Reference-based QbD development of an enteric microtablet-in-capsule formulation for monomethyl fumarate with in vitro–in vivo performance assessment

Abstract

The development of enteric multiparticulate systems requires precise control of coating architecture and release behavior to ensure consistent in vivo performance. In this study, a reference-based quality-by-design (QbD) approach was applied to develop an enteric-coated microtablet-in-capsule formulation of monomethyl fumarate (MMF).

Comparative preformulation studies revealed that MMF-Ca, despite its higher aqueous solubility, exhibited poor manufacturability, including inadequate compactibility and a high capping tendency, whereas MMF showed favorable physicochemical and processing characteristics suitable for robust microtablet production. A systematic risk assessment and failure mode and effects analysis (FMEA)-based prioritization identified sub-coating level, enteric coating weight gain, and plasticizer concentration as critical variables governing coating integrity, acid resistance, and post-transition release behavior. These variables were further optimized using a design of experiments (DoE) approach.

The results demonstrated that enteric coating weight gain and sub-coating level had dominant effects on acid resistance and release kinetics, while plasticizer concentration contributed to coating robustness and reproducibility. The optimized formulation achieved negligible drug release under acidic conditions and rapid, reference-like release following pH transition.

Biorelevant dissolution studies revealed condition-dependent release behavior, with delayed drug release under fed conditions. These in vitro findings were consistent with in vivo pharmacokinetic profiles, including a delayed T_max under fed conditions. Furthermore, convolution-based analysis reproduced the overall temporal shift in absorption profiles observed under fasted and fed conditions.

Overall, this study demonstrates that the integration of risk assessment, FMEA-driven prioritization, and DoE-based optimization provides a robust framework for the development and bioperformance assessment of enteric multiparticulate systems.

Continue reading here

Materials

Monomethyl fumarate (MMF) was obtained from BetaPharma (China). Monomethyl fumarate calcium (MMF-Ca) was provided by Hanmi R&D Center (Republic of Korea). Dimethyl fumarate (DMF), used as a reference active pharmaceutical ingredient, was purchased from Jiaoda Weinan Pharmaceutical Co. (China).

Microcrystalline cellulose (Prosolv® SMCC) was supplied by JRS Pharma (Germany) and used as a filler and dry binder. Croscarmellose sodium (Ac-Di-Sol®) was obtained from FMC BioPolymer (USA).

Taek Kwan Kwon, Ho Taek Im, Jung Hyun Cho, Reference-based QbD development of an enteric microtablet-in-capsule formulation for monomethyl fumarate with in vitro–in vivo performance assessment, Journal of Drug Delivery Science and Technology, Volume 127, Part 2, 2027, 108962, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108962.