This article is part of PharmTech's supplement "API Synthesis and Formulation 2009."
New drug-delivery technologies are often championed by contract manufacturing organizations. For new technologies that provide
significant clinical as well as financial value, research and innovation in the contract-manufacturing and pharmaceutical
segments lead to the emergence of numerous competing versions of the technologies.
Such a technology evolution has been evident for orally disintegrating tablets (ODTs). Designed to disintegrate rapidly on
contact with saliva and enable oral administration without water or chewing, these formulations offer increased convenience
and ease of administration with the potential to improve compliance, particularly in certain populations where swallowing
conventional solid oral-dosage forms presents difficulties.
The Zydis (Catalent Pharma Solutions, Somerset, NJ) lyophilization technology provided the first approved ODT (Claritin Reditabs,
Schering Plough, Kenilworth, NJ) in the United States in 1996. The earliest US regulatory definition for an ODT reflected
the lyophilized ODTs that prevailed at the time. An ODT was defined as "a solid-dosage form containing medicinal substances which disintegrates rapidly, usually within a matter
of seconds, when placed on the tongue (1)."
The emergence of multiple ODT technology platforms created some regulatory challenges due to increasing variance in the critical-product
attributes of ODTs, notably disintegration time and tablet size. It can be assumed that the regulatory challenge was most
acute for generic product applications. Hypothetically, in an abbreviated new drug application, the disintegration time of
a generic product could be 30–45 s, and the disintegration time of a reference product 0–10 s.
Prolonged disintegration times may result in failure to meet the defining performance characteristics of the ODT dosage form,
such that the product might require water for administration or chewing to facilitate swallowing. Where the patient or caregiver's
expectation is for rapid dispersion in the mouth, larger units with slower disintegration times could result in confusion
regarding the product quality and even present a choking hazard. Thus, in addition to product definition, patient safety is
also a significant consideration.
The US Food and Drug Administration responded to this challenge with the 2008 publication of Guidance for Industry: Orally Disintegrating Tablets (2). Three main points stand out in the final guidance:
- ODTs should have an in vitro disintegration time of approximately 30 s or less (using United States Pharmacopeia disintegration test or equivalent).
- Generally, the ODT tablet weight should not exceed 500 mg, although the combined influence of tablet weight, size, and component
solubility all factor into the acceptability of an ODT for both patients and regulators.
- The guidance serves to define the upper limits of the ODT category, but it does not supersede or replace the original regulatory
definition mentioned. In other words, disintegration within a matter of seconds remains the target for an ODT.
The public comment process for the guidance provided valuable insight into the broad range of patient, regulatory, and industrial
interpretation of the requirements for ODTs. One theme evident in the guidance document and the associated discussion is that
patient acceptance is especially critical for ODTs. In addition to tablet size and disintegration rate, factors affecting
patient acceptance of ODTs include palatability (i.e., taste, texture, and mouthfeel) and convenience (i.e., ease of handling).
Patient acceptance can be harder to measure, quantify, and define appropriate limits for compared with other product attributes.
What is regarded as acceptable is influenced by factors such as the condition being treated, frequency of dosing, and motivation
of the patient.
Although these additional factors may determine patient preference for the product and potentially influence compliance as
well as the overall commercial success of an ODT, they are not considered the key defining characteristics of the dosage form.
The inclusion of palatability criteria was debated during the guidance-consultation process, but its eventual omission suggests
FDA recognition of this. Nevertheless, patient-acceptability considerations are evident in all aspects of the FDA guidance
document, which sets the precedent for future growth and innovation in the ODT sector.
Despite the publication of the FDA guidance for ODTs, this category of dosage form lacks globally harmonized nomenclature
and criteria. For example, the European Pharmacopeia defines orodispersible dosage forms as having a disintegration time of less than 3 min (3). It is the authors' experience
that such differences do not result in inconsistent regulation of ODTs in different regions, but greater harmonization would