Near-infrared spectroscopy (NIRS) is an analytical technique based on absorption measured in the near-infrared (NIR) region
of the electromagnetic spectrum between the visible and the mid-infrared. The strong fundamental absorption bands of functional
groups occur in the mid-infrared. The overtone absorptions of these fundamental bands occur in the NIR spectral region and
allow direct measurement without sample preparation because of the relative weakness of absorption. The OH, CH, NH, and SH
bonds have the strongest overtone absorbance in the NIR region. Because of the overlapping absorbance bands in the NIR region
of the spectrum, quantitative spectroscopic methods require the application of multivariate analysis methods known as chemometrics.
Chemometrics use mathematical and statistical algorithms to model the spectral response to chemical properties of a calibration
or training set (1, 2).
The US Pharmacopeia monograph on content uniformity (CU) requires 10 samples to be tested at random from each batch to demonstrate
CU. The industry has expressed interest in testing solid dosage form samples nondestructively and more frequently than the
10 per batch specified. FDA's process analytical technology (PAT) initiative for better process understanding and production
monitoring has increased the interest in using NIR for intact tablet assay and CU testing (3).
Table I: Formula compositions (mg/tablet) with five-level fractional factorial design formulas.
NIR can be implemented for at-line analysis along with the thickness, hardness, and weight testing commonly performed in close
proximity to the tablet press to obtain nearly real-time feedback during a production batch. Diffuse NIR transmission through
the tablet is preferred to reflectance analysis because it can interrogate the bulk of the tablet cores. Reflection NIRS is
used for coating analysis, but for bulk intact tablet analysis, transmission NIRS yields excellent results (4).
Figure 1: Tablet analysis in a FOSS XDS MasterLab instrument. The actual tablets under test in this study were white cores.
Wet-chemistry laboratory analysis of tablets for assay and CU is time consuming. It is routinely performed by high-performance
liquid chromatography (HPLC), which requires lengthy calibration runs, the mixing of buffers, and the procurement and disposal
of solvents. Analyzing 10 tablets for content uniformity could take hours, and the results may not be available to the tablet-press
operators or for batch release for many days, or even weeks, after the tablets are compressed. Quality by design (QbD) techniques
can be applied to measure the intact tablets with NIR at line, thus minimizing the risk of batch discrepancies and working
toward the ultimate goal of parametric release (5).
Figure 2: A representative chromatogram shows the peaks of phenylephrine (phe) and chlorpheniramine (cpm).