Process analytical technology (PAT) approaches allow continuous monitoring and real-time control of processes. Among the key monitoring technologies is Raman spectroscopy, which offers inline measurement that can reduce personnel time and sampling complexity
The chemical industry faces new challenges with increased demands on productivity, shifting geopolitical factors, intensified consumer focus on environmental sustainability and new initiatives in the circular economy. To be globally competitive, manufacturers are adopting new strategies in manufacturing that will improve efficiency, help realize energy savings, optimize resources and assure quality in real-time without the safety risks of collecting a grab sample. One strategy is the adoption of Industry 4.0 principles for improved connectivity, digitalization and automation. This approach encompasses automated, data-based control of the process and “smart sensors” that not only form the foundation of advanced process control but also indicates when sensor recalibration or replacement is necessary. A key component of Industry 4.0 is the use of inline sensors that report on the physical and chemical aspects of a chemical process. These sensors achieve real-time process monitoring and control, ensuring efficient use of energy, time and materials. While the integration of these sensors or analyzers with automation platforms and artificial intelligence is new, the concept of inline analysis is well-known in the chemical industry.
PAC and PAT approaches
Process analytical chemistry (PAC) was introduced in the 1980s with the use of process infrared (IR), process near-infrared (NIR), and at-line gas chromatography (GC) [1]. By 2011, PAC tools extended to microanalytical systems, sampling systems, mass spectrometry (MS), flow injection analysis, process Raman spectroscopy and process chemometrics [2]. PAC concepts were adopted by the pharmaceutical industry as process analytical technology (PAT) in 2004 as a framework to encourage innovation in pharmaceutical manufacturing [3, 4]. PAT solutions are intended to help users understand bio-based and chemical processes, with the ultimate goal of controlling quality throughout all stages of product manufacturing and of achieving quality by design (QbD).
An important goal of PAT implementation is to promote real-time release of products to decrease the cycle time and cost of production. This framework is meant to shift manufacturing to a risk-based approach where “quality should be built into a product with a thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks.” The pharmaceutical industry has embraced the PAT framework, which has moved the field of inline analysis forward with QbD and “Pharma 4.0” concepts that are proven to reduce time to market and improve manufacturing robustness. Advancements in PAT and QbD practices can benefit the chemical industry particularly as the industry reexamines inline analyses and adopts processes that involve biotechnology or bio-based materials.
The PAT toolbox
It is important to consider PAT as a toolbox. Analyzers and sensors comprise the tools of PAT, and they can be installed in a variety of locations, as shown in Figure 1. The most robust, most resilient PAT approach looks at laboratory and process using fit-for-purpose technology. An inline installation (a) is where a sensor or probe is placed directly into a reactor or stream, or through a sight glass, and measurements are continuously performed. At-line measurement (b) performs continuous measurement similar to inline, but measures the sample as it is diverted using a slip stream or diverting line. For an at-line (c) or off-line (d) implementation, a sample is taken from the reactor or stream and measured either next to the line or in a laboratory. Specifically for inline purposes, analyses include physical process parameters and chemical process parameters [5].
FIGURE 1. PAT tools can be implemented in a variety of installation sites, including the following: (a) inline; (b) at-line via a slip stream; (c) at-line next to the line via grab sample; and (d) off-line in the laboratory via grab sample
Physical parameters, such as turbidity, viscosity, flow, level, color, conductivity, pressure and temperature, provide necessary information on the process operation. Color, pH, conductivity, turbidity and viscosity provide indirect information on the sample chemistry. Analyzers complement physical and indirect chemical measurements. Inline chromatography, vibrational spectroscopy or optical analyzers provide more specific chemical identification that can infer physical or chemical properties. Vibrational spectroscopy includes near-infrared (NIR), infrared (IR), and Raman spectroscopy. These techniques can measure the chemical composition and molecular structure of sample. They are generally non-destructive and can be installed in a variety of laboratory or process environments.
