(M1130-11-60) Effect of Medium Viscosity on Swelling and Disintegration of Immediate Release Solid Oral Tablet

Purpose: To develop biorelevant testing protocols to simulate fed conditions, the mechanism of disintegration in viscous media needs to be understood. This study aims to investigate swelling behavior of an immediate release midodrine hydrochloride tablet drug product under different viscous hydroxypropyl methylcellulose (HPMC) media. Such investigation offers valuable insights into how tablets may swell and disintegrate under simulated fed conditions, thereby advancing our understanding of drug dissolution kinetics in physiologically relevant settings.

Methods: HPMC (Millipore Sigma, viscosity: ~4,000 cP, 2 % in H₂O (20°C)) was used to simulate fed state food-induced viscosity as reported by Langguth et al.¹ The HPMC solution was characterized for pH, density, viscosity, and surface tension. The fasted state stomach was simulated using USP buffer media at pH 1.2 (0.1 N HCl without enzyme). Three generic drug products (G1-3) of midodrine hydrochloride were tested for in vitro dissolution (USP Apparatus II, Agilent 708DS) under a modified method to mimic taking tablet with a glass of water under the fed condition. The tablet was exposed to USP media (50 mL, 2 min, no agitation) followed by adding 1% HPMC (900 mL final medium volume, 50 RPM, simulating gradually increased viscosity under fed conditions). The texture analyzer (Texture Technologies Corp, TA.XTplus Texture Analyser), with flow through method² was used to monitor the swelling behavior of generic drugs (G1-3) in USP media (fasted condition), and the media reservoir method³ was used to monitor the swelling behavior of G2 in different concentrations of HPMC solutions (fed state). The media reservoir method was used here due to high viscosity of the testing media. With the media reservoir method, briefly, the tablet was compressed with the probe of texture analyzer under a constant force of 15 g in the dissolution media (at 37^oC). Dissolution media was stirred at a constant rate of 100 rpm with a magnetic stir bar, and the probe displacement with time was recorded. TGA experiments⁴ were carried out for HPMC solutions (0.25%, 0.5%, 0.75% and 1%) by ramping the temperature up and isotherm at 38^oC. The % weight loss of the media was obtained as a function of time.

Results: The current study indicated that G1-3 drug products showed similar dissolution profiles closer to a 100% drug release within 10 minutes in modified dissolution method, that mimicking drug taken with water under the fed condition. The texture analyzer records initial displacement of the probe upwards (negative values) caused by the swelling of the tablet. After the tablet is completely swollen it starts to disintegrate. This shows in the graph as a positive value (displacement of probe downwards) (Figure 1a). Disintegration time in USP media for tablets G1 and G2 was below 60 seconds while G3 showed the longest disintegration time (Figure 1b). G3 had the slowest swelling rate, aligning with the trend from disintegration tests (Figure 1c). Average swelling times were increased while swelling rates decreased with the increasing viscosity of the media for measured G2 drug product (Figure 2). These results suggest there is a positive correlation between swelling time and the disintegration time, suggesting that midodrine hydrochloride release from IR tablet upon initial swelling of the tablet. Disintegration is achieved by the penetration of the physiological fluid into the tablet and the subsequent disruption of the particle-particle bonds which maintain the structural integrity of the dosage form⁵. The TGA analysis shows that the water evaporation rate slowed down with the increase of the HPMC concentration (Figure 3a), suggesting the amount of free water present in the solution is decreased. Water molecules are prone to form a cage like structure around nonpolar groups in HPMC⁶ which will reduce the amount of free water in the solution (Figure 3b). Thus, less available free water penetrates the tablet, slowing the swelling rate and tablet disintegration.

Conclusion: Initial tablet swelling is crucial in determining drug release rate and a small volume of free water is sufficient to facilitate this process. High viscosity dissolution media slows down the tablet swelling rates which lead to longer time for tablet disintegration and drug dissolution. Tablet composition plays a significant role in tablet swelling. Further investigations to assess different excipient effect on drug intrinsic dissolution rate in viscous media are ongoing. These investigations will provide deeper insights into drug dissolution kinetics in physiologically relevant settings.

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, https://doi.org/10.1002/bdd.1798
2. Gao, Z.; Cao, L. N. Y.; Liu, X; Tian, L.; Rodriguez, J. D. An In Vitro Dissolution Method for Testing Extended-Release Tablets Under Mechanical Compression and Sample Friction, Journal of Pharmaceutical Sciences. 2022, 111(6). 1652-1658 https://doi.org/10.1016/j.xphs.2021.10.036.
3. Gao, Z.; Tian, L.; Rodriguez, J. D. Nifedipine Release from Extended-Release Solid Oral Formulations Using In Vitro Dissolution Testing Under Simulated Gastrointestinal Compression, Journal of Pharmaceutical Sciences. 2020, 109(7), 2173-2179, https://doi.org/10.1016/j.xphs.2020.03.023.
4. Geng, P; Zore, A; Van De Mark, M. R. Investigation of the Evaporation Rate of Water from Colloidal Unimolecular Polymer (CUP) Systems by Isothermal TGA. 2020, 12 (11). 2752, https://doi.org/10.3390/polym12112752
5. Markl, D. and Zeitler, J. A. A Review of Disintegration Mechanisms and Measurement Techniques. Pharm Res. 2017, 34. 890-917, https://doi.org/10.1007/s11095-017-2129-z
6. Silva, S. M. C., et al. Aggregation and gelation in hydroxypropylmethyl cellulose aqueous solutions. Journal of Colloid and Interface Science. 2008, 327(2): 333-340 https://doi.org/10.1016/j.colsurfa.2009.09.040

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


a) Schematic diagram of tablet swelling and probe displacement b) disintegration time in USP media of the generic tablets G1-G3 and c) tablet swelling data of generic tablets G1-G3 acquired with Flowthrough Method in USP media (*n=3 and the data are represented as mean ± standard deviation (SD))


Tablet swelling data of G2 acquired with Media Reservoir Method3 in different compositions of high MW HPMC media (*n=3 and the data are represented as mean ± standard deviation (SD))


a) TGA analysis of high molecular weight HPMC solutions (0.25%, 0.5%, 0.75% and 1%) and USP media b) schematic diagram of the water molecule penetration within polymeric chains