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Tablets & Capsules March 2015 13 Excipient contaminants. Trace amounts of contaminants in excipients have been shown to interact with gelatin cap- sules. Formaldehyde, just one of a variety of reagents and contaminants capable of interacting covalently with gelatin, has been studied most extensively [5]. In one study, hard gelatin capsules exposed for as long as 24 hours to a simu- lated atmosphere containing a small amount (parts per bil- lion) of formaldehyde were filled with a commercially sourced amoxicillin formulation. The capsules were scanned using NIR, after which each exposure group was subjected to dissolution testing (figures 3 and 4). A strong correlation was established between the first six principal components and the percentage of amoxicillin dissolved in pH 1.2 media for 45 minutes [6]. Polyethylene glycol (PEG)—a common component of softgel fill materials—is known to contain trace amounts of formaldehyde, which can migrate into the gelatin shell. In a study of how NIR can monitor that migration [7], five treat- Figure 4 Correlation of the actual dissolution of drug from hard gelatin capsules that were exposed to formaldehyde to the dissolution predicted from NIR spectral data. Cross-validation samples are superimposed on the calibration line; error bars represent the range (extreme values). Adapted from Gold et al. [6]. Actual weight (%) 100 80 60 40 20 0 Predicted (%) 0 20 40 60 80 100 Figure 3 NIR spectra of hard gelatin capsules exposed to formaldehyde for different periods. Adapted from Gold et al. [6]. 1.20 1.16 1.12 1.08 1.04 1.00 0.96 Wavelength (nm) Absorbance 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 ment groups of softgels were filled with PEG 400 that con- tained 0, 0.05, 0.10, 0.20, and 0.40 percent (v/v) of aqueous formaldehyde. These were stored for 48 hours, after which the PEG 400 was emptied from the capsules, and NIR scans were obtained from each treatment group (Figure 5). The results showed excellent correlation between the actual concentration of formaldehyde in the PEG-filled capsules and the principal-component values obtained from the NIR spectra (Figure 6). The crosslinking reaction—which the study's authors had hypothesized would occur—was con- firmed by spectral changes that occurred in the NIR. Figure 5 NIR spectra of empty soft gelatin capsules that had been filled with a PEG solution containing different amounts of formaldehyde. Adapted from Gold et al. [7]. Wavelength (nm) 1200 1400 1600 1800 2000 2200 2400 1.3 1.2 1 1 Absorbance Figure 6 Correlation between the actual concentration of formaldehyde in PEG-filled capsules and the principal- component values obtained from the NIR spectra. The calibration line (r2=1) is shown superimposed on the data points. Adapted from Gold et al. [7]. Predicted concentration (ml of 37% w/w formaldahyde solution/ml PEG) from empty capsule 0.4 0.3 0.2 0.1 0 Actual concentration (ml formaldehyde solution/ml PEG) inside 0 0.1 0.2 0.3 0.4