Raman spectroscopy
Raman spectroscopy has unique attributes, including the ability to measure in aqueous media without a defined pathlength. In addition, it exhibits relative insensitivity to particle size, as well as compatibility with solids, liquids, gases or turbid media. Its ability to scale from the laboratory to pilot to manufacturing without significant scale-specific model rework is another benefit that makes Raman spectroscopy a strong “lab-to-process” PAT candidate.
Raman spectroscopy is useful for three main industrial purposes: qualitative (identification), quantification (how much) and monitoring and controlling change. For qualitative uses, molecular spectroscopy can identify the chemical composition of a material and its molecular structure. The identification usage of molecular spectroscopy is broadly applied to measure the composition of solids, liquids or gaseous materials for the following reasons:
• Understanding multiple aspects of a complex material
• Understanding the molecular structure of a polymer
• Understanding moisture content
• Identifying contaminants in a mixture
For quantification uses, molecular spectroscopy can provide the concentration of single or multiple components, or the ratio of those components. The quantification capabilities can be used to monitor change of a process, which is especially useful for determining when to end a processing step or when to add more ingredients to a long-running process. Quantification by molecular spectroscopy can be applied to solids, liquids and gases. Some examples of quantification or change monitoring by molecular spectroscopy include: measuring feed and byproducts; and monitoring the relative amount of starting material and end material in a chemical reaction.
Finally, quantification and change monitoring can lead to process-control applications. Some examples of process control applications include the following:
• Integration of multivariate analysis to understand and monitor several components in a mixture
• Automated timing for adding new material media
• Stopping a processing step based on the amount or quality of the product formed
Key applications for Raman
The following are brief descriptions of three key application areas for Raman spectroscopy, when used in a PAT context.
Polymerization monitoring. Polymerization processes have become more complex and often require tighter control of process parameters. There are several important business reasons for polymerization monitoring. Some reasons include the improved safety of not needing to pull a grab sample, timely endpoint detection and ensuring correct polymer grade. Closed-loop control strategies are necessary to achieve these business goals, especially to produce large volumes. Inline analyses is a critical component of that strategy to ensure the safe production of high-quality product.
An example of successful polymer analysis with Raman spectroscopy is polystyrene, an important polymeric material with many uses. Figure 2 shows a Raman spectrum of polystyrene. What should be noted about the spectrum is that the peaks correspond to known chemical moieties. Raman peaks are sharp, identifiable and quantifiable, which makes robust process monitoring and control possible. Styrene polymerization can be easily quantified using the area or intensity ratio of the styrene vinyl bond at 1,630 cm−1 to the 1,000-cm−1 aromatic ring breathing.
FIGURE 2. The chemical structure of polystyrene (upper right) and its Raman spectrum. The sharp Raman bands of polystyrene correspond to specific chemical structures and can be used to identify, monitor and quantify the polymer
Raman-derived concentration predictions closely match measurements carried out by gravimetry, but without the need for sample extraction. The work reported by Brun and others [6] indicates that Raman spectroscopy could be part of a control strategy to avoid process upsets and ensure quality of the polymer product. Specifically, these results demonstrate the utility of Raman spectroscopy for monitoring the polymerization of styrene into polystyrene. The data were able to be generated quickly (in a matter of seconds) and corresponded well with data obtained by classical gravimetric methods, which are known to give good results, but which are also cumbersome and time-consuming.
Reaction monitoring. An application similar to polymerization is reaction monitoring. In one example, Csontos and others [7] developed a feedback control loop based on Raman spectroscopy for a hazardous exothermic oximation reaction. They were able to determine the end point of the process reaction by following the quantification of reaction components and an unstable intermediate.
