(M0930-11-61) Investigating Impact of Food Induced Fluid Viscosity on Immediate Release Tablet Disintegration and Drug Dissolution

Purpose: Biorelevant dissolution tests are currently under extensive investigation for predicting oral bioavailability and bioequivalence in drug discovery and drug development. The purpose of this study is to assess the impact of food-induced viscosity changes on the in vitro disintegration and dissolution profiles of immediate-release solid oral drug product using midodrine hydrochloride tablets as model product. The findings of the study seek to contribute towards understanding of the impact of food-induced viscosity changes on bioavailability and bioequivalence assessment for immediate release (IR) oral products.

Methods: To explore the impact of food-induced fluid viscosity on tablet disintegration and drug dissolution, both fed and fasted conditions were simulated. The fed state of stomach was simulated by adding a viscosity enhancing additive, hydroxypropyl methylcellulose (HPMC, Millipore Sigma, viscosity: ~4,000 cP, 2 % in H₂O (20°C)) to standard buffer media at pH 1.2 as reported by Langguth et al.¹ The HPMC solution was characterized for pH, density, viscosity, and surface tension. To simulate the fasted state stomach, USP buffer media at pH 1.2 (0.1 N HCl without enzyme) was used. Five generic drugs of midodrine hydrochloride tablets (G1-G5) were tested for in vitro dissolution (USP Apparatus II, Agilent 708DS) and disintegration (PharmaTest).  Each 5 mg solid oral tablet (G1-5) was characterized by hardness, diameter, thickness, and weight. The dissolution studies were performed according to the USP conditions² described for midodrine hydrochloride tablets.  Then experiment was conducted in 1% HPMC varying the agitation speed (50 RPM, 75 RPM and 100 RPM) for 30 min (MM1) and extended the dissolution time to 2 hours (MM2) to mimic possible longer time that drug may stay in the stomach after food intake. Further, seven stages were developed to change medium viscosity to reflect possible dilution due to stomach secretion after food intake in modified method 3 (MM3).

Results: The target viscosity of the dissolution media for the study was chosen as ~100 cP, because it reflects the viscosity of FDA breakfast with 200 mL of water. All generic tablets showed very fast disintegration times in USP buffer media (~30 seconds) except G3 (the highest hardness among the five), which took 2.33 min. The disintegration times were significantly increased for all tested tablets in 1% HPMC medium (Figure 1). The in vitro dissolution profile of midodrine hydrochloride tablets in the pH 1.2 media showed the tablet was completely dissolved at 30 minutes.  However, under simulated fed conditions, all 5 products showed a release only about approximately 20-30% of label claim (at 30 minutes under 50 RPM), indicating a significant retardation in the release kinetics of the drug (Figures 2a-e). Further, the release rate was increased with the increase in agitation for G2, G4 and G5 due to possible diffusion layer decrease³ while G1 and G3 did not get affected by the agitation speed which might be due to differences in formulation. An increase in the amount of drugs release was shown when prolong the dissolution testing time from 30 minute to 2 hours (Figure 3a). But the rate of drug release in viscous medium did not change. Results also showed drug dissolution did not change with decreasing medium viscosity under simulated stomach secretion (Figure 3b).

Conclusion: The in vitro disintegration times and dissolution profiles were significantly delayed under simulated fed conditions, suggesting that food-induced fluid viscosity may play an important role in the disintegration and dissolution process. A longer testing time may be needed for dissolution study in viscous media. The simulated dynamic viscosity change of the stomach after the introduction of food may not affect drug dissolution. However, the current simulated fed dissolution methods may underestimate the drug release from IR formulations. Investigating swelling behavior and formulation effects on drug release in simulated fed conditions will help us develop dissolution methods to better simulate in vivo fed conditions.

References: 1. Radwan, A; Amidon, G. L.; Langguth, P. Mechanistic investigation of food effect on disintegration and dissolution of BCS class III compound solid formulations: the importance of viscosity. Biopharm Drug Dispos. 2012, 33, 403–416
2. The United States Pharmacopeia Convention; 2009. Chapter
3. Aparna, C., et al. Effect of Rate of Agitation on Dissolution. International Journal of Pharmaceutical Research and Applications; 2023, 8(4), 828-833.

Acknowledgements: This work reflects the views of the authors and should not be construed to represent FDA’s views or policies. Fathima T. Doole was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and U.S. FDA


Disintegration time of five midodrine hydrochloride tablet generic drug products (G1-G5) tested in USP media (blue) and 1% HPMC media (orange)


Dissolution profiles of the tested five midodrine hydrochloride tablet generic products (G1-G5) in USP media (Blue) and 1% HPMC media at different agitation speeds (a-e). % of drug release of generic products in 1% HPMC media at different agitation speed (f). (*n=3 and the data are represented as mean ± standard deviation (SD))


Extended dissolution time for 120 minutes (MM2) in 1% HPMC Media (a), dissolution profiles when gradually adding 0.1N HCl in seven stages to mimic secretion induced dilution (MM3) (b) and the calculated HPMC concentrations at each stage and the viscosity profile (c). MM3 was conducted only with G1-3 generic drug products due to relatively similar formulation composition. (*n=3 and the data are represented as mean ± standard deviation (SD))