Selecting Superdisintegrants for Orally Disintegrating Tablet Formulations

During the past several years, there has been rapid growth in the number of orally disintegrating tablets (ODT) available on the market. An ODT is generally recognized as a solid dosage form containing a medicinal substance that disintegrates rapidly and dissolves in the mouth without water within 60 seconds or less. ODTs are also known as quick dissolves, fast melts, or fast-dissolving, rapid-dissolve, or orally dissolving tablets. The European Pharmacopoeia recognizes ODTs as orodispersible tablets or tablets intended to be placed in the mouth that subsequently disperses rapidly before being swallowed (1). These products have increased in popularity because consumers, old and young, find them convenient and easy to use. In addition, pharmaceutical companies have found an opportunity to extend product life cycles or differentiate their products by offering new dosage forms (2).

Today, ODTs are available in a range of sizes and shapes, with some requiring special packaging. In general, ODTs can accommodate as much as 500 mg of active ingredient, although 100–200 mg is a reasonable limit for more rapid disintegration (3).

Several technologies are available to manufacture ODTs. The most common preparation methods are molding, lyophilization or freeze-drying, and direct compression. Other methods include cotton-candy, spray drying, and sublimation (4), and each offers advantages and disadvantages. For example, although lyophilization produces tablets with very fast disintegration (<5 s), the tablets are often less robust and usually require special packaging.

Direct compression is a commonly used tablet manufacturing process to produce ODTs. Because it uses existing high-speed tablet press equipment and common excipients, it is often favored over other manufacturing processes for ODTs. A direct-compression formulation has better physical properties relative to other methods that may eliminate the need for special packaging such as blister packages.

Excipients in direct-compression ODT formulations

A direct-compression ODT formulation usually contains diluent, disintegrant, lubricant, flow aid, flavor, sweetener, and often color. A review of currently marketed ODT product labels shows that mannitol is a commonly used diluent or bulk excipient. Directly compressible mannitol grades exhibit an appropriate balance of sweetness, mouth feel, solubility, and rapid dispersibility because of wicking (5). As a result, mannitol has gained in popularity for ODTs over other diluents typically used in direct compression such as lactose.

To achieve rapid disintegration, direct-compression ODT formulations typically contain high levels of a superdisintegrant. Depending on the level and characteristics of the active pharmaceutical ingredient (API) and the desired release profile, the levels of superdisintegrant used can be 10–20 wt % of the formulation, and it can be higher or lower in some cases. Thus, in developing an ODT formulation for direct compression, choosing the optimal superdisintegrant is critical.

As with most direct-compression formulations, additional excipients are likely to include a suitable flow aid and lubricant for tablet manufacture. Because the tablet is intended to dissolve in the mouth, ODTs often include flavors and sweeteners to mask the taste of bitter actives. Finally, color may be added to the formulation to add elegance and to aid in identification of the final dosage form.

Selecting the superdisintegrant

Although the superdisintegrant primarily affects the rate of disintegration, when used at high levels it can also affect mouth feel, tablet hardness, and friability. Thus, several factors must be considered when selecting a superdisintegrant.

Disintegration. The disintegrant must quickly wick saliva into the tablet to generate the volume expansion and hydrostatic pressures necessary to provide rapid disintegration in the mouth.

Compactability. When manufacturing an ODT, it is desirable to have tablets with acceptable hardness at a given compression force to produce robust tablets that avoid the need to use specialized packaging while maximizing production speed. Thus, a more compactable disintegrant will produce stronger, less-friable tablets.

Mouth feel. To achieve patient compliance, ODTs must provide a palatable experience to the patient. Large particles can result in a gritty feeling in the mouth. Thus, small particles are preferred. If the tablet forms a gel-like consistency on contact with water, however, it produces a gummy texture that many consumers find objectionable.

