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Received January 7, 2000; accepted April 28, 2000
Purpose. To determine if changes in the in vitro dissolution of hard and soft gelatin acetaminophen capsules, which result from gelatin crosslinking, are predictive of changes in the bioavailability of the capsules in humans.
Methods. Both hard and soft gelatin capsules were "stressed" by a controlled exposure to formaldehyde, resulting in unstressed, moderately stressed and highly stressed capsules. In vitro dissolution studies were conducted using water or SGF with and without pepsin as the media. Separate 24-subject, 3-way crossover human bioequivalence studies were performed on the unstressed and stressed acetaminophen capsules. Plasma acetaminophen was determined by high performance liquid chromatography (HPLC) for 12 hr after each dose.
Results. The in vitro rate of dissolution of hard and soft gelatin capsules was decreased by crosslinking. The bioequivalence studies showed that both hard and soft gelatin capsules, which failed to meet the USP dissolution specification in water, but complied when tested in SGF containing pepsin, were bioequivalent to the unstressed control capsules. The capsules that were cross-linked to the greatest extent were not bioequivalent to the unstressed control capsules, based on Cmax. A trend toward an increase in Cmax with increased level of crosslinking was observed, but this was only significant for the severely stressed capsules.
Conclusions. On the basis of this study a two-tier in vitro dissolution test was developed using enzymes to distinguish between bioequivalent and bioinequivalent gelatin capsules.
KEY WORDS: Gelatin capsules; acetaminophen; crosslinking; dissolution; human bioequivalence.
INTRODUCTION
When gelatin is exposed to high humidity, elevated temperature or aldehydes, the gelatin may become crosslinked (or stressed), rendering the gelatin resistant to dissolution in water. Digenis et al. (1) have reviewed the pharmaceutical implications of the crosslinking of gelatin capsules. Dey et al. (2) have investigated the dissolution of etodolac in hard gelatin capsules exposed to high relative humidity and temperature. They also studied the stressed and unstressed capsules in bioavailability studies using dogs and humans. Others (3) have studied changes in the in vitro dissolution of soft gelatin capsules containing acetaminophen or nifedipine. While changes in the dissolution of gelatin capsules with time are well known, correlations between the in vitro dissolution and in vivo bioavailability of stressed capsules have not been studied in detail....