Extending Calibrations for Near Infrared Assay of Tablets Using Synthetic Modeling and Variance from Placebos - Pharmaceutical Technology

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Extending Calibrations for Near Infrared Assay of Tablets Using Synthetic Modeling and Variance from Placebos
The authors extend the range of a near-infrared calibration model for tablet assay using production 'seed' spectra and synthetic spectra generated from placebos and 'pure' active pharmaceutical ingredient spectra.

Pharmaceutical Technology
Volume 33, Issue 3, pp. 120-124


Figure 4
For this study, the authors used the XDS MasterLab NIR instrument (FOSS NIRSystems, Laurel, MD). The system can automatically measure multiple tablets after they are positioned in a special tray (see Figure 1). Spectra were collected in the transmission mode from 800 to 1650 nm with 0.5 nm data intervals and 32 scans were co-added to produce a single spectrum.

Figure 5
Ten chlorpheniramine maleate (CPM) tablets of nominal 1.0 mg and 10 placebo tablets of the same excipient composition were scanned on the MasterLab transmission instrument. The tablets from a 1.0-mg CPM batch were sent for HPLC analysis after NIR scanning. The spectra of the first five of the 1.0 mg tablets were averaged, and the placebo spectra were averaged. The other five tablets measured were saved for a validation set. The average placebo spectrum was subtracted from spectrum of the average of the five 1.0-mg tablets in the FOSS Vision software. This resulted in a simulated transmission spectrum of pure CPM. This spectrum could not be obtained in transmission because the pure CPM would have had to be pressed as a tablet.

Table I: Real tablet high performance liquid chromatography (HPLC) analysis and fraction adjusted by mean tablet value.
The pure CPM spectrum was multiplied by factors to obtain a range of pure spectra from 85% to 115% in 5% increments of label claim. The average HPLC value for the five real tablet spectra was calculated. The average value was multiplied times each fraction from 0.85 to 1.15 to correct for the HPLC versus nominal tablet CPM values. The fractional pure spectra from 85% to 115% were then added to the 10 individual placebo spectra resulting in 70 spectra. The five real tablet spectra were added to the synthetic calibration set as "seed" spectra resulting in 75 spectra in the total calibration set.


Figure 6
Figure 2 shows the 75 raw NIR spectra from the calibration set. Figure 3 shows the spectrum of the simulated pure CPM. By taking the second derivative of the spectra, as shown in Figure 4, the baseline was normalized and the spectral features were enhanced so that the fanning out of the analytical region for CPM was observed at 1138 nm. The second derivative causes the absorption bands to be inverted and increase in the downward direction. The second derivative pretreatment was applied using a smoothing with a segment of 10 and a gap of 0. The standard normal variate (SNV) pretreatment was applied to reduce scattering effects. An integral thickness correction was applied as a math pretreatment to correct for tablet thickness and density variance from 1280 nm to 1350 nm.

Figure 7
Figure 5 shows the expanded second derivative of the aromatic CH stretch analytical band demonstrating the fanning out from 0.85 mg to 1.15 mg CPM (adjusted to 0.875 mg to 1.1838 mg from HPLC analysis). Table I shows real tablet values and the fractional adjustment that was made using the mean tablet value. The adjusted values are the constituent values that were used for modeling.


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