Raman Spectroscopy as a Tool for Process Analytical Technology

Significance of the Topic

Raman spectroscopy offers molecular-level insights in chemical and pharmaceutical processes. Its rapid, noninvasive nature supports raw material verification under cGMP and PIC/S guidelines and real-time monitoring of reactions and crystallization processes. By enabling high-frequency, multivariate data collection, Raman facilitates enhanced process understanding, consistent product quality, and streamlined PAT implementation.

Objectives and Study Overview

The study aims to demonstrate portable Raman systems for three PAT applications:

• Raw material identification
• In-situ monitoring of API synthesis (2-phenylimidazo[1,2-a]pyridine)
• Real-time quantitative control of a boric acid crystallization process

Each case highlights the versatility of handheld or portable devices in development labs and production environments.

Methodology and Instrumentation

Raman measurements were carried out using B&W Tek's portable instruments:

• i-Raman Plus spectrometer with 785 nm, 300–350 mW laser, CCD detector spanning 65–3200 cm⁻¹
• Fiber-optic immersion probes for in-situ sampling
• NanoRam handheld unit for polymorph discrimination through packaging

Data acquisition parameters included 3 s integration with 10 co-additions for reaction monitoring and hourly acquisitions for crystallization control. Spectra were baseline-corrected and processed using univariate peak trends and multivariate PLS regression models developed in BWIQ software.

Main Results and Discussion

API Synthesis Monitoring:

• Reactants (2-aminopyridine at 847 cm⁻¹, 2-bromoacetophenone at 1684–1702 cm⁻¹) and product (2-phenylimidazo[1,2-a]pyridine at 1547 cm⁻¹ and 1603 cm⁻¹) peaks were tracked every minute.
• Trends revealed simultaneous decay of reactant signals and growth of product peaks, indicating reaction completion within 2 h, consistent across replicates.

Boric Acid Crystallization:

• Raman models quantified sodium sulfate (target 22–34 %) and boric acid concentrations via PLS over the 993 cm⁻¹ sulfate band.
• Online deployment over a month showed stable control below the solubility limit of 31.8 %, minimizing waste and optimizing yield.

Benefits and Practical Applications

Raman PAT provides:

• Noninvasive raw material verification, even through packaging
• Real-time reaction end-point detection, reducing reliance on sampling-intensive methods (e.g., TLC, HPLC)
• Quantitative process control via robust multivariate calibration
• Flexibility to transfer instruments between development and plant environments

Future Trends and Applications

Advances expected in detector sensitivity, probe design, and real-time chemometric algorithms will extend Raman PAT into continuous flow synthesis, bioprocess monitoring, and tighter integration with control systems. Miniaturization and wireless connectivity will foster wider onsite deployment and autonomous process feedback loops.

Conclusion

Portable Raman devices deliver comprehensive molecular data across the PAT lifecycle: from raw material ID to reaction monitoring and crystallization control. Their specificity, rapid acquisition, and adaptability support consistent product quality and process optimization in pharmaceutical and chemical manufacturing.

References

1. Bakeev KA (ed.), Process Analytical Technology, 2nd ed. Wiley, 2010.
2. US FDA Guidance for Industry: PAT, 2004.
3. EMA Guideline on Real Time Release Testing, 2012.
4. Slater JB et al., Handbook of Raman Spectroscopy, CRC Press, 2001.
5. Jestel NL, Process Analytical Technology, Wiley, 2010.
6. Paudel A et al., Adv Drug Deliv Rev, 2015.
7. Rantanen J, J Pharm Pharmacol, 2007.
8. Reid GL et al., Am Pharm Rev, 2012.
9. Chen X et al., Org Process Res Dev, 2015.