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How to Reduce Cross-Linking of Gelatin Capsule Shells?

It is important to try to reduce or eliminate cross-linking for a couple reasons. First, cross-linking is not a reversible reaction and can't be stopped. Second, not all regulatory agencies allow the use of enzymes! Some populations tend to have higher pHs in the stomach and as a result the enzymes are felt to lead to non-discriminatory results. When working on formulations, one should be mindful on why cross-linking occurs and how to deal with it proactively.

Some considerations when working with capsule shell methods:

1. Choose high quality gelatin! If gelatin comes from bad sources, it can come with pre-cursors to cross-link before the capsule shells are even made. Gelatin from porcine and bovine sources are the most common, but gelatin derived from fish tends to be higher quality as well as complying with kosher/halal requirements.

2. Manufacture the gelatin into capsule shells carefully, overheating, over/underdrying, etc. in the process can also drive cross-linking reactions.

3. Be mindful of the excipients being chosen. Excipients with aldeyhydes, metal ions, oxidizing agents, sugars, and more can react with gelatin and create cross-linking.

4. Proper packaging will protect the capsules from light and humidity which can drive reactions. Don't add too much desiccant though because overly dry environments can also speed the reaction. Blister packs are a preferred approach.

5. If the API itself may react to form cross-linking, you should seriously consider using an HPMC capsule instead of gelatin. HPMC does not have the cross-linking reaction and can be an excellent choice. These capsules are more expensive, but for certain APIs they are well worth the cost. Be aware that HPMC capsules are newer and there is less literature about them - finding good quality capsules is still key. You may find higher shear forces are needed for HPMC capsules to rupture and an apex/peak vessel, stationary basket over paddle method, or USP Apparatus 3 may be good considerations in dissolution method development.

Related: Dissolution Testing for Gelatin Capsules

Resource Person: Ken Boda (Dissolution Product Specialist at Agilent Technologies)

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