Qualifying ODT Excipient Systems Beyond Disintegration Performance

Orally disintegrating tablets (ODTs) can offer many advantages for patients, but only if formulated with the optimum excipient system. In addition to rapid disintegration and dissolution, ODT excipient systems should provide long-term stability and performance over a wide range of active pharmaceutical ingredient (API) loading levels.

Why Formulate as an Orally Disintegrating Tablet? 

Rapid disintegration in the mouth without the need for liquid offers many advantages. For patients that have difficulty swallowing, most often children and seniors, orally disintegrating tablets (ODTs) eliminate the burden of chewing or swallowing whole tablets. This mode of administration is also beneficial to patient groups who prefer the convenience of a dosage form that doesn’t require water for administration or do not have access to potable water. 

ODTs are typically used to formulate medication for indications that must offer fast relief, such as antihistamines, hypnotics, sedatives, antipsychotics, and pain, and anti-migraine medications.

ODT formulations may also offer the potential for enhanced bioavailability in certain APIs by enabling the rapid onset of action due to quick dissolution and fast absorption.¹ Increased bioavailability of drugs absorbed in the mouth, pharynx, and esophagus avoids hepatic metabolism, allowing for similar effects at reduced doses.^2–4 

The increased convenience, enhanced bioavailability, and greater patient compliance of ODTs make this formulation and administration route attractive for product life cycle extension. An orally dispersible form of a marketed drug may allow a manufacturer to prolong market exclusivity, create a value-added product line extension, and continued patent protection. 

Several ODT Excipient System Options 

There are a range of approaches available for ODT formulation, such as lyophilization, direct compression, molding, and spray-drying. Direct compression presents the most straight-forward and cost-effective approach, as it relies on commonly available, conventional equipment.^5–7 

Several excipient systems specifically designed for use in ODT formulations have been introduced to the market. Most ODT excipient systems contain several binders and a superdisintegrant. Thus, the amount of regulatory work required for registration increases due to the greater number of components added especially with regards to Quality by Design (QbD). This work could be significantly reduced if an ODTs only contained two components: one binder plus a superdisintegrant. Mannitol is often used because it exhibits a sweet taste and pleasant mouthfeel, is stable and non-hygroscopic, and is inert to virtually all APIs. Parteck^® ODT excipient is a combination of D‑mannitol (a binder) and croscarmellose sodium (a superdisintegrant). Croscarmellose sodium is the sodium salt of a cross‑linked, partly O-(carboxymethylated) cellulose. Both are well accepted by regulatory authorities, which may help to accelerate the registration procedure of a formulation.

Different ODT excipient systems provide different performance and stability properties for final ODT formulations. Table 1 presents an overview of the compositions of five different ODT excipient systems available on the market. 

Dissolution and Disintegration Properties are Crucial

When selecting an ODT excipient system, both disintegration and dissolution should be evaluated, because different systems provide significantly varying behaviors. The wide range of performance properties was demonstrated using tablet formulations (Table 2) made with a model API (ibuprofen) and the five ready-to-use ODT excipient systems listed in Table 1.⁸

Disintegration was performed on six tablets of each excipient system according to USP/Ph. Eur. guidelines. Most tablets disintegrated in 30 seconds or less, but only when tablet hardness was low (30 N or less), which would be considered rather weak for tablets produced on an industrial scale. When hardness increased, disintegration times rose well beyond 30 seconds. While compendial specifications vary, 30 seconds is the generally accepted performance standard for ODT per FDA recommendations.⁹ These results demonstrate the importance of evaluating the disintegration behavior at the desired hardness during industrial production.

With respect to the dissolution of the poorly soluble model API ibuprofen from these test tablets, a variation in release profiles was also observed. As can be seen in Figure 1, most of the excipient systems did not provide immediate release of the API. These studies revealed that API release appears to be dependent on the properties of the API — most likely hydrophobicity for ibuprofen — and on the excipient system. Excipient system A showed the best release and the least sensitivity to the API in its release. These results were confirmed with other APIs (data not shown).

The differences in dissolution rates can be partly explained by the surface structures and porosities of the excipient combinations (Figure 2). These factors influence how well water penetrates the tablet, leading to different speeds of action of the superdisintegrants contained therein.

