Methods. Two classifications of stressed HGCs were artificiallyproduced by exposure to formaldehyde (HCHO). HGCs were categorizedas, a) pass/pass (p/p) which met in vitro dissolution criterion (75%drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p)which failed dissolution criterion in the absence of enzymes and passedin the presence of enzymes, and c) severely crosslinked fail/fail (f/f)which failed in vitro standards with or without enzymes. A six-way,single dose bioequivalence study (n = 10) administered the three HGCsunder the fasted and fed condition. In vivo capsule rupture and GItransit were monitored via gamma scintigraphy, and blood sampleswere collected through six hours.

Results. Each crosslinked HGC was bioequivalent to the control p/pcapsule when using AUC(0–) and Cmax for comparison. Meanin vivo disintegration of the p/p capsule was 7 ± 5 min for the fastedcondition and 11 ± 7 min for the fed condition. In vivo rupture forthe f/p capsule was 22 ± 12 min and 23 ± 11 min for the fasted andfed studies, respectively, while the f/f HGC ruptured at 31 ± 15 minand 71 ± 19 min under the fasted and fed condition, respectively.Onset of amoxicillin absorption was dependent on in vivo HGC ruptureand subsequent entry of the released radioactive marker into the smallintestine. Consequently, fasted Tmax values were significantly laterfor the f/p HGC (1.62 ± 0.53 hr) and f/f HGC (1.85 ± 0.58 hr) ascompared to the p/p HGC (1.17 ± 0.30 hr). Fed Tmax values werestatistically different only for the f/f capsule (2.55 ± 0.44 hr) whereTmax values for the p/p and f/p HGCs under the fed condition were1.50 ± 0.47 hr and 1.60 ± 0.46 hr, respectively.

Conclusions. A two-tier dissolution procedure that retested across-linked hard gelatin capsule with addition of gastric or intestinal enzymesprovided an adequate in vitro indicator of the formulation'sin vivo performance. The observed delays in the onset of amoxicillin absorptionand Tmax for the severely crosslinked f/f HGC was attributed todelayed in vivo capsule rupture, however, this delay did not adverselychange AUC(0–) nor Cmax.