Predicting The Fate Of Crosslinked Gelatin Capsules In Gastrointestional Milieu

Gelatin has been used extensively in the pharmaceutical capsule industry due to its favorable properties:  solubility in aqueous solutions, glossy appearance, ease of swallowing, ability to hold dyes and opacifiers, and strong flexible backbone.  The versatility of gelatin capsules has long been known, as proven by the wide range of formulations which have been incorporated into both soft and hard gelatin capsules.

Gelatin is susceptible to chemical modification by a variety of reagents, of which formaldehyde has been examined in greatest detail (3).  Crosslinking of proteins by aldehydes has been used extensively by the biological (4,5) and medical sciences (6,7) as well the leather (8) and photographic industries (9).  The utility of crosslinking is limited however, in the pharmaceutical industry.  Specifically, gelatin capsules which are intended for immediate release and biovailability of their contents are rendered insoluble upon exposure to even trace levels of such aldehydes (10).  It has been reported, for example, that corn starch, a common drug excipient and fill material in hard gelatin capsules (HGCs), may contain low levels of hexamethylenetetramine stabilizer (11-14), which decomposes under humid conditions to give ammonia and formaldehyde.