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Tablets & Capsules March 2015 11 Raman spectroscopy differs from FTIR and NIR. It measures the light scattered from the sample, not the light it absorbs. Raman instruments can use visible or NIR laser light as their source, and Raman technology is com- plementary to mid-range and near infrared because it is sensitive to compounds that exhibit weak absorption (e.g., inorganic compounds and symmetric linkages such as C5C, C[C, S-S, and C5N). NIR analysis occurs through one of three primary modes: diffuse reflectance, transmittance, or fiber optic sys- tems. When diffuse reflectance is used, the sample rests in an integrating sphere or reflector cone (Figure 1). Samples placed directly on a conical reflector have incident NIR light that is reflected—both directly and diffusely—and absorbed. The diffusely reflected light is collected and sent to a detector. In contrast, transmittance analysis involves incident light that is collected by the detector after it passes through the sample. With fiber optics, a cable carries the NIR source light to a probe sampling window, and after it has interacted with the sample (via reflectance or transmit- tance) the light returns to the NIR analyzer. NIR spectroscopy has been used in a number of phar- maceutical applications, including raw-material identifica- tion, in-process quantitative analysis, and finished-product assessment. Most materials lend themselves to NIR analy- sis, but those that do not (e.g., calcium phosphate and sodium chloride) are almost exclusively used as raw materi- als and can be analyzed by other spectroscopic techniques (e.g., Raman) or other technologies, including inductively coupled plasma (ICP) and ICP-mass spectroscopy. Raw-materials testing NIR unambiguously identifies most raw materials by comparing a sample spectrum of each lot to a reference spectrum held in a "library." One of the greatest advan- tages of NIR instruments is their ability to scan materials through glass bottles, plastic bags and, in some cases, plastic drum-liners. This method of analysis is non- destructive and eliminates sampling. Several companies offer both hand-held and benchtop NIR analyzers. The photo above shows a benchtop ana- lyzer that can provide just-in-time analysis of pharmaceu- tical raw materials. Other instruments, such as the one shown below, can measure materials with or without con- tacting them, which adds flexibility. Another advantage of NIR is the ability to analyze raw materials in both solid and liquid form. One key hurdle, or drawback, to using NIR for testing raw materials is the need to assemble a spectral reference library. Such libraries must often be custom-made because different companies or sites may use different grades of the same chemical. Microcrystalline cellulose, for example, comes in a variety of particle-size grades, and each would present different reference spectra, possibly complicating sample identification. This could be especially problematic at contract research organizations (CROs), which can test and release hundreds of different raw materials, including various grades of the same material. Assembling a library of reference spectra requires a large investment of time. Once the library is ready and the NIR analyzer has collected the data, a multivariate analysis tool, such as principal component regression (PCR) is used to process the data. PCR reduces the dimensionality of a data set— Figure 1 Diagram of a conical (90-degree) reflector used to scan hard gelatin capsules within an NIR spectrophotometer Aluminum reflector Hard gelatin capsule Steel wire for positioning capsule An FT NIR analyzer (Antaris II, Thermo Fisher) FT-NIR spectrometer with a fiber optic coupling for use with flow cells and conventional probes that are suitable for solids and liquids (Matrix-F, Bruker Optics)