QbD-based development of extended-release floating furosemide tablets: Formulation and in vitro/in vivo evaluation

This study aimed to develop gastro-retentive formulations of furosemide using a Quality by Design approach to enhance its bioavailability and diuretic effect, evaluated through in vitro and in vivo studies. The research started by defining the Quality Target Product Profile and conducting a Risk Assessment to identify factors affecting Critical Quality Attributes (CQAs). Pre-formulation tests determined factor levels for a Design of Experiments study, which identified key variables influencing CQAs. Tablets were prepared with hydrophilic polymers (HPMC k15M, HPMC k100 LV), alone or combined, and an effervescent mixture of sodium bicarbonate and citric acid. All batches met quality specifications. Formulations with over 16.5 % effervescent mixture floated for more than 8 h (n = 3) and achieved over 32 % dissolution in gastric pH (n = 3). The ratio between hydrophilic matrix and effervescent mixture significantly influenced flotation time, furosemide release, and matrix erosion (p < 0.05). Increasing the effervescent mixture improved buoyancy and dissolution but compromised matrix integrity due to higher erosion (p < 0.05). Formulation 10, comprising 18 % effervescent mixture and HPMC k100 LV as the sole matrix polymer, exhibited greater bioavailability than the reference formulation (Lasix®), as indicated by a Test/Reference urinary furosemide recovery ratio of 1.37 in an exploratory in vivo study. However, faster absorption led to rapid urinary excretion, limiting a sustained diuretic effect. The study demonstrated that formulation design and ingestion conditions significantly impact stomach physicochemical properties and drug behavior, highlighting the need for slower, prolonged absorption compared to immediate-release formulations. Future work will explore pH-independent strategies and matrix optimization to achieve sustained effect. • QbD-based gastro-retentive formulation enhances furosemide bioavailability. • HPMC/effervescent mixture ratio was critical while matrix composition mattered less. • System design and ingestion conditions alter stomach environment and drug delivery. • Clinical evaluation confirmed the performance of gastro-retentive formulations.