Is another ODT excipient necessary?

Formulations for tablets with fast melt characteristics were originally demanded for special patients and indications, where swallowing tablets led to poor patient compliance, particularly in children and geriatric patients.¹ Soon after, however, the market demanded more of these easily administrable formulations and companies realized their marketing advantage compared with conventional tablets; the ability to take tablets anywhere without water for swallowing made them more attractive. Moreover, companies regarded this new formulation and administration route as a product lifecycle extension — a strong economic driving force these days. Soon, this special application niche was named ODT — orally dispersible tablet.

Fast disintegrating formulations have long been available, but how do ODTs differ from other technologies? The answer is not straightforward because definitions of an ODT vary: the US Pharmacopeia describes an ODT as a tablet with a disintegration time of <30 s; whereas the European Pharmacopoeia gives a disintegration time of <180 s.^2,3 Ultimately though, it is the therapy's acceptance in the market as well as the patients that have coined the definition of an ODT: a tablet that dissolves quickly in the mouth without water, and has a pleasant mouth feel and taste, without an adverse aftertaste (if the mouth feel or taste are unpleasant even the shortest disintegration time will be too long!).

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ODTs can be categorized into two main groups: lyophilized formulations and directly compressed tablets. Thin film strips are a third category, but are limited in dosage up to approximately 30 mg. This technology does, however, keep its niche for certain actives; for example, in cold and flu indications. Lyophilization plays a minor role owing to its cost and difficult handling, though it does remain important for very sensitive drug molecules. Undoubtedly, the greatest interest of pharmaceutical formulators is in direct compression, because it is a cost-effective production technology with a broad application range that has the least limitations with regards to the active. Furthermore, the finished product resembles what patients are used to, which guarantees good acceptance and aids compliance.

Numerous excipient systems for ODT applications are already available on the market including, for example, Pharmaburst, F-Melt and Ludiflash (directly compressed ODTs), and Pharmafreeze, Zydis and Lyoc (lyophilized ODTs). One might, therefore, ask the question: is there a need for yet another basic excipient system for direct compression and fast disintegration? We believe the answer is "yes".

Developing a two-component excipient

As a minimum requirement, most directly compressed ODTs rely on the inclusion of a sugar alcohol combined with a superdisintegrant. The use of superdisintegrants has been widely described; they are generally accepted as a necessary component of ODT formulations to speed dissolution.^4,5 Another important feature of an ODT is its taste; it must taste good otherwise the product will never get off the ground. In general, polyols are known to exhibit a sweet taste and a pleasant mouth feeling, with mannitol being one of the most commonly used of this class because of its crucial qualities; it is not hygroscopic, it is stable and it is inert to virtually all APIs.

However, polyols are not thought to be sweet enough to mask bitter-tasting actives, and are, therefore, deemed to be insufficient for taste-masking in ODT formulations. As a result, they are hardly used as sweeteners in pharmaceuticals and instead serve as effective binders. A supersweetener, such as aspartame or sucralose (sucralose does not exhibit the same unpleasant aftertaste as most other sweeteners and has a similar, pleasant taste to sucrose), may be better in this scenario.

When considering ODT excipient systems, it is nonsensical to include a sweetener at this stage because its dosage will be dependent on the nature and taste of the active and other ingredients.

Most ODT excipient systems on the market contain more than the two essential components; that is, they include several binders and a superdisintegrant. Thus, the amount of regulatory work required for registration increases with the greater number of components added. We believe that this work could be significantly reduced if all ODTs only contained two components: one binder plus a superdisintegrant.

Parteck ODT is a combination of spray-granulated D-mannitol (a binder) and croscarmellose sodium (a superdisintegrant). Both are well accepted by authorities, which accelerates the registration procedure. Croscarmellose sodium is the sodium salt of a cross-linked, partly O-(carboxymethylated) cellulose.^6–9 This paper examines the practical use of this new excipient system.

The disintegration test

To demonstrate the disintegration time required for tablets containing Parteck ODT, two drug formulations (Table 1) with different grades of ascorbic acid as the active were compared.

Table 1: Ingredients for Formulations 1 and 2 used to test tablet disintegration time.

Parteck ODT, ascorbic acid and Evogran orange flavour were blended together for 5 min in a Turbula (Glen Mills Inc., NJ, USA) shaker-mixer. Afterwards, sucralose granular (Merck KGaA) and Parteck LUB MST magnesium stearate were sieved through a 250-μm sieve onto the mixture, and then all components were again blended for 5 min. The tabletting mixture was then compressed on a Korsch EK 0 single punch instrumented tablet press (Korsch AG, Berlin, Germany [52 rpm, 11 mm diameter punch, biconvex]) into tablets each weighing 400 mg.

The drug release test

To show the drug release kinetics in vitro, two Parteck ODT drug formulations (Table 2) with acetaminophen of different grades and provenience as active substance were assessed. For each formulation, Parteck ODT, acetaminophen and silicon dioxide highly dispersed were blended for 5 min and passed through a 1.0-mm sieve. Lubricant (Dynasan 118 micro fine for Formulation A and PRUV sodium stearyl fumarate for Formulation B) was then sieved through a 250-μm sieve onto the mixture and then all components again blended for 5 min in a Turbula shaker-mixer. The tabletting mixtures were then compressed on a Korsch EK 0 single punch instrumented tablet press into 500 mg tablets.