Although the major pharmacopeias do not account for particle structure in excipient monographs — instead focusing on the chemical parameters of the individual components — particle morphology plays a major role in the performance of solid dosage forms. It remains likely that the particule structure of excipients results in differences in galenic behavior. Other factors are also involved as well. For example, some excipients contain polymers known to have retarding effects; swelling starch can produce a similar result. Formulators should, therefore, evaluate ODT excipient systems on additional criteria beyond a simple disintegration test to find the most suitable excipient system for their respective API and desired final product performance.

Simpler Can Be Better

In addition to evaluating the varying performance of different ODT excipient systems, it is also important to consider their complexity. Most ODT excipient systems on the market contain several binders and a superdisintegrant. The higher the number of components, the greater the work involved when implementing quality-by-design development approaches and for regulatory registration

ODT excipient systems comprising just two components present a lower burden. Parteck^® ODT excipient, for instance, is a combination of D‑mannitol (a binder) and croscarmellose sodium (a superdisintegrant). Croscarmellose sodium is the sodium salt of a cross linked, partly O-(carboxymethylated) cellulose. Both are well accepted by regulatory authorities, which may help to accelerate the registration process for ODT formulations.

As a result, the morphology of the Parteck^® ODT excipient system is rough and structured when viewed under a scanning electron microscope (SEM) (Figure 3). This microstructure leads to good compression behavior, and thus high tablet strength is achievable with low compression forces.

This type of polyol excipient typically shows a great deal of wear of the granulated particles upon mechanical stress. The morphology of the Parteck^® ODT material remains unchanged after mixing and compression, however, resulting in a very large specific surface area of the tablet matrix of up to 3.5 m²/g.^8,10

One benefit is the minimization of the wear of tableting equipment. Also, such an exceptionally large surface area can adsorb large quantities of small API particles well and prevent de mixing during the manufacturing process. Indeed, up to 50% API can be directly compressed with Parteck^® ODT, compared with a typical content of approximately 20–30%. Water uptake and disintegration of the tablet matrix are also enhanced. Clearly, both the superdisintegrant and the unique surface structure of the binder are responsible for fast disintegration of the overall product.

In addition, the Parteck^® ODT system does not exhibit any sensitivity toward different lubricants. When added to a randomly chosen set of lubricants (2% sodium stearyl fumarate, 3% trimyristin, 1% Parteck^® LUB MST magnesium stearate, or 5% polyethylene glycol 6000) in placebo formulations, no significant effect on disintegration behavior was observed. As a result, formulators have greater flexibility to resolve specific formulation problems.

Disintegration and drug release tests for tablets including Parteck^® ODT excipient and different model APIs have also been evaluated.¹¹ In one example, two Parteck^® ODT drug formulations (Tables 3 and 4) with paracetamol of different grades and sources were used to investigate drug release kinetics in vitro.

Notably, after 10 minutes more than 95% of the API in the two formulations was released with Parteck^® ODT as directly compressible excipient. In addition, friability at a very low compression force (e.g., 5 kN) of < 0.4% was achieved (data not shown), allowing for the manufacture of extremely robust tablets that can survive processing and handling during manufacture, packaging, and use.

In another example with sildenafil as the API, disintegration times were found to be well within the range expected for ODT applications, and good tablet hardnesses and low tablet friabilities were observed even at low compression forces. Importantly, producing hard and stable tablets did not cause the disintegration time to suffer. As can be seen in Figure 4, the disintegration time remained constant over a wide range of tablet strengths. This attribute is a major difference from some ODT excipient systems on the market, which display fast disintegration only for rather soft tablets.

Stability is Essential

In addition to examining disintegration and dissolution properties immediately after production, the stability of ODT formulations and their performance over their shelf-life must be evaluated. As the composition of some excipient systems is not disclosed it is sometimes difficult to foresee possible instabilities in the final formulation due to the potential presence of impurities. Since excipient systems for ODT formulations are usually a combination of two or more components, their composition can be ambiguous to the formulator.

Among the commonly observed impurities in solid dose excipients are peroxides. Therefore, the peroxide content in the five ODT excipient systems listed in Table 1 was determined using the DAB method,¹² which is based on iodometric titration but not widely known.¹³ Significant differences in peroxide content were found across the five excipient systems. The peroxide contents of systems C and E, which contained povidone and/or crospovidone, were particularly high in comparison to that of systems A and D (peroxide counts of 27.7 and 26.7 vs. 0.6 and 1.6, respectively). The lowest peroxide content was determined for system A, Parteck^® ODT excipient (0.6).

