Comprehensive Evaluation of Push-Pull Osmotic Pump Tablets Using Biopredictive Dissolution Tests in Advanced Modular Platform, MRI Visualizations, and Pharmacokinetic Simulations

Abstract

Formulation and manufacturing of push-pull osmotic pump (PPOP) tablets are perceived to be complex technological processes. Multiple factors affect drug release kinetics, including polymer grade, drug-to-osmotic agent ratio, membrane characteristics, and manufacturing methods. In this study, we comprehensively investigated how manufacturing techniques impacted glipizide PPOP tablet performance. PPOP tablets comprised push and drug layers manufactured via wet granulation and/or direct compression methods, and different grades of poly(ethylene oxide) (molecular weights 5000 kDa and 4000 kDa) were used in the push layer. Tablets were characterized using biopredictive dissolution tests in the Advanced Modular Platform (AMP) apparatus under both fasted and fed conditions, simulating physiologically relevant mechanical stress events. Magnetic resonance imaging (MRI) was employed to noninvasively monitor tablet hydration, swelling dynamics, and water distribution in the PPOP during hydration. Physiologically based biopharmaceutics modeling (PBBM) was used to simulate glipizide plasma concentrations. All manufactured PPOP tablets released glipizide similarly, following zero-order kinetics, regardless of the manufacturing method and polymer grade in the push layer. Push and drug layer swelling patterns were also comparable. Under simulated mechanical stress conditions, even those exceeding physiological values, all batches maintained consistent release profiles without dose dumping. Only one batch, with both layers directly compressed, showed slightly slower release under fed conditions, but the PBBM model showed a limited influence on the predicted glipizide plasma concentrations. In conclusion, the manufacturing method and polymer grade had minimal impact on PPOP tablet performance, with direct compression providing a viable alternative to wet granulation. PPOP tablets demonstrated robust resistance to physiologically relevant mechanical stress, confirming their prominent role as controlled drug delivery systems.

Keywords: OROS; biopredictive dissolution; mechanical stress events; motility patterns; poly(ethylene oxide); push−pull osmotic pump (PPOP).