Abstract

Introduction: Dissolution testing is an important attribute that provides insight into in vivo performance, batch-tobatch uniformity and consistent clinical quality. Demonstrating discriminatory power of the dissolution method ensures that any changes in manufacturing processes or composition can be reflected through dissolution. Although discriminatory power is demonstrated through multiple experiments, modeling software such as Dose Disintegration and Dissolution Plus (DDDPlus) can be utilized. In the present case, for an extended-release formulation containing a class 3 (Biopharmaceutics Classification System) API, the regulatory agency indicated that the dissolution method lacked discriminatory power with respect to polymer content based on pilot test formulations in humans. Although formulations with varying polymer concentration showed differences in in vivo results, the in vitro dissolution were similar. DDDPlus was used to investigate the root cause for the lack of discriminatory power. Methods: A DDDPlus model was developed and validated using formulations with different polymer content. Simulated formulations with up to 70% less polymer content were used to test the model, and a cut-off for polymer content resulting in dissolution dissimilarity was determined. Results: When the polymer level was less than 50% of the original, similarity failure was observed, but formulations with higher polymer levels achieved similarity. This was attributed to the presence of highly soluble class 3 API in the formulation (> 50% w/w) coupled with a relatively low polymer level (20% w/w). This justification was accepted by the regulatory agency and further re-development of dissolution method was not necessary. Conclusion: This work opens new avenues for demonstrating discriminatory power of a dissolution method using software such as DDDPlus, which can reduce analytical workload, increase productivity, and speed up regulatory filings.

By Sivacharan Kollipara, Adithya Karthik Bhattiprolu, Rajkumar Boddu, Mahendra Chougule, Paramita Saha, and Tausif Ahmed