Investigating the Impact of Food Induced Fluid Viscosity on Disintegration and Dissolution of Immediate Release...

The prediction of bioavailability (BA) and bioequivalence (BE) for immediate-release (IR) solid oral dosage forms is critical during development and post-approval phases of drug products. ICH M13A provides the option of using in vitro tests, such as disintegration and dissolution in biorelevant media, pilot studies, and modeling to justify not conducting in vivo fed BE studies. The gastrointestinal (GI) tract environment changes significantly after food intake, including variations in pH, enzyme activity, and fluid viscosity that influence drug dissolution and absorption. Existing biorelevant dissolution media (FeSSIF, FeSSGF etc.) simulate human GI fluid composition but do not account for food-induced viscosity changes. This study explored impacts of food-induced fluid viscosity (pH 1.2 buffer containing hydroxypropyl methylcellulose (HPMC)) on disintegration and dissolution profiles of midodrine HCl tablets. Using USP Apparatus II and disintegration testing, we evaluated dissolution and disintegration of five approved generic midodrine HCl tablets with demonstrated BE. High-viscosity media significantly delayed tablet disintegration and drug dissolution compared to low-viscosity fasting conditions. We modified dissolution methods to closely simulate fed state GI conditions by varying agitation speed, prolonging dissolution time, adding medium stagewise to simulate dilution of gastric fluid, and adding water to mimic co-administered drinks. Results showed increased dissolution with higher agitation speeds and continued dissolution in viscous media over extended time. Stagewise dissolution in medium with reduced viscosity to mimic gastric secretion did not accelerate drug release compared to viscous media. In contrast, co-administered water enabled tablet swelling and disintegration, leading to complete drug release within 15 min, which is more consistent with the in vivo PK data under fed conditions. These findings may help refine in vitro dissolution conditions to better mimic fed-state.