemical and physical parameters can be determined simultaneously, further saving the analysis time. One added benefit of mid-IR spectroscopy is the fact that it is a non-destructive analytical tool, thus enabling the sample to be preserved to render it available for later analysis.

Despite the need for chemometric techniques (for example, Fourier transformations) for interpreting spectroscopic data, the software required to perform such calculations is readily available. Thus, data analysis can be fully automated. In addition, results are obtained electronically, thus allowing the results to be easily matched with spectral archives for rapid identification of components by even non-specialist operators.

Latest enhancements to the mid-IR technologies have rendered it feasible to use them with liquid chromatographic techniques (for example, HPLC) to determine even trivial chemical attributes of a sample.

With the FDA establishing the process analytical technology initiative, the advantages have turned out to be especially valuable.

Mid-IR Spectroscopy in the Pharmaceutical Industry

In the pharmaceutical industry, the end product is specifically expected to be precisely as intended to make sure that medicines have the targeted efficacy. Therefore, effective molecular, microbiological, and elemental analyses are important in every stage of the production process, from characterizing the raw materials and preparation processes to quality control of the final product.

Hence, mid-IR imaging has turned out to be a promising technology in the pharmaceutical industry as it is well-suited for analyzing liquid, solid, and biotechnological pharmaceutical forms.3 Mid-IR imaging enables the assessment of reactions at the time of production, quick visualization of the distribution of excipients and active components in tablets, and the detection of contaminants. Incorporation of spectroscopic analysis into the routine process control enables the use of highly efficient processes to ensure the manufacture of safer medicines. The method also allows characterizing drug formulations and determining drug release mechanisms and kinetic processes.

Particularly, mid-IR spectra seem to be specifically sensitive to the distinctive polymorphic forms of a drug. The polymorphic form taken by a drug could have an impact on the ease of manufacturing, stability, and efficacy of a pharmaceutical compound. Therefore, it is highly advantageous to be in a position to identify and detect the polymorphic forms that exist during the production of pharmaceuticals.

The ever-growing presence of biogenic treatments, such as monoclonal antibodies, has rendered the monitoring of pharmaceutical production more complicated. As the final product in biogenic treatments is usually a protein, it is vital to ensure it folds correctly to achieve the suitable, efficacious structure. In the same way, in case post-translational modification of the protein is necessary (for example, glycosylation), care should be taken to ensure that the modification is performed accurately. Mid-IR spectroscopy can reassure both these conditions in real time.

Mid-IR Chemical Imaging—The Spero™

Despite the fact that Fourier transform spectrometers have continued to dominate the market for mid-IR spectrometry, constant innovation has been pursued to create instruments with higher sensitivity or resolution.

One such innovative mid-IR imaging technology is the high-power quantum cascade laser (QCL), which allows greater detail to be achieved within a fraction of time required in the case of traditional infrared spectroscopy. Being a leading provider of mid-IR, QCL sources, analyzers, and microscopes, Daylight Solutions has developed the first commercially accessible laser-based infrared microscope called Spero®.4

Their state-of-the-art QCL-infrared spectroscopy technology, integrated into the Spero™, has a tunable, ultra-bright laser light source that provides higher resolution with a broad field of view. Taken together, these aspects enable a rapid throughput of samples that can render sample screening rapid by several orders of magnitude. Furthermore, they offer a live mode that facilitates imaging to be performed in real time.

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Apart from the Spero mid-IR microscope, a mid-IR liquid analyzer has been developed to allow liquid process monitoring, which involves aqueous protein monitoring, in the pharmaceutical industry. The ChemDetect™ Liquid Analyzer taps the power of QCLs for analyzing and identifying chemicals, apart from being being portable and compact.4 It integrates the most recent widely tunable, high-speed QCL technology with enhanced, uncooled detection capability. An embedded computer programmed with chemical identification algorithms guarantees speed and accuracy.


  1. Buckley K and Ryder AG. Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review. Applied Spectroscopy 2017;71(6):1085–1116.
  2. Cozzolino D. Infrared Spectroscopy as a Versatile Analytical Tool for the Quantitative Determination of Antioxidants in Agricultural Products, Foods and Plants. Antioxidants 2015;4(3):482–497.
  3. Griffiths PR. Mid-Infrared Spectroscopy in the Pharmaceutical Industry. American Pharmaceutical Review 30 November 2015. Available at
  4. Daylight Solutions website.

This information has been sourced, reviewed and adapted from materials provided by Daylight Solutions Inc.

For more information on this source, please visit Daylight Solutions Inc.

Last updated: Jun 8, 2018 at 3:23 PM

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