This study systematically integrated critical material attributes (CMAs) influencing drug release, focusing on factors such as particle size and excipient composition, and characterization of polymorphic form. As a model compound, a BCS class II drug Telmisartan was selected, and the methodology was evaluated using seven different formulations of Telmisartan through comprehensive analysis. The orthogonal analytical techniques, including chromatography, hot-stage microscopy, NMR spectroscopy, and dissolution testing were employed for evaluating critical quality attributes (CQAs). Systematic efforts were made to develop a biopredictive dissolution method using USP dissolution Apparatus I, II, and IV. Based on the tmax value of telmisartan, a multi-stage dissolution strategy was developed to understand the behaviour of formulation in acidic and neutral pH corresponding to the stomach and duodenum under fasting conditions. After de-formulation experiments, formulations were categorized into different buckets based on the size of API particles(d90 value of 8 ± 2 µm; 12 ± 2 µm and >15 µm), the type of excipients present (functional excipient and non-functional excipients), and the micro-environmental pH of the formulations. A rank-based approach was applied to evaluate a robust framework for understanding the differences between these generic formulations. This approach not only supports comprehensive formulation development through CMA-CQA correlations, but also aligns with regulatory expectations for adopting multi-dissolution methods as in vitro testing in cases of formulation change requirements with a bioequivalence waiver for post-approval formulation changes.
Keywords: Biopredictive dissolution method; Critical material attributes; In vitro drug release; Reverse engineering; Telmisartan.
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