Flow. As with all direct-compression tablet formulations, attaining good flow and content uniformity is important to achieving the required dosage per unit. In typical tablet formulations, superdisintegrants are used at 2–5 wt % of the tablet formulation. With ODT formulations, disintegrant levels can be significantly higher. At these higher use levels, the flow properties of the disintegrant are more important because it makes a greater contribution to the flow characteristics of the total blend.

The selection of the optimal disintegrant for a formulation depends on a consideration of the combined effects of all of these factors.

Evaluating physical characteristics of commercial superdisintegrants

Currently available disintegrants were evaluated for particle size, particle-size distribution, flowability, compactability, particle shape, and morphology. The following superdisintegrants were studied:

• crospovidone A1 (standard particle-size grade) (Polyplasdone XL, International Specialty Products, Wayne, NJ);

• crospovidone A2 (fine particle-size grade) (Polyplasdone XL-10, ISP);

• crospovidone B (Kollidon CL, BASF, Ludwigshafen, Germany);

• sodium starch glycolate (Explotab, JRS Pharma, Patterson, NY);

• croscarmellose sodium(Ac-Di-Sol, FMC, Philadelphia, PA).

Table I: Particle size and flowability index.

Crospovidone is an insoluble, neutral cross-linked homopolymer of N-vinyl-2-pyrrolidone. It is available in various particle sizes. The US Pharmacopeia defines sodium starch glycolate as the sodium salt of a carboxymethyl ether of starch or of a cross-linked carboxymethyl ether of starch, and croscarmellose sodium is defined as the sodium salt of a cross-linked, partly O-(carboxymethylated) cellulose.

Particle size and distribution. A comparison of particle sizes of various disintegrants is shown in Table I and Figure 1. Sodium starch glycolate and croscarmellose sodium show similar average particle sizes; however, sodium starch glycolate has a narrower distribution, which contributes to the good flow properties. The particle size differences between the various types of crospovidones are shown. Because crospovidone A2 offers the smallest average particle size (~30 μm), it is often preferred because small particles result in a smoother mouth feel.

Figure 1: Particle size distribution.

Flowability. Flowability index results are shown in Table I. Sodium starch glycolate provides the best flow as a result of its spherical particle morphology and narrow particle size distribution.

Particle shape and morphology. When examined under a scanning electron microscope, sodium starch glycolate particles are spherical (see Figure 2). Crospovidone particles appear granular and highly porous, although crospovidone B particles appear less porous. This porous particle morphology facilitates rapid wicking of liquid into both particle and tablet and contributes to the compactability of the material. Croscarmellose sodium particles have a fibrous structure.

Figure 2: Particle morphology.

Compactability. The compactability of each of the disintegrants was evaluated by comparing the breaking force, at various compression forces, of pure compacts of each disintegrant with small amounts of lubricant and glidant added (see Figure 3). Results indicate that crospovidone is the most highly compactable disintegrant tested, thus producing the highest tablet-breaking force at a given compression force.

Figure 3: Compaction profile of pure compacts.

Nonetheless, the results also show that crospovidone A1 and B, with similar particle size, perform significantly differently. Crospovidone A1 is more compactable than crospovidone B.

Table II: Placebo ODT formulation.

Formulation examples

Example 1: Compaction profile evaluation of placebo tablets. In recent studies, 1-g placebo tablets were prepared with 20 w/w % of each disintegrant according to the formulation shown in Table II. The ingredients were dry blended and then compressed using an instrumented rotary press (Stokes B2) at three compaction forces (8.9, 17.8, and 26.7 kN) using half-inch round, flat-faced tooling.

Figure 4: Placebo tablet-breaking force.

The tablets were evaluated for breaking force and friability. At the highest compaction force (26.7 kN), capping was observed with tablets containing sodium starch glycolate (see Figure 4). Note that at the lowest compaction force, all of the tablets were extremely friable (>5%), so these results were included in Figure 5. Subsequently, the disintegration time for each tablet was evaluated (see Figure 6).

Figure 5: Placebo tablet friability.

