Springer Online Journal Archives 1860-2000
Chemistry and Pharmacology
Abstract Purpose. To determine if changes in the in vitrodissolution of hard and soft gelatin acetaminophen capsules, which resultfrom gelatin crosslinking, are predictive of changes in the bioavailabilityof the capsules in humans. Methods. Both hard and soft gelatin capsules were“stressed” by a controlled exposure to formaldehyde, resultingin unstressed, moderately stressed and highly stressed capsules. invitro dissolution studies were conducted using water or SGF with andwithout pepsin as the media. Separate 24-subject, 3-way crossover humanbioequivalence studies were performed on the unstressed and stressedacetaminophen capsules. Plasma acetaminophen was determined by highperformance liquid chromatography (HPLC) for 12 hr after each dose. Results. The in vitro rate of dissolution of hardand soft gelatin capsules was decreased by crosslinking. The bioequivalencestudies showed that both hard and soft gelatin capsules, which failed tomeet the USP dissolution specification in water, but complied when tested inSGF containing pepsin, were bioequivalent to the unstressed controlcapsules. The capsules that were cross-linked to the greatest extent werenot bioequivalent to the unstressed control capsules, based on Cmax. Atrend toward an increase in Cmax with increased level of cross-linking wasobserved, but this was only significant for the severely stressedcapsules. Conclusions. On the basis of this study a two-tier invitro dissolution test was developed using enzymes to distinguishbetween bioequivalent and bioinequivalent gelatin capsules.
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