Near Infrared Analysis of Tablets Containing Two Active Ingredients

The study evaluates near-infrared analysis of tablets nominally containing 4 mg of chlorpheniramine maleate and 10 mg of phenylephrine hydrochloride per dose.
Nov 02, 2011
Volume 35, Issue 11

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).

Table I: Formula compositions (mg/tablet) with five-level fractional factorial design formulas.
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).

Figure 1: Tablet analysis in a FOSS XDS MasterLab instrument. The actual tablets under test in this study were white cores.
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 2: A representative chromatogram shows the peaks of phenylephrine (phe) and chlorpheniramine (cpm).
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).

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