Analyse this – the rise of Raman spectroscopy

14 April 2014



A powerful tool for identifying and analysing raw materials, Raman spectroscopy is quickly showing its potential. In light of strict regulations and a rise in anti-counterfeiting efforts, Dr Sulaf Assi, associate lecturer of forensic sciences at Bournemouth University, explains why pharmaceutical labs would do well to implement this fast-evolving technique.


The identification of raw materials is a vital process when it comes to validating the authenticity of pharmaceutical products. This was brought to light in July last year when the European Commission introduced the Falsified Medicines Directive.

The edict requires all imported active pharmaceutical ingredients (APIs) to be manufactured in compliance with tougher good manufacturing processes and regulatory measures.

According to the Commission, "Falsified medicines represent a serious threat to global health and call for a comprehensive strategy both at a European and international level."

As a result, the currency of Raman spectroscopy continues to rise as the pharmaceutical sector looks for more fool-proof means of raw material verification.

The technique, which is non-destructive, is based on the interaction of light and matter, and can be used to observe the vibrational wavelength shifts of molecules. Because each molecule has its own unique set of vibrational energy levels, Raman can, in effect, collect individual footprints (or signatures), allowing technicians to specifically identify the composition of a material.

And it's easy to use. Spectra can be acquired on tablets and powders, bypassing the need for sample preparation; data can also be collected by simply pressing a fibre-optic probe against the sample.

This is particularly useful for verifying the level of APIs - and excipients - in pharmaceutical products, says Dr Sulaf Assi, associate lecturer in forensic sciences at Bournemouth University, UK.

"In general, APIs are Raman active; excipients are not," she explains. "This provides a significant advantage in the quantification process. This is really important, given that last year's Falsified Medicines Directive has created tougher rules on the quantities of APIs and excipients in pharmaceutical products."

While Raman spectroscopy's conception dates back to the late 1920s - it is named after CV Raman, an Indian physicist, who specialised in light-scattering techniques - it is only in the last decade that the method has seen its status shift from highly specialised to readily available.

Today, it is deployed across a number of fields of application in the industry, including product authentication, quality control and final product checks.

"With pharmaceutical formulation, a lot of monitoring needs to be made," says Assi. "That goes for raw material characterisation - assessing that it is stable before use - and also for the formulation making. Probes can be inserted into a material and can be used to assess every stage for stability.

"As well as the specification of specific ingredients, Raman applies to excipients because they play a role in the solution of the product and its effect on the body. So the technique can be very useful for chemometric models, because you can quantify active ingredients and excipients at the same time."

Benefits of Raman

With anti-counterfeiting high on the agenda for regulators (the illicit trading of drugs is said to cost the pharmaceutical industry billions of dollars each year), the advantages of Raman spectroscopy are manifest.

It is also particularly speedy in yielding results; unlike traditional analytical techniques, such as liquid chromatography and mass spectroscopy, it can provide vast amounts of material data and information "within seconds".

"The technique can be very useful for chemometric models, because you can quantify active ingredients and excipients at the same time."

"Raman spectroscopy is very good for anti-counterfeiting," says Assi. "It has the ability to go through transparent blister packaging so as to authenticate the tablet or medicine. Also, using a proper chemometric algorithm, it can give an answer on whether a batch is bad or good very quickly."

It is therefore hardly surprising that Raman spectroscopy is riding a fresh wave of commercialisation. Devices, once cumbersome and bulky, are now smaller and handheld, and can cost in the region of £12,000-15,000. Given the benefits on offer, Assi believes that such prices are more than justified.

"I think devices are pretty affordable compared with other lab-based instruments," she states. "You just have to think of the advantages - it dramatically cuts down on sample extraction, enabling green chemistry. It can also save on the cost of sample preparation, which is another environmental benefit."

The commercialisation of Raman

Another upshot of the technology's commercialisation has been the increased number of laser options, allowing for greater sensitivity. Aside from standard 785nm-wavelength lasers, many new portable devices feature 1,064nm-excitation lasers.

"The good thing that's happened with the commercialisation of Raman is that we now have the 1,064nm device," says Assi. "While you can still get a lot of sensitivity from the 785nm technology, these new instruments can also operate with single and dual lasers, making it a two-in-one combination. The 1,064nm can also remove fluorescence - commonly cited as one of the main reasons for erroneous results when using Raman spectroscopy."

Given that Raman spectroscopy appears to be a technology that is relatively easy to operate, do staff working in pharmaceutical labs require any form of training or guidance?

"It obviously depends on the application, but, in general, Raman devices demand minimal training," says Assi. "For instance, it is fairly easy for staff in the lab to use in-built algorithms through the instrument, or measure simple matrices such as tablets. It's only when staff are working on optimising algorithms for Raman libraries that more rigorous forms of training are needed."

So as to further increase the versatility of Raman, there have recently been efforts in developing data library software and algorithms, through which Raman spectra can be identified and matched more quickly and efficiently.

"Libraries are essential," says Assi. "Once they have been built, comparability studies between known and unknown minerals and compounds can be conducted within seconds. The algorithms are also very powerful in tackling certain types of matrices."

Future potential

Another novel technique we can expect to see gain further traction in the coming years is that of spatially offset Raman spectroscopy. Requiring no prior knowledge of the container surface or layer, the process has the ability to provide an accurate analysis of drugs packaged in opaque layers or containers.

While still in its infancy, its potential - particularly in light of the industry's aforementioned fight in tackling counterfeiting - could be significant, believes Assi.

"It's already an emerging application in other sectors, such as forensics and archaeology, while police and customs staff have also started testing it [for explosives detection in security checks]," she says. "But I am sure it will be used more and more in the pharma environment, too - again, it can cut down a lot of cost, and it can save on importing samples. It's also very easy to use."

Raman spectroscopy, like all technologies, has room for improvement; in addition to fluorescence, subsampling remains a serious issue, for instance.

But there is every reason to believe that the upswing of interest in the technique over the last few years will continue apace for the foreseeable future.

Dr Sulaf Assi is associate lecturer in forensic sciences at the school of applied sciences, Bournemouth University, UK. Previously she obtained a PhD in pharmaceutical analysis at the school of pharmacy, University of London.


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