Raman microspectroscopy and imaging of pharmaceuticals

The application of Raman spectroscopy in the field of pharmaceuticals is showing immense potential. Previous progress has been hindered due to the high cost and poor user-friendliness of the old Raman technology.

Recently, major advances in technology have prompted Renishaw to manufacture a high efficiency, easy to use, compact and inexpensive Raman microscope. Further pressure from industry has seen the recent development of fibre optic Raman analysers for in-situ process monitoring and laboratory use. Indeed, in the past couple of years laboratories in multinational companies have established the Raman method as a compelling technology for the study of pharmaceuticals.

The Raman method has offered these laboratories:

• the rapid identification of goods in;
• the analysis of drug mixtures, actives and excipients;
• the identification of contaminants;
• the characterisation of formulated materials and the understanding of the blending processes involved in pharmaceutical formation.

What is Raman spectroscopy?

Raman spectroscopy involves the interaction of light with matter. Incident laser light causes the bonds between atoms to vibrate. Analysis of the scattered light, as a Raman spectrum, reveals information about a sample's chemical structure and physical state.

Detection of polymorphism

The Raman method provides a unique molecular fingerprint of compounds. This is true equally of solids and liquids. As Raman is based on the molecular vibrations of the molecule, it is thus sensitive to small changes or modification in molecular structure, clear scope for differentiating polymorphs.

Analysis of polymorphs using more traditional methods such as infrared spectroscopy is difficult owing to the water hydration which can swamp the spectrum. This is not the case with dispersive Raman, which also offers the ability to sample directly substances contained in glass vessels without any hindrance from the container.

Analysis of blended materials and matrix inhomogeneties

One of the challenges facing the pharmaceutical industry is the analysis of blended and tableted materials. Typically, excipients, friction agents and active ingredients are blended to provide an homogenised mixture with a particle size on the micron scale.

The application of Raman microscopy to these samples, which has the advantage of not damaging the sample in a 1 µm area from a solid surface, offers a means to analyse the homogeneity achieved in the blending process.

In some products, such as tables, anomalies in the particle size/crystallite make up can sometimes be seen (with reflected light microscopy). We have taken as an example a proprietary tablet in which white fibrous like material could be seen on the surface. The difference is clear, with a strong additional peak seen at around 2900 cm-1 (typically assigned to an alkyl chain) in the fibre spectrum. Interestingly a weak feature is seen at a similar position in the bulk material. From these observations one would probably conclude that the fibre is an agglomeration of one of the ingredients in the tablet which has not for some reason been evenly dispersed within the matrix.

A set of confirmatory experiments would be to acquire Raman data from each of the ingredients used to cross match the peaks observed.

Mapping experiments from this sample have also been carried out (Figure 2) to confirm the occurrence of this additional peak around 2900 cm-1 as being part of the fibre. The data are illustrated below as a map of the 2900 cm-1 peak (red) from the fibre and the matrix band at 3100 cm-1 (green).

Without any pretreatment, Raman mapping techniques with spatial resolution down to 100 nm scale provides a detailed structural analysis on the distribution in blends and mixtures of excipients and actives, in formulated products.

The advanced Renishaw Raman microscope system is an easy-to-use, effective tool for in-situ sampling in the pharmaceuticals and materials industry.