This was a successful example of how Raman spectroscopy can provide visibility into an industrial chemical reaction, allowing for real-time control of the overall process. Similarly, Hart and others [8] were able to develop an accurate Raman calibration model for end-point determination of an etherification, where the residual level of chloropyrazine starting material needed to be minimized. At the outset, they were aware that the reaction may be scale-dependent, since a heterogenous base (K2CO3) was used. They successfully demonstrated that the calibration work for reaction end-point determination carried out at the laboratory scale was easily transferred to the scaled-up pilot plant, with predicted results closely matching manual off-line high-performance liquid chromatography (HPLC) results. Raman spectroscopy has also been used to improve the scientific community’s understanding of the reaction kinetics of many processes, such as mechanochemical Knoevenagel condensations [9]. In one such study by Hart and others, crystallization properties were examined for the condensation of three fluorinated benzaldehyde derivatives and malononitrile using in-situ Raman spectroscopy.
Carbon capture, utilization and storage (CCUS). As the industrial community continues to find ways of dealing with climate change, Raman spectroscopy will play an increasingly significant role in controlling and optimizing industrial processes that involve greenhouse gases like carbon dioxide (CO2). Amine-based materials are effective in capturing and storing CO2, and Raman spectroscopy is emerging as an important tool to ensure optimal CCUS processes. Jinadasa and others [10] demonstrated the ability of Raman spectroscopy to effectively monitor speciation of a CO2-capture process for both the lean and rich amine streams at the laboratory scale. The integration of Raman spectroscopy into a lean amine stream during acid-gas removal was described by Bergmann and van der Veer [11]. They found that Raman spectroscopy provided an inline measurement of multiple components, including methyldiethanolamine (MDEA), water, piperazine, carbon dioxide and hydrogen sulfide.
Other chemical process involving carbon chemistry, such as the common Suzuki-coupling reactions of the C-C bond, can also benefit from Raman spectroscopy through yield optimization. In this scenario, parameters like temperature and concentration can be varied independently within reaction limits to find optimal operating conditions. In doing so, Heteni and Janagap were able to develop a robust partial least squares model using their experimental Raman spectra. Online predictions from the model agreed well with offline GC-MS measurement of reaction yield [12].
Concluding remarks
As industrial manufacturing becomes more automated with increased demands on sustainability, we see a renewed enthusiasm for PAC and PAT. PAC has a rich 40-year history to support industrial processes and has evolved since the early 2000s into the PAT framework. The PAT framework encourages innovation using risk-based manufacturing approaches and the integration of analytical technologies. Inline analysis allows for 24/7 monitoring without the need to collect samples. With inline PAT, there are additional benefits, including the ability to quickly gain product or process knowledge, implement advanced control strategies, realize real-time product release and ensure process and product quality in real time.
Identification of the right technology (or technologies) for the right process has business and application considerations. Raman spectroscopy is a valuable tool in the PAT framework with proven successes across many industries. A key value for Raman spectroscopy lies in its potential to replace offline laboratory measurements with an inline method. An inline Raman system reduces the need to manually sample from the process that saves personnel time, reduces complexity in obtaining an offline sample, and increases safety through unmanned monitoring of hazardous processes or products. Raman’s measurement capabilities, integration into automation, and process-ready equipment facilitate rapid process development from the laboratory to manufacturing. New prospects in Raman spectroscopy that include sustainable energy, biotechnology processes and “ease-of-use” design aspects make Raman a practical analytical tool for the chemical industry.
Edited by Scott Jenkins
References
1. Callis, J.B., Illman, D.L., Kowalski, B.R., Process analytical chemistry. ACS Publications. https://doi.org/10.1021/ac00136a001.
2. Workman, J., Lavine, B., Chrisman, R., Koch, M., Process Analytical Chemistry, Analytical Chemistry, 83 (12), 4,557–4,578, 2011. https://doi.org/10.1021/ac200974w.
3. Center for Drug Evaluation and Research (CDER). Pharmaceutical Quality for the 21st Century: A Risk-Based Approach Progress Report. U.S. Food and Drug Administration (FDA), 2007.
4. U.S. Food and Drug Administration. Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, 2004.
5. O’Donnell, C.P., Cullen, P.J., Emerging PAT Technologies, In Process Analytical Technology for the Food Industry, O’Donnell, C.P., Fagan, C., Cullen, P.J., Eds., Food Engineering Series, Springer, New York, N.Y., pp 247–267, 2014.
