Using Enhanced Raman Reflection Spectroscopy for Process Analytical Technology

As part of the process analytical technology (PAT) initiative put forth by the U.S. food and drug administration (FDA), pharmaceutical producers are encouraged to implement real-time analytical instrumentation to acquire a complete understanding of their manufacturing processes.

Rather than studying the end product at the outset this approach would allow real-time process control and provide a better understanding of versatile quality control measures that need to be followed during the entire manufacturing process.

A major focus of analytical chemistry and pharmaceutical technology is the development of methods for real-time process analysis. Over the years, Raman spectroscopy, near infrared (NIR) spectroscopy and other vibrational techniques have become popular as they provide complete chemical data whilst having immense possibilities for strong and robust modeling.

These spectroscopic methods can also be deployed in a non-contact mode. Raman spectroscopy, in particular, offers a number of benefits over infrared spectroscopes.

For instance, this technique is unaffected by the presence of water, and hence, has been shown to be valuable in pharmaceutical process monitoring. Also it needs little or no sample preparation. The ability for simultaneous analysis of complex-layered solids is of major importance in pharmaceutical processing.

This article shows how the improved Raman reflection spectroscopy is used for studying multi-layered samples, which are analogous to pharmaceutical tablets. It also highlights its applications used presently in the pharmaceutical sector.

Reflection and Transmission Raman

Both transmission and reflection modes can used in Raman spectroscopy. In the transmission mode the collection probe is situated on the sample’s opposite side from the laser so that Raman scattered photons can be easily collected. These photons exit the sample in a specific direction. In the reflection or backscattering mode, the light is dispersed back towards the incident laser light source and this light is collected via the same lens used to focus the incident laser.

The Raman intensities from the transmission mode and the reflection mode are associated with the sample layer depth. This is seen under standard conditions (Figure 1). In the reflection mode most of the Raman signal originates near the sample surface, whilst most of the Raman signal in the transmittance mode comes from the sample core.

Reflection and Transmission Raman

Figure 1. Origin within a 0.5-cm-thick sample of Raman signal intensity (X) in both reflectance (R) and transmittance (T) modes. Here XT is magnified 2x with respect to XR.

Transmittance Raman allows for in-depth sample analysis. The same ability can be imparted to reflectance Raman spectroscopy through BaSO4 backscattering. BaSO4 serves as a diffuse white reflectance target. This article shows a proof of concept that Raman reflection spectroscopy is capable of producing intense Raman signals across a sample depth, making it possible to study the entire depth of a solid sample analogous to a pharmaceutical tablet.

Experimental Procedure

Cylindrical discs were used as samples in this analysis. These discs include layers of different thicknesses of cellulose paper, polytetrafluoroethylene (PTFE), mannitol or acetylsalicylic acid (ASA). In some samples BaSO4 was employed as a white diffuse-reflectance standard. Kaiser Optical Systems’ RamanRxn Systems™ Raman analyzer equipped with a 785-nm Invictus™ laser was used for collecting both reflection-mode Raman spectra.

A PhAT technology probe head was then used to collect the dispensed laser light. Figure 2 shows the sampling geometries for transmission - and reflection-mode Raman.

Sampling geometries for reflection- and transmission-mode Raman spectroscopy

Figure 2. Sampling geometries for reflection- and transmission-mode Raman spectroscopy. The work described in this note used the reflection mode.

Enhanced Reflectance Raman

Six experiments were carried out on PTFE cylindrical samples with cellulose paper. Tandem transmission and reflection Raman is involved in experiments 1 through III and improved reflection Raman using a BaSO4 backscattering layer is involved in experiments IV through VI. The results of these experiments are shown in Figure 3.

Enhanced Reflectance Raman

Figure 3. Enhanced reflectance Raman signal intensity (XR) of 733-cm-1 band of PTFE using a BaSO4 diffusereflectance standard.

In the case of improved reflection Raman trials, the intensity of the Raman signal originating from the PTFE layer is improved three to four times irrespective of its position with regard to the BaSO4 reflector and the paper layer.

Given that the intensity of the Raman signal originating from the PTFE layer is unaffected by its location in the sample, the outcomes suggest that the whole sample is studied in a uniform manner. In the case of experiment IV, a black background was evaluated against the improved Raman reflection approach. The outcomes suggest a 3.5 times enhancement of the PTFE intensity with regard to the PTFE’s Raman intensity on the blank substrate.

Conclusion

Improved reflectance Raman can be used to acquire spectral data from across an entire sample when there is a need to define the entire content of a sample.

This study demonstrates how improved Raman reflection spectroscopy can be used for PAT in the pharmaceutical sector. This method is currently being used in pharmaceutical process lines. Whilst it is possible to achieve depth profiling through transmission mode Raman, improved Raman reflection spectroscopy can be easily incorporated into existing processes to promote real-time measurement. As improved Raman reflection spectroscopy can be used with non-transmissive belts and other current equipment, process monitoring and control is also ensured.

This information has been sourced, reviewed and adapted from materials provided by Kaiser Optical Systems, Inc..

For more information on this source, please visit Kaiser Optical Systems, Inc..

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