Dissolution or disintegration – substitution of dissolution by disintegration testing for a fixed dose combination product

Abstract

According to International Council for Harmonisation (ICH) guideline Q6A, dissolution testing can be replaced by disintegration testing if it can be shown that the active pharmaceutical ingredient is highly soluble and the formulation is rapidly releasing. In addition, a relationship between dissolution and disintegration has to be established. For a fixed-dose combination tablet of empagliflozin and linagliptin, this relationship was established by applying two different approaches. In the first approach, the extent to which the disintegration process of the film-coated tablets contributes to the release of the active ingredients was investigated. In the second approach, the mean disintegration times in a disintegration tester were correlated with the mean dissolution rates at a selected sampling time point. By correlating disintegration times in the dissolution vessel with the dissolution rate at selected sampling times it is demonstrated that the disintegration into primary particles is the rate limiting step for the dissolution process. A direct correlation of disintegration times in the disintegration tester with dissolution rate at a selected sampling time is established supporting a relationship between dissolution and disintegration testing for this type of formulation. Additionally, it could also be shown that the disintegration test method exhibits at least a similar discriminatory power compared to the proposed dissolution method. Based on a statistical approach and data from a bioavailability study, a clinical relevant specification for the disintegration time was established. All presented data support the replacement of dissolution by disintegration testing according to ICH Q6A for the selected fixed-dose combination product.

Keywords:

• Dissolution
• disintegration
• fixed-dose combination
• empagliflozin
• linagliptin
• justification of specification limits
• correlation

Acknowledgments

The authors thank Alfred Fetscher and Albert Barta for providing formulations, Julia Buske and Gerd-Michael Maier for supporting dissolution analyses, and Johannes Krämer for fruitful discussions on this topic.

Disclosure statement

The authors are employee of Boehringer Ingelheim.