Applications of Raman spectroscopy in pharmaceutical analysis T. Vankeirsbilck, A. Vercauteren, W. Baeyens*, G. Van der Weken Laboratory of Drug Quality Control, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium F. Verpoort Laboratory of Organometallics and Catalysis, Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281 (S3), B-9000 Ghent, Belgium G. Vergote, J.P. Remon Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium As Raman spectroscopy enables rapid, non-destruc- tive measurements, the technique appears a most promising tool for on-line process monitoring and analysis in the pharmaceutical industry. This article gives a short introduction to Raman spectroscopy and presents several applications in the pharmaceu- tical field. # 2002 Published by Elsevier Science B.V. All rights reserved. Keywords: Pharmaceutical analysis; Polymorphism; Quantitative Raman analysis; Raman spectroscopy 1. Introduction The phenomenon of inelastic light scattering is known as Raman radiation and was first documented by Raman and Krishnan in 1928 [1]. When a substance is irradiated with mono- chromatic light, most of the scattered energy comprises radiation of the incident frequency (Rayleigh scattering). In addition, a very small quantity (0.0001%) of photons with shifted fre- quency is observed. The fraction of photons scattered from molecular centres with less energy than they had before the interaction is called Stokes scattering. The anti-Stokes photons have greater energy than those of the exciting radiation (Fig. 1). Both infrared (IR) and Raman spectra are concerned with measuring associated molecular vibration and rotational energy changes. How- ever, the requirement for vibrational activity in Raman spectra is not a change in dipole moment, as it is in IR spectra, but a change in the polarizability of the molecule. (It is therefore possible to obtain spectral information from a homo-nuclear molecule by Raman spectro- scopy.) The energy resulting from this shift is equal to the vibrational energy gap that is excited in IR spectroscopy. Two major technologies are used to collect the Raman spectra: dispersive Raman; and, Fourier transform Raman (FT-Raman) [2,3]. The differences between both technologies are the laser that is used and the way the Raman scattering is detected and analysed. Each tech- nique has unique advantages and the method that best suits the sample should be preferred. The applications listed in Table 1 are limited to the analytical field. Two related techniques are important in the pharmaceutical area. The first is confocal Raman microscopy, which is a useful technique for non-destructively probing depths of the sample without cross-sectioning. Confocal 0165-9936/02/$ - see front matter # 2002 Published by Elsevier Science B.V. All rights reserved. PII: S0165-9936(02)01208-6 trends in analytical chemistry, vol. 21, no. 12, 2002 869 *Corresponding author. Tel.: +32 9-264.80.97; Fax: +32 9-264.81.96. E-mail: willy.baeyens@rug.ac.be