Biorelevant simulation of GI variability and its impact on the release behavior of non-disintegrating formulations: A case study using DHSI-IV (NERDT) system as a novel in vitro tool.

Gastrointestinal (GI) physiological variability significantly influences dissolution and bioavailability of non-disintegrating solid drug systems. This study employed the dynamic human stomach-intestine (DHSI-IV, branded as NERDT) system to characterize how gastric emptying kinetics and intestinal environmental dynamics affect drug release, using extended-release metformin matrix tablets (Glucophage XR®) and metformin osmotic pump tablets (Nida®) as model formulations. The DHSI-IV (NERDT) system accurately simulated three fasting-state gastric emptying profiles (30-120 min complete emptying) with excellent fit to the modified Elashoff model (R2 = 0.989) and clinical-matched kinetic parameters such as k and β. With the above gastric physiological simulations, Glucophage XR® tablets (length > 12 mm) retained in the stomach due to the pylorus released over 75 % drug within 6 h, whereas potential pyloric passage (tablet width/height < 12 mm) allowed entry into the intestine with delayed dissolution. Delayed emptying of tablets or ingested water enhanced metformin exposure to dissolution medium, with tablet retention exerting a more pronounced effect. In intestinal simulations, Nida® release under peristalsis increased approx. 4-fold at 6 h versus non-peristaltic conditions, attributed to larger dissolution volume, prolonged residence time of dissolution medium, and late-stage burst release. By integrating dynamic gastric and intestinal parameters, the DHSI-IV (NERDT) system addresses limitations of static models in capturing GI dynamics and predicting formulation-specific responses to GI variability, enabling more precise in vivo dissolution replication. This dynamic in vitro approach provides mechanistic insights into size-dependent release and motility-induced burst release, offering a novel strategy for data-driven optimization of solid drug formulations.