▶ Raman and process monitoring
Basic Information

Raman could help generate valuable process data to ensure optimal process control, comprehensive process understanding at a molecular level and maximum efficiency in pharmaceutical production.

Various factors can possibly induce solid state changes during pharmaceutical processing, as illustrated below.

To ensure a robust processing, a key aspect of FDA's process analytical technology (PAT) philosophy is that every stage of the manufacturing process should be monitored and understood so that the end product is right first time, every time.

FDA's PAT initiative that asserts "quality cannot be tested into products, it should be built in or should be by design" has generated a large amount of interest in new technologies for pharmaceutical analysis. In practice, the implementation of PAT requires a range of analytical tools capable of operating throughout the manufacturing process: at-line, on-line and in-line.

In-line: the sample is not removed from the process stream

On-line: pick up sample, analyze (fast) and return sample to the process stream

At-line: like on line, but more time consuming analysis

Off-line: remove sample from process area

Raman technology has advanced greatly in the last few years giving vastly improved performance, ease of use and general applicability to 'real' world problems. Encouraged by the opportunities that will arise as a result of the PAT initiative, the Raman instrument manufacturers and scientific community are now putting considerable effort to develop the technique as a PAT tool.

In principle, all that is required to obtain a Raman spectrum is to shine monochromatic laser light on a sample, and collect and spectrally analyse the resulting scattered light. There are many possible configurations to achieve this. Fibre optic delivery of the laser light and collection of the Raman light is particularly suitable for achieving its PAT applications.

Why is Raman a potential PAT tool?

◆ Well resolved, information rich spectra

◆ Flexible sampling (remote sampling)

◆ Confocal optics

◆ Measuring through glass windows, or from samples inside sealed-glass containers

◆ Measurement of various types of samples (liquids, slurries, pastes, solids, powders, etc.)

◆ Ease of use

◆ Quick sample acquisition

It is also worth noting the flexibility with which Raman spectroscopy can be implemented also increases the potential for integration with other analytical techniques for instance NIR to perform multiparametric measurements and, therefore, increases the amount of information obtained from the sample during the process.

Raman can be employed to inline monitoring and quantifying the solid state transformation of theophylline granules during fluid bed drying.

Theophylline was found to transform from the starting monohydrate to its most stable anhydrate form during fluid bed drying.

Further reading:Aaltonen et al. Chem. Eng. Sci. 62 (2007) 408-415.

Formation of two solid forms during crystallization was monitored by Raman.

Further reading:Tian F, Qu H, Louhi-Kultanen M, Rantanen J, Journal of Crystal Growth 2009, 311: 2580-2589

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