The first orally disintegrating tablets (ODTs) received FDA approval in 1996, offering a valuable alternative for patients who struggle with swallowing traditional tablets, such as children and the elderly. These rapidly dissolvable tablets also offer a faster onset of action and better bioavailability for some drugs. However, their effectiveness is constrained by size, with the FDA typically limiting most ODTs to a maximum weight of 500 mg.
High-dose Orally Disintegrating Tablets are rare—often, only 20% of a 500 mg tablet will be active ingredient, but they can be crucial under certain circumstances. In this blog, we will share a case study that showcases an example of this with an anti-epileptic drug that is often prescribed for essential tremors. During an episode, this patient population is likely to have difficulty swallowing a conventional tablet. A high-dose ODT that dissolves in seconds could have a big impact on patients.
Due to the multiple, often competing, requirements, it takes a CDMO with specialized experience to deliver a successful high-dose ODT formulation, but very few have demonstrated an ability to do so.
Key Takeaways
- ODTs were first FDA-approved in 1996, but the FDA typically caps them at 500 mg, making high-dose ODTs (where the API alone can be 250 mg or more) especially difficult to formulate.
- Cost control for generic ODTs depends on non-proprietary excipients, multi-source sourcing, and simplified processes like dry granulation instead of wet granulation.
- ODTs must disintegrate in under 30 seconds while surviving compression, handling, and packaging. This is a balance so precise that a 1-2 mg weight change can make a tablet too fragile or too slow to dissolve.
- In LGM’s case study, a 250 mg anti-epileptic ODT required functional score lines for pediatric dosing flexibility, adding further complexity to the formulation.
- Embedding in-process quality controls (rather than relying on end-product testing) can reduce regulatory scrutiny and streamline FDA submissions.
Moderating Costs of Orally Disintegrating Tablets
Because many ODT products are generic, cost control is often crucial, limiting the use of high-end excipient or expensive technologies. Typically, Orally Disintegrating Tablets are packaged individually in blister packs to provide structural support—but when cost is an issue, investments like a dedicated new packaging line might not be an option.
Cost-saving strategies can make manufacturing feasible. This starts from the strategic choice of non-proprietary, widely available excipients. Sourcing materials from at least two or three manufacturers ensures price competition and supply chain flexibility. Experienced manufacturers may have important industry connections to facilitate finding the best price.
Production is another area where experience can help to maximize value. As production scales up to commercial levels, additional processing steps compound costs, driven by increased time, labor, and material demands. Streamlining requires simplified, low-step manufacturing processes. One major cost-saving decision is dry granulation, which significantly reduces energy consumption and production time (including 8-14 hours of drying) compared to wet granulation.
ODT Regulatory Adherence
There are multiple restrictions posed by regulations for Orally Disintegrating Tablets – for example, FDA’s 500 mg weight limit, and a requirement that tablets must disintegrate in less than 30 seconds. For generics, the shape and size must closely match the reference or branded drug.
ODTs are inherently fragile, making tablet strength optimization crucial despite the constraints of various formulation and manufacturing guidelines. These tablets must withstand multiple stresses, including compression, equipment transfers, and final packaging, to ensure their integrity throughout production and distribution.
When it comes to tablet strength, the formulation must be incredibly precise for high-dose orally disintegrating tablets. Reducing weight by even a little can make a tablet too fragile, while making it too heavy can make it too hard to disintegrate quickly enough—especially for high dose drug products. Striking the perfect balance can take years.
In some cases, breakage can be mitigated by refining manufacturing and packaging processes. Modifying tablet design—such as adjusting shape, softening edges, and fine-turning material characteristics—can enhance durability. Additionally, optimizing flow properties can further improve handling and reduce risk of damage. This is particularly challenging for high-dose orally disintegrating tablets, as many APIs have poor compressibility and flowability, making it harder to achieve both strength and rapid disintegration. When the API comprises a larger portion of the tablet, an experienced team is essential to optimize formulation and material performance.
Case study: a high-dose anti-epileptic ODT
LGM recently filed an ANDA with the FDA for the highest-dose orally disintegrating tablet we have developed, containing 250 mg of active ingredient—already halfway to the maximum weight of 500 mg, making formulation a critical factor.
Another challenge was packaging. Typically, ODTs are packaged individually in blister packs to provide structural support. However, our client required bulk packaging—100 tablets together—which meant the tablets would experience a significant drop (6–12 inches) during handling.
The proper tablet strength was especially important for this product, which comes in 50 mg and 250 mg doses, as the client required functional score lines on both. These score lines enable pharmacists, healthcare providers, and patients to precisely titrate doses for individuals with a narrow therapeutic index. A pediatric patient, for example, can be administered 25 mg or 75 mg from a 50 mg tablet. This level of dosing flexibility was critical to the product’s success and introduced additional complexity to both the formulation and tablet design.
Balancing rapid disintegration, tablet hardness, and manufacturability required deep expertise, material knowledge, and experience. On this project, the margin for error was thin. We found that by reducing the tablet weight by just 1–2 mg, it became too fragile. If we increased it by the same amount, it would become too hard. And despite their fragility, the tablets also needed functional scoring so they could be split to allow for precise pediatric dosing.
Meeting all the requirements took time, but our team’s continuous research on material properties and experience in optimizing formulations prepared us to meet both hardness and disintegration requirements. Ultimately, we were able to design a tablet with a breaking force of 3.5 kP, ensuring it remains intact through all manufacturing stages while maintaining its disintegration properties. This process helped us develop proprietary knowledge that we can apply to other ODT formulations.
We have also embedded cost-saving strategies that give us a competitive edge. Instead of relying heavily on extensive end-product testing, we embedded strict in-process controls at multiple stages of manufacturing. This proactive approach signals to the FDA that our process includes built-in quality control, reducing the likelihood of additional regulatory scrutiny or extensive final-product testing requirements.
The outcome speaks for itself—our client proactively awarded us additional orally disintegrating tablet projects, as a testament to their confidence in our expertise and ability to deliver high-quality, cost-effective formulations.
Frequently Asked Questions
- Why are high-dose ODTs harder to formulate than standard ODTs?
Because the FDA generally limits ODTs to 500 mg total weight, a high-dose ODT must pack more active ingredients into that same small allowance. This leaves very little room for the binders and excipients needed for tablet strength. - What’s the biggest formulation challenge with high-dose ODTs?
Balancing strength and disintegration speed. A tablet needs to survive compression, handling, and packaging without breaking, but must still dissolve in under 30 seconds and even a 1-2 mg weight change can push it too far in either direction. - Why does packaging matter for ODT durability?
ODTs are fragile, so they’re usually blister-packed individually for protection. Bulk packaging (where tablets can experience drops of 6-12 inches during handling) requires a much sturdier formulation. - What manufacturing choices help control ODT production costs?
Using non-proprietary, multi-sourced excipients and simplified processes like dry granulation (instead of wet granulation, which requires 8-14 hours of drying) can meaningfully cut time, energy, and labor costs. - How does in-process testing reduce regulatory risk?
Building quality controls into each manufacturing stage, rather than relying mainly on final-product testing, signals a more mature, controlled process to the FDA, which can reduce the likelihood of added scrutiny.
Want to learn more? Join us for our upcoming webinar to discover strategic approaches to ODT development that minimize costs while maintaining critical quality attributes. REGISTER TODAY!
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Subject Matter Expert for this Blog:
Deepak Thassu, Ph.D.
SVP of R&D and Regulatory