The results show that acceptable tablet-breaking force was achieved at the two highest compaction forces for all the superdisintegrants, although crospovidone shows significantly higher tablet breaking force at equivalent compaction force than the other disintegrants. The friability results also reflect this trend. Crospovidones A1 and A2 showed the lowest friability, with results below 0.4% at the highest compaction force. The disintegration results show crospovidone achieved the fastest disintegration (<30 s) and croscarmellose sodium provided the slowest disintegration (>1 min).

Figure 6: Placebo tablet disintegration.

When representative placebo tablets with crospovidone A2, sodium starch glycolate, and croscarmellose sodium were placed in a Petri dish with a small amount of water, the relative ability of the various disintegrants to wick water into the tablet was observed (see Figure 7). One minute after contact with water, the tablet containing crospovidone A2 was fully hydrated and soft throughout because crospovidone quickly wicks water into the tablet. Meanwhile, the centers of the tablets made with sodium starch glycolate and croscarmellose sodium remained dry and hard. Although the tablet with sodium starch glycolate swelled, the outer edge appeared gel-like.

Table III: Acetaminophen ODT formulation.

Example 2: Compaction profile evaluation of acetaminophen tablets with various superdisintegrants. In this study, 158-mg acetaminophen tablets (1 g total weight) were prepared with 20 w/w % of each disintegrant according to the formulation in Table III.

Figure 7: Placebo tablets in water.

To mask the taste of the active, an encapsulated acetaminophen (88% active acetaminophen) was selected. The active level in the tablet formulation is representative of currently marketed ODT products. To prepare this formula with acetaminophen, the level of mannitol was reduced compared with that used in the placebo while all other ingredients were held constant. The formulation was dry blended and then compacted under three different compaction forces as in the placebo study.

Figure 8: Acetaminophen tablet compaction profiles.

Once again, the tablets were evaluated for breaking force, friability, and disintegration (see Figures 8–10). At all compaction forces, the acetaminophen tablets with croscarmellose sodium were highly friable (>5%), so the results are not shown in Figure 9.

Figure 9: Acetaminophen tablet friability.

Similar to the results from the placebo study, crospovidone produced the strongest tablets at a given compaction force. Compared with the results from the previous study, the overall breaking force of the tablets was somewhat reduced because of the replacement of the mannitol with the active. The friability also followed the same trend as outlined in the previous example. The disintegration results show that crospovidone produced the fastest disintegration.

Figure 10: Acetaminophen tablet disintegration.

Summary

Because ODT formulations typically use high levels of superdisintegrants to achieve rapid disintegration in the mouth, it is important to select a disintegrant that provides optimal performance. The disintegrant should produce rapid disintegration, a smooth mouth feel, good flow, and high compactability. Results show that crospovidone A2 has the best combination of properties for producing physically robust ODTs with the best performance and highest potential consumer appeal.

Wayne Camarco* is the North America manager of pharmaceutical technical services, wcamarco@ispcorp.comDipan Ray, PhD, is a section manager of pharmaceutical R&D, and Ann Druffner is the North America market manager of pharmaceuticals at International Specialty Products, 1361 Alps Road, Wayne, NJ 07470, tel. 973.628.4000, fax 973.628.3311, www.ispcorp.com

*To whom all correspondence should be addressed

References

1. European Directorate for the Quality of Medicines, www.pheur.org, European Pharmacopeia 5.2, 3151 (2006).

2. K. Cremer, "Orally Disintegrating Dosage Forms Provide Life Cycle Management Opportunities," Pharm. Technol. Formulation and Solid Dosage 2003, 22–28 (2003).

3. "Orally Fast-Dissolving Drug Delivery," Technology Catalysts International, p. 3 (Aug. 2003).

4. S.R. Parakh and A.V. Gothosakar, "A Review of Mouth Dissolving Tablet Technologies," Pharm. Technol. 27 (11), 92–100 (2003).

5. X. Duriez and A.A. Joshi, "Starches A Versatile Source," Pharma Form. Qual. 6 (3), 48–50 (2004).