Cross-linking of gelatin is the alteration of gelatin such that the shell disintegrates slower and releases the formulation slower as a result. It can come in the form of internal cross-linking which occasionally results when the capsules experience high heat and humidity. The second form is called ‘external cross-linking’ and is due from exposure to an external agent like aldehydes, peroxides and sulfanic acids which chemically alter the gelatin. Even a small amount of aldehydes and peroxides have been found to exist in some commonly used excipients. Often the addition of enzymes to the dissolution media of internally cross-linked gelatin can resolve the issue just as in vivo the natural enzyme content of the gastrointestinal tract would. But externally cross-linked gelatin capsules may become significantly altered and enzyme addition to the dissolution media may not resolve the issue. Here, chemical incompatibility may point to need for an alternative polymer to gelatin. Dissolution studies show that HPMC is not affected by either internal or external cross-linking.