Unveiling Swelling and Erosion Dynamics: Early Development Screening of Mirabegron Extended Release Tablets

Abstract

Although the development of extended release (ER) matrices has been extensively investigated, understanding the most appropriate mechanism of drug release to achieve the desired release remains a cost- and time-consuming challenge in the early stages of formulation development. This study aimed to investigate the early stage of developing ER hydrophilic matrix tablets containing mirabegron as a model drug, focusing on the effects of polymer type, diluent type, and polymer amount on critical quality attributes (CQAs), namely, tablet swelling and erosion behavior. A full factorial design was employed to explore the interactions of control factors through multivariate regression analysis, emphasizing the application of quality by design (QbD) principles.

The swelling and erosion performances of 72 formulations were evaluated. The swelling data were fitted to the Vergnaud model. Finally, in vitro drug release profiles were investigated for four of the formulations studied. The polymer type, diluent type, and polymer amount had distinct effects on the swelling and erosion behavior of the ER matrix tablets. Compared with those with isomalt (G720) or dextrate (DXT), formulations with polyethylene glycol 8000 (P8000) consistently exhibited greater swelling. Additionally, higher molecular weight was correlated with increased swelling within the same polymer type.

Hydroxypropylmethylcellulose (HPMC) and polyethylene oxide (PEO)-based formulations showed higher swelling rates, while polyvinyl alcohol (PVA-80) displayed the highest erosion percentage. The findings highlight the significance of incorporating early-stage screening designs to maximize efficiency and optimize time and resource. This approach enables the development of a comprehensive understanding of drug release mechanisms from ER matrix tablets.

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Materials

Mirabegron was used as a model drug and was purchased from Dr. Reddys Laboratories Ltd., Hyderabad, India. The excipients were purchased from or provided by Dow Chemical Company (Midland, MI, USA), Lubrizol (Westerlo, Belgium), Merck & Co. (Kenilworth, New Jersey, USA), BENEO (Mannheim, Baden-Wurttemberg, Germany), JRS Pharma (Rosenberg, Baden-Wurttemberg, Germany), DuPont (Dartford, UK) and UNDESA (Barcelona, Spain). Table I summarizes the excipients used in the study. Four grades of PEO, namely N-750, 1105, N-60 K and 303, were used with a viscosity range at 25 ºC of 600–1200 mPa.s (5% solution), 8800–17,600 mPa.s (5% solution), 2000–4000 mPa.s (2% solution) and 7500–10,000 mPa.s (1% solution), respectively. Two grades of HPMC (USP type 2208), K4M and K100M, were used with viscosities ranging from 2663 to 4970 mPa.s and 75,000–100,000 mPa.s, (2% w/w aqueous solution at 20 ºC), respectively.

Table I Excipients Used in the Study and Their Function in Formulation

Excipients used in the study: Methocel™ K4M Premium, Methocel™ K100M Premium C, Carbopol^® 71G NF Polymer, Parteck^® SRP80, galenIQ™ 720, EMDEX^®

Sousa, A.S., Serra, J., Estevens, C. et al. Unveiling Swelling and Erosion Dynamics: Early Development Screening of Mirabegron Extended Release Tablets. AAPS PharmSciTech 25, 277 (2024). https://doi.org/10.1208/s12249-024-02994-5

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