Evaluation of orally disintegrating tablets: regulatory pathways, administration practices and harmonization of bioequivalence study design

Abstract

Orally disintegrating tablets (ODTs) are a solid oral dosage form designed to rapidly disintegrate in the mouth without the need for water, improving patient compliance—particularly among pediatric, geriatric, and dysphagic populations. Despite their advantages, ODTs pose formulation and regulatory challenges due to their unique administration characteristics and potential for pregastric absorption. This review examines the regulatory approval pathways for ODTs, including 505(B)(1), 505(B)(2), 505(J), and 505(J)(2)(C), and highlights examples of marketed ODT products approved through each pathway. The differences in in-vivo absorption behavior between ODTs and conventional tablets are discussed, including their influence on pharmacokinetic parameters such as Cmax, Tmax, and AUC. Emphasis is placed on the impact of water co-administration on ODT bioavailability, where factors like fluid volume and administration route can alter drug dissolution and absorption. This paper evaluates product-specific guidances (PSGs) and reference listed drug (RLD) labeling for 39 ODT products approved before the release of the FDA’s guidance, M13A guidance on Bioequivalence for Immediate-Release Solid Oral Dosage Forms. Of these, 17 ODT PSGs recommended different instruction for administration of water than that from their respective product labeling. These PSGs were subsequently updated to align with FDA M13A guidance recommendations. Lastly, this paper provides a comprehensive framework for optimizing bioequivalence assessments of ODTs and supports future development of ODT formulations for new and generic drugs.

Introduction

The oral route is preferred for drug administration due to its accuracy, low cost, ease of use, and non-invasiveness, promoting high patient compliance (Parkash et al. 2011). While liquid formulations may offer high bioavailability, they lack dosing precision—a limitation addressed by unit dose forms like tablets and capsules that enable accurate dosing and efficient mass production (Cilurzo et al. 2018). However, conventional tablets may be restricted in pediatric, geriatric, and bedridden patients, as well as individuals with swallowing difficulties or limited water access (Seager 1998). To overcome these challenges, orally disintegrating tablets (ODTs) were introduced in the 1980 s, providing a rapidly dissolving, water-free option that enhances both convenience and patient compliance (Center for Drug Evaluation and Research 2008; Pfister 2005). ODTs are solid dosage forms that quickly dissolve on the tongue without water, with both U.S. Food and Drug Administration (FDA) and European Pharmacopoeia defining them as tablets that disperse rapidly in the mouth. ODTs offer advantages including easier administration for vulnerable populations, faster onset, and improved absorption for certain drugs (Ghosh et al. 2005). However, ODT development presents challenges. Taste masking is essential because dissolution occurs in the mouth, requiring techniques to reduce bitterness and improve palatability (Kadota et al. 2021; Douroumis 2011). ODTs are more fragile due to low compression and porous materials, making them prone to breakage (Bharawaj et al. 2010). They are also moisture-sensitive, necessitating specialized packaging like blister packs for stability and proper handling. ODTs utilize specialized excipients including high concentrations (4–15%) of superdisintegrants (crospovidone, croscarmellose sodium, sodium starch glycolate) and water-soluble fillers (mannitol, sorbitol, xylitol) to achieve rapid disintegration and enhanced dissolution. Water-soluble binders (gelatin, polyvinyl alcohol, polyethylene glycol) and lubricants like sodium stearyl fumarate replace traditional hydrophobic excipients that could impede breakdown. Additional components include taste-masking agents, saliva stimulants, and effervescent agents to optimize patient experience (Badgujar and Mundada 2011).

In the development of study designs for new drug applications (NDAs), ODTs may be administered with water, without water, or using both methods, depending on the specific requirements of the study. For generic drug development, the bioequivalence (BE) study design follows the reference listed drug (RLD) labeling instructions regarding water use. The dual administration approach necessitates careful consideration of optimal BE and bioavailability (BA) study parameters for product approval. Administration method selection is essential, as it can determine whether BE is successfully demonstrated between the test product and the RLD. The current thinking on appropriate recommendations for conducting BE studies is reflected on a product-by-product basis and published in a product-specific guidance (PSG) for the respective generic product. For a generic ODT product, how the product is recommended to be administered in a BE study is reflected in the PSG and the drug product labeling.

This work was conducted to provide a comprehensive evaluation of ODTs, with a focus on regulatory practices, administration methods, and BE study design. We begin by examining the various regulatory pathways available for ODT approval—including 505(B)(1), 505(B)(2), 505(J), and 505(J)(2)(C)—and how each pathway influences the evidentiary requirements for approval. We then explore the in vivo absorption characteristics of ODTs, which differ from conventional oral dosage forms due to potential pregastric absorption and the influence of fluid volume on drug dissolution. Building on this, we analyze current administration practices—particularly with or without water—and their implications for BE outcomes. Finally, we assess the consistency of administration recommendations between product labeling and PSGs for approved ODTs and propose a harmonization strategy aligned with the FDA M13A Bioequivalence for Immediate Release Solid Oral Dosage Forms guidance (FDA M13A). This work aims to support more scientifically robust and globally consistent approaches to ODT evaluation and approval.

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Bagde, S., Xi, X., Boyce, H. et al. Evaluation of orally disintegrating tablets: regulatory pathways, administration practices and harmonization of bioequivalence study design. AAPS Open 12, 2 (2026). https://doi.org/10.1186/s41120-025-00138-y