Cross-linking is a common issue when it comes to dissolution testing of gelatin capsules. Cross linked capsules will not open and release their contents into the dissolution medium. This altered dissolution behaviour often results in the product failing the dissolution test. Interestingly, studies have shown that such dissolution failures do not always reflect a possible failure to dissolve in the body.
The US Pharmacopeia therefore allows the use of enzymes in the dissolution medium and requires two tier dissolution testing if the gelatin capsule fails dissolution test due to evidence of cross-linking.
Why pre-treatment?
A challenge here is possible enzyme-surfactant interaction. As an example, sodium lauryl sulphate, commonly used as a dissolution medium surfactant, can denature enzymes vital for overcoming gelatin cross-linking in dissolution tests for capsules.
For such cases where the dissolution medium includes surfactants, USP recommends a pretreatment procedure.
How is the pre-treatment procedure performed?
In the 1st step of Tier 2 of the dissolution procedure, the cross-linked capsules are run in the designated dissolution medium WITH enzymes but WITHOUT surfactants (typically under 15 minutes).
After the pre-treatment time, the 2nd step of Tier 2 involves addition of the medium containing surfactant to the dissolution vessel. This maintains the surfactant concentration specified in the method while the test continues for the remaining time.
The pretreatment duration is part of the overall dissolution test time. For instance, if the total test time is 45 minutes and a 15-minute pretreatment is conducted, adding the surfactant extends the test by 30 minutes, resulting in the total 45 minutes as specified in the method.
Examples
I have listed some examples of this approach found in the FDA's recommended Dissolution Methods Database.
Read also:
- Dissolution Specification Setting Procedure as per FDA Guidance
- Can Disintegration be Used Insted of Dissolution?
- Guide to Determine Sink Conditions in Dissolution Testing