Table 2: Ingredients for Formulations A and B used to test drug release kinetics.

What do the results say?

Good compression, low wear and tear

Using a scanning electron microscope (SEM), the morphology of the Parteck ODT formulation appeared very rough and structured. This microstructure leads to good compression behaviour and means that high tablet strength is achievable with low compaction forces. This structure is also ideal for minimizing wear of the tabletting equipment or to introduce high amounts of active; up to 50% active can be directly compressed with Parteck ODT — usually the content of active in direct compression is limited to about 20–30% (Table 3 and Figure 1).

Table 3: Physical data for acetaminophen tablets based on Parteck ODT.

Experience with this type of polyol excipient usually shows a great deal of wear of the granulated particles upon mechanical stress. Thus, one would expect that the needle-like structure of the Parteck ODT material, as seen on the SEM, would be crushed during compression. The morphology, however, surprisingly remains unchanged after mixing and compression. This contributes to a very large specific surface area of the tablet matrix of up to 3.5 m²/g. Such an exceptionally large surface area can bind small API particles well and prevent de-mixing. In addition, this enhances the water uptake and dissolution of the tablet matrix. So it is not only the superdisintegrant that is responsible for fast dissolution of the overall product; the unique surface structure of the binder contributes too.

Figure 1: Compression profiles for ascorbic acid tablets based on Parteck ODT with 80 mg ascorbic acid, 1% magnesium stearate, 0.5% orange flavour and 0.2% sucralose.

Rapid and constant disintegration

Disintegration is a key factor for the success of an ODT formulation. In our study, we tested this using a formulation with two different grades of ascorbic acid as active. The disintegration times for Parteck ODT were shown to be well within the range expected for ODT applications. More importantly, however, producing hard and stable tablets does not cause the disintegration time to suffer. As Figure 2 shows, the disintegration time remains constant over a wide range of tablet strengths. This is a major difference from some ODT formulations on the market, which display fast disintegration only for rather soft tablets.

Figure 2: Influence of tablet strength on disintegration time using Parteck ODT with 80 mg ascorbic acid, 1% magnesium stearate, 0.5% orange flavour and 0.2% sucralose.

Dissolution not affected by active

Another key factor for any kind of formulation is the release time of the active. Experience shows that fast disintegration is not always concomitant with fast release. Some excipients retard the release of active.

Our study showed that, after 10 min, all of the acetaminophen in the two formulations was released with Parteck ODT as directly compressible excipient (Figure 3). There is no negative Parteck ODT influence observed on the acetaminophen dissolution behaviour, regardless of the grade of active.

Figure 3: In vitro acetaminophen release from Parteck ODT-based tablets.

Thus, we believe that we have shown that Parteck ODT allows the design of a robust dosage form with both fast disintegration and fast dissolution irrespective of the drug substance grade, tablet weight and tablet size.

In addition, friability over a broad strength range is exceedingly low, as it is desirable for handling during production and application. Even at a very low compaction force (e.g., 5 kN) — friability of <0.4% can be achieved. This characteristic of Parteck ODT allows the manufacture of extremely rugged tablets.

Finally, the sensitivity of Parteck ODT added to a randomly chosen set of lubricants (PRUV sodium stearyl fumarate (2%), Dynasan 114 Powder (3%), Parteck LUB MST magnesium stearate (1%) or Polyglycol 6000 (5%)) was tested using placebo formulations. No significant effect on disintegration behaviour was observed, giving the formulator flexibility to resolve specific formulation problems.

The author says...

Yes, we do need a new ODT excipient

In answer to the earlier question "Is there a need for another excipient system for direct compression and fast dissolution?", we believe that the answer is "yes"; there is certainly a use for a new ODT formulation. The combination of two components in Parteck ODT — one binder and a superdisintegrant — shows valuable characteristics for direct compression. Through its large surface area, the formulator can achieve high tablet strength at low friability while still achieving fast disintegration and a pleasant mouth feel. Tablets produced with Parteck ODT exhibit rapid disintegration within the oral cavity, as well as fast release of the active. We believe that this excipient system speeds up the regulatory registration process and is compatible with most actives, making it a good, economical option.

H. Leonhard Ohrem is Technical Manager at Merck KGaA (Germany). Hans-Leonhard.Ohrem@merck.de

Roberto Ognibene is Technical Support, Merck KGaA (Germany).

References

1. P. van Arnum, Pharm. Technol., 31(10), 66–76 (2007).

2. FDA Guidance for Industry — Orally Disintegrating Tablets, December 2008. www.fda.gov

3. European Pharmacopoeia 6.0, Orodospersible Tablets, July 2007.

4. R. Bohnacker et al., Pharm. Ind., 67(3), 327–335 (2005).

5. W. Camarco, D. Ray and A. Druffner, Pharm. Technol., 30(10), 27–37 (2006).

6. USP 24-NF 19.

7. M. Bertoni, F. Ferrari and C. Caramella, Pharm. Technol. Eur., 17(11), 17–24 (1995).

8. M.S. Gordon, B. Chatterjee and Z.T. Chowhan, J. Pharm. Sci., 79(1), 43–47 (1990).

9. C. Ferrero et al., Int. J. Pharm., 147, 11–21 (1997).