Next, the compressibility and potential for quick disintegration of the excipient systems listed in Table 1 was evaluated when used in placebo formulations containing the ODT excipient mixed with 1% magnesium stearate and processed using a single punch press. A tablet hardness of 100 N is the goal, as this ensures easy handling and enables the use of conventional packaging. Thus, tablets weighing 300 mg with a diameter of 11 mm and a hardness of ~100 N were produced at compression forces of 13–30 kN. The disintegration time and potential discoloration were evaluated after storage in closed containers under accelerated conditions (40 °C, 75% r.H.) after 1 day and 1, 2, 4, 8, 12, and 26 weeks.

The desired tablet hardness of > 100 N was achieved for all of the directly compressible excipients tested. As can be seen in Figure 5, Parteck^® ODT excipient (system A) reached its highest tablet hardness (132 N) at the lowest compression force (13 kN). These tablets also exhibited the shortest disintegration time of just 21 seconds. Two of the other ODT excipients (B and D) had disintegration times between 39 and 46 seconds, while the remaining two systems had disintegration times of 2 minutes or more (C and E).

A significant increase in disintegration time was observed at longer storage times for B and E, while Parteck^® ODT excipient (A), as well as systems C and D, showed adequate stability over 26 weeks under accelerated conditions (Figure 6).

Changes in tablet color are a further indication of instability. Tablets manufactured using ODT excipient system E clearly showed discoloration during storage under accelerated conditions, with a significantly increased delta value after just one week of storage. After 26 weeks, a strong discoloration visible to the naked eye was observed. On the other hand, the products produced using excipient systems A, B, C, and D showed acceptable stability with no visual changes detected (Figure 7). 

Coated ODTs

Tablet coating is often desired to enable taste-masking; to protect sensitive APIs from light, oxygen, or moisture; or as an anti-counterfeiting measure. Because ODT formulations are designed to disintegrate very fast upon the contact with very little water, most of the current ODT formulations are compressed to rather weak units with low tablet hardness. This is why coating is generally considered to be impossible for ODT formulations.

The Parteck^® ODT excipient system, however, is compatible with aqueous coatings. The performance of the five ODT excipient systems presented in Table 1 was evaluated in placebo formulations subjected to a coating process using a commercially available aqueous coating system based on polyvinyl alcohol.¹⁴

All of the placebo formulations were compressed to a hardness of approximately 50 N to allow for a comparison of the disintegration times of the tablet cores. Aqueous coating of ODT formulations is possible if the appropriate excipient system is used. As a result of the coating process, tablet hardness was observed to increase for all of the tablets (Figure 7). However, only the Parteck^® ODT excipient system showed a constant disintegration time before and after the coating. For all others, the increased disintegration time made them inappropriate for use as ODT formulations.The tablet edges were also observed to be chipped and eroded for several of the applied ODT excipient systems. Similar results for increasing hardness and disintegration times were reproduced for tablets containing API (20% w/w ascorbic acid; data not shown) and when using a different commercially available aqueous coating system based on HPMC.¹⁴ 

The Parteck^® ODT Advantage

ODT formulations provide significant benefits, including convenience, improved adherence, the potential for enhanced bioavailability, and product life cycle extension. While there are many choices of ODT excipient systems, they differ in key areas that should be considered before inclusion in a formulation.

The combination of two components in Parteck^® ODT excipient — a binder and a superdisintegrant — shows valuable characteristics for direct compression. Owing to large surface area, the formulator can achieve high tablet strength at low friability while still achieving fast disintegration and a pleasant mouthfeel.

As demonstrated, Parteck^® ODT excipient allows the design of robust dosage forms with fast dissolution irrespective of the drug substance grade, tablet weight, and tablet size. It combines excellent compressibility with a short disintegration time and stable performance under accelerated storage conditions. In addition, tablets produced using Parteck^® ODT excipient have attractive properties with respect to tablet hardness, API stability, low levels of peroxide, and long-term stability. Aqueous coating of ODT formulations containing the Parteck^® ODT excipient system is also possible with no impact on disintegration time.

Given all of these attributes, the compatibility of Parteck^® ODT with most actives, and its simplicity, this excipient system can help to accelerate both formulation development and the regulatory registration process, making it a viable, economical option for ODT formulations.

References

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