CROSS-LINKING OF GELATIN CAPSULES AND ITS RELEVANCE TO THEIR IN-VITROIN-VIVO PERFORMANCE

The present review deals with the chemistry of gelatin cross-linking u nder conditions that are relevant to pharmaceutical situations. Mechan istic rationalizations are offered to explain gelatin cross-linking un der ''stress'' conditions. These include elevated temperature and high humidity conditions. In addition, the chemical interactions between g elatin and aldehydes, such as formaldehyde and other formulation excip ients, are discussed. The literature on the in vitro and in vivo disso lution and bioavailability of a drug from stressed gelatin capsules an d gelatin-coated tablets is reviewed. Cross-linking phenomena, occurri ng in stressed hard gelatin capsules and gelatin-coated tablets, could cause considerable changes in the in vitro dissolution profiles of dr ugs. However, in a few cases, the bioavailability of the drug from the stressed capsules is not significantly altered when compared to that obtained from freshly packed capsules. It is concluded that, as with o ther drug-delivery systems, careful attention should be paid to the pu rity and chemical reactivity of all excipients that are to be encapsul ated in a gelatin shell. It is suggested that in vitro dissolution tes ts of hard gelatin-containing dosage forms be conducted in two stages, one in a dissolution medium without enzymes and secondly in dissoluti on media containing enzymes (pepsin at pH 1.2 or pancreatin at pH 7.2, representing gastric and intestinal media, respectively) prior to in vivo evaluation. Such in vitro tests may constitute a better indicatio n of the in vivo behavior of gelatin-an capsulated formulations. Furth ermore, testing for contamination with formaldehyde as well as low mol ecular weight aldehydes should be a standard part of excipient evaluat ion procedures.