In-Process Raman Spectroscopy of Layered Materials

Key Issues:

• Sampling flexibility of Raman enables cross-sectional and /or bulk product analysis

• Large volumetric measurements provide data on subsurfaces in layered samples

• Enhanced reflection improves Raman sensitivity for in-process measurements

Materials such as pharmaceutical tablets or graft copolymers are chemically and spatially heterogeneous materials. Chemical analysis of these materials requires non-destructive techniques in order to also capture the spatial heterogeneity of the layers or bulk product. Optical spectroscopy, such as Raman spectroscopy, is widely used to analyze heterogeneous samples. Raman provides detailed chemical information and requires no sample homogenization: enabling bulk or cross-sectional analysis in a spatially heterogeneous sample.

Raman spectroscopy approaches to measuring layered samples may be applied to pharmaceutical tablets, copolymers or biological materials such as cells or engineered scaffolds. The sampling principles have been also applied to axially heterogeneous polymers (1). Three techniques: backscattered Raman, large volumetric Raman (also called wide area Raman) and enhanced reflection Raman are highlighted.

Sampling Flexibility in Raman

Figure 1 shows variants of reflectance-based Raman spectroscopy techniques using fiber-optic probes. A commonly used approach is backscattered Raman (left), where incident and Raman-scattered light share the same optical path, or one that is minimally offset. Large volumetric Raman (middle) uses a wide laser beam and multiple collection fibers to obtain data from surface and subsurface layers. Enhanced reflection is an option for processes needing additional sensitivity (2). Inclusion of a reflectance standard such as barium sulfate or a fluoropolymer into the wide volumetric geometry is called enhanced reflection (right). Metalized mirrors or dielectric mirrors are other enhanced reflection materials and they offer minimal Raman signatures. Large volumetric or enhanced reflection are useful tools for in-process measurements of content uniformity or processing solids or turbid media. Another configuration of note is Raman microscopy. The high spatial resolution of Raman microscopy can provide detailed information on inter-layer mixing or verification of polymorphic form in the API layer during a cross-sectional analysis of tablets. These four variants provide sampling flexibility from early development to manufacturing, in applications from laboratory QA to in-process monitoring, testing, or control.

Conclusion

Sampling flexibility is a significant benefit of Raman spectroscopy. The use of fiber-optic probes and microscopes enables fast switching between scenarios. This attribute contributes to good method transferability across instruments and across scales.

Enhanced reflectance Raman is a process friendly option that can be used to obtain spectral information from throughout the bulk of the sample, with applications commonly used in pharmaceutical processing. While depth profiling is also possible using transmission Raman, enhanced reflection spectroscopy provides similar information without the experimental complexity because it can be integrated into processes using existing equipment such as non-transmissive belts.

References

(1) N. Brun, M.-C. Chevrel, L. Falk, S. Hoppe, A. Durand, D. Chapron, et al., Chem. Eng. Technol. 37(2), 275–282 (2014).

(2) D. Oelkrug, E. Ostertag, R.W. Kessler, Anal. Bioanal. Chem. 405(10), 3367–3379 (2013).

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