6. Brun, N., Youssef, I., Chevrel, M.C., Chapron, D., Schrauwen, C., Hoppe, S., Bourson, P., Durand, A. In Situ Monitoring of Styrene Polymerization Using Raman Spectroscopy. Multi-Scale Approach of Homogeneous and Heterogeneous Polymerization Processes: Journal of Raman Spectroscopy, 44 (6), 909–915, 2013. doi.org/10.1002/jrs.4279.
7. Csontos, I., Pataki, H., Farkas, A., Bata, H., Vajna, B., Nagy, Z.K., Keglevich, G., Marosi, G.J. Feedback Control of Oximation Reaction by Inline Raman Spectroscopy. Organic Process Research & Development, 19 (1), 189–195, 2015. doi.org/10.1021/op500015d.
8. Hart, R.J., Pedge, N.I., Steven, A.R., Sutcliffe, K., In Situ Monitoring of a Heterogeneous Etherification Reaction Using Quantitative Raman Spectroscopy. Organic Process Research & Development, 19 (1), 196–202, 2015. doi.org/10.1021/op500027w.
9. Haferkamp, S., Kraus, W., Emmerling, F., Studies on the Mechanochemical Knoevenagel Condensation of Fluorinated Benzaldehyde Derivates. J. Mater. Sci., 53 (19), 13713–13718, 2018. https://doi.org/10.1007/s10853-018-2492-0.
10. Jinadasa, M.H., Jens, K.J., Øi, L.E., Halstensen, M., Raman Spectroscopy as an Online Monitoring Tool for CO2 Capture Process: Demonstration Using a Laboratory Rig. Energy Procedia, 114, 1179–1194, 2017.
11. Bergmann, R., van der Veer, M., The Development Journey, Hydrocarbon Engineering, May 2019.
12. Hetemi, D., Janagap, S., Application of Experimental Design and Multivariate Analysis in the On-Line Reaction Monitoring of a Suzuki Cross-Coupling Reaction by Raman Spectroscopy and Multivariate Analysis. Vibrational Spectroscopy, 100, 93–98, 2019.
13. King, P. P., Biotechnology: An Industrial View, Journal of Chemical Technology and Biotechnology 1982, 32 (1), 2–8, 1982.
14. Noda, I., Green, P.R., Satkowski, M.M., Schechtman, L.A., Preparation and Properties of a Novel Class of Polyhydroxyalkanoate Copolymers. Biomacromolecules, 6 (2), 580–586, 2005.
Acknowledgements
The images that appear in this article are provided by Endress+Hauser
Authors
Karen Esmonde-White is a Product Manager at Endress+Hauser (2350 Endress Place, Greenwood, IN 46143; Phone: 888-363-7377; LinkedIn profile: https://www.linkedin.com/in/karen-esmonde-white-067a823/), focusing on optical analysis in food & beverage and chemical applications. She completed her Ph.D. in biomedical engineering at the University of Michigan in 2009. She also holds a M.Eng. in pharmaceutical engineering and a M.S. and B.S. in Chemistry. In addition to her research, Karen is an active volunteer for the SciX conference, Federation of Analytical Chemistry and Spectroscopy Societies, the Society for Applied Spectroscopy and the Coblentz Society, and serves as a reviewer for spectroscopy, clinical and biomedical optics journals.
Carsten Uerpmann is working as a business industry manager focusing on the use of optical analysis in the chemical industry. Starting chemistry at the University of Heidelberg (Germany), he completed his Ph.D. in metal-organic chemistry at the University of Montpellier (France) in 2003 and a post-doctoral fellowship in medicinal chemistry in Barcelona, Spain in 2005. He started working for E+H Process Analytical Support in Lyon, France in 2005. Uerpmann is also an active member of the PAT working group of the German Chemical Society, as well as a supporter for the Process Analytical Award for Young Scientists.