Raw-Material Authentication Using a Handheld Raman Spectrometer

Using a handheld Raman spectrometer, the authors developed methods for 28 commonly used excipients and active ingredients.
Mar 02, 2008
Volume 32, Issue 3

Pharmaceutical manufacturing facilities are moving toward 100% inspection of incoming raw materials to confirm the content of each container is verifiable at the molecular level. Current practice requires incoming raw-material containers to be opened and samples to be extracted. The materials are then typically transported to a laboratory for chemical analysis, a process that may take several days or longer, during which time the material is unavailable for production. Technologies used for laboratory identification tests include high-pressure liquid chromatography (HPLC), near-infrared (NIR) and mid-infrared (mid-IR) spectroscopies, and other wet chemical methods (1–6). Among these methodologies, Raman spectroscopy has proven efficient and effective for a wide range of pharmaceutical applications, including identity testing of pharmaceutical raw materials, in-process analysis, and authentication of final dosage forms (7–9).

Renewed enthusiasm for Raman technology has been spurred on by numerous technological advances. Raman scattering was historically very difficult to detect because the scattering phenomenon is very weak. NIR lasers, charge-coupled device (CCD) detectors, and Rayleigh rejection filters have made Raman spectroscopy a practical laboratory analysis technique by increasing the sensitivity and decreasing nuisance signal contributions from fluorescence. Furthermore, modern Raman instrumentation is faster, more robust, and less expensive than previous systems. In addition, advances in component miniaturization have led to the availability of portable, handheld Raman systems (see Figure 1).

Operational attributes are important to take into account when selecting a measurement technology for a research or manufacturing environment. In the context of material identification, portable solutions (e.g., the handheld Raman instrumentation used in this study) can quickly verify material identity at the point of need. Furthermore, Raman spectra can be acquired through transparent packaging materials such as the plastic bags commonly used to line drums containing incoming raw materials (10, 11). This means of testing reduces the time between receipt and availability to the production line, minimizes handling and, for materials packaged in transparent media, eliminates the risk of contamination posed when the packaging seal is breached. NIR measurements also can be acquired through transparent packaging; however, special care must be taken when making NIR measurements through plastic containers because subtle variations from one container to another can manifest themselves quite markedly in the spectra. In contrast to Raman and NIR, mid-IR techniques require direct contact with the material and are not conducive to measurement through packaging.

Figure 2
In terms of analytical characteristics, Raman spectroscopy is particularly effective for identity testing because of its high degree of selectivity (12). Every chemical compound with covalent bonds produces its own characteristic pattern of Raman shifts, which can be used to chemically fingerprint and therefore identify the compound. Raman spectra for acetylsalicylic acid and acetaminophen are shown in Figure 2, illustrating the excellent selectivity provided by distinct, well-defined peaks.

Some challenges with using other types of spectroscopy, notably NIR, have been method development and method transfer between instruments. As Figure 2 shows, Raman spectra have distinct peaks that are characteristic of the material producing the spectrum. Therefore, like Fourier transform infrared (FTIR) spectroscopy, the intrinsic molecular selectivity means that spectral differences between materials are extremely pronounced relative to nuisance factors. This article describes how Raman methods generated from measurements on one unit can be easily transferred to another, simply by transferring the reference library files.

NIR spectra are less distinct, with broader peaks that result in poorer selectivity, and sometimes require computationally intensive methods to detect differences. As a result, the creation, transfer, and maintenance of NIR methods often require expert oversight and intervention. Variability among various NIR units' optics and other components is sometimes of the same order as the differences among samples tested. As a result, in transferring an NIR method to a different instrument, additional reference spectra and/or tuning of method parameters may be required.

lorem ipsum