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The functionality and performance of three types of commercial superdisintegrants were evaluated in the application of orally disintegrating tablets.
The orally disintegrating tablet (ODT) is a solid dosage form that disintegrates and dissolves in the mouth without the need of water within 60 seconds or less (1). According to the US Food and Drug Administration, ODT is "a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue" (2). By FDA guidance, ODTs should have an in vitro disintegration time of 30 seconds or less, based on the US Pharmacopeia disintegration test method.
ODTs are also called fast-disintegrating, orodisperse, mouth-dissolving, quick-dissolve, fast-melt, and rapid-disintegrating tablets, and freeze-dried wafers (3–5). They are different from conventional sublingual tablets, lozenges, and buccal tablets, which require more than one minute to dissolve in the mouth. In 2005, ODTs were the only quick-dissolving dosage form recognized by FDA and listed in the Orange Book (6).
ODTs have attracted attention as an alternative to conventional oral dosage forms such as tablets and capsules due to their advantages of convenient administration, increased patient compliance, and as a way to extend the product life cycle of a drug. For example, recent market studies indicate that more than half of the patient population prefers ODTs to conventional tablets or capsules. One very practical reason is that many patients such as children and the elderly have difficulty swallowing tablets and capsules. There are other patients who simply prefer the convenience of a readily administered dosage form like an ODT. In addition, there are business needs that drive ODT development as a means to expand product lines, improve life-cycle management, and extend patent life. It is not a surprise, therefore, to see that the demand for ODT-adapted drugs is forecast to increase 8.9% annually to nearly $2.6 billion in 2012 (7).
ODTs can be made by direct compression (DC), lyophilization, and molding technologies (4, 8, 9). Of these manufacturing processes, DC is the most economical as it uses conventional equipment, commercially available excipients, and relatively simple process steps. This study chose DC as the manufacturing process to produce ODTs.
The disintegration rate of ODTs is a critical success factor. For ODTs produced through the DC process, the disintegration time depends on the disintegrants, matrix, tablet weight, and tablet hardness. In many cases, the disintegrant has a major role in the disintegration process, and the disintegrant use level will impact tablet hardness and mouthfeel. The choice of a suitable disintegrant and an optimal use level, therefore, are critical to ensure a high disintegration rate.
The objective of this study was to evaluate the functionality and performance of three types of commonly used commercial superdisintegrants, crosslinked croscarmellose sodium (XL-CMC), crospovidone, and sodium starch glycolate (SSG), in the application of ODTs. For each superdisintegrant, a wide range of disintegrant use levels (0.5–20%) was investigated in commonly used ODT model matrices at different compaction forces (4–12kN). Tablet disintegration time, hardness, friability, and stability were compared. An optimal use level was identified for each superdisintegrant. A further comparison between XL-CMC and crospovidone in mouthfeel was conducted at their optimal use level. In addition, an analytical method was developed to monitor the ODT-softening process in a small amount of water to mimic the oral cavity condition.
Table I: Commercial superdisintegrants.
Materials and methods
Materials. Pearlitol 200 SD (Roquette, Paris), a direct-compressible mannitol, was used as a tablet matrix former. Magnesium stearate (Mallinckrodt, St. Louis, MO) was used as a lubricant. The superdisintegrants evaluated in this study were obtained from commercial suppliers and used as received (see Table I). The chemical structures of the three superdisintegrants are shown in Figure 1.
Figure 1: The chemical structures of the three superdisintegrants: crosslinked croscarmellose sodium (XL-CMC), crospovidone, and sodium starch glycolate (SSG) (ALL FIGURES ARE COURTESY OF THE AUTHORS)
ODT preparation and evaluation. Formulation design and tablet preparation. The detailed formulations that were used to evaluate the four commercial superdisintegrants (three types) in typical mannitol ODT model matrixes are shown in Table II.
Table II: Placebo orally disintegrating tablet formulations.
To prepare each formulation, Pearlitol 200 SD and the disintegrant were weighed and premixed in a V-blender for 15 min. Magnesium stearate (MgSt) was added and mixed for an additional 2 min. The batch size for each formulation is 1 kg.
To prepare the tablets, each formulation was compressed individually on a tablet press (Stokes 512, Stokes-Merrill, Bristol, PA) with four stations. Standard 7/16 in. concave punches and corresponding dies were used. Tablet weight was adjusted to 400 mg. A data-acquisition system (SMI Director, SMI Incorporated, Lebanon, NJ) was used to record compaction process. A series of compaction forces, 4kN, 6kN, 8kN, 10kN, and 12kN were applied to each formulation to produce tablets with different levels of hardness.
Characterization of ODTs. Disintegration times of the tablets were determined using a disintegration test system (Hanson QC-21, Hanson Research, Chatsworth, CA). The test was conducted at 37 ± 0.5 °C in a medium of distilled water. Six tablets per sample were analyzed, and the mean was reported (see Figure 2).
Figure 2: Tablet disintegration time overview.
Tablet-crushing strength along with tablet weight, thickness, and diameter were determined using an automatic tablet-testing system (AT4, Dr. Schleuniger Pharmatron, Switzerland). The tablet-crushing strength data reported are the mean of 10 individual determinations. Tablet weight and thickness were tested; the data are not reported here but they were controlled in a tight range.
Tablet friability was measured on a friabilator (VanKel Friabilator, VanKel Industries, Edison, NJ) rotated at 25 rpm for 5 min. Twenty tablets per sample were randomly selected for the study. The friability for each sample was calculated using the following equation:
Friability (%) = (Wb–Wa) / Wb ×100
Where Wb and Wa are the weights before and after the friability test.
All initial tablet characterization studies (tablet-crushing strength, disintegration time, and friability) were performed on tablets that were stored for 24 h at ambient conditions in tightly closed and doubled plastic bags. The tablets were stored at ambient conditions in the same tightly closed and doubled plastic bags for four months, and tablet-crushing strength, disintegration time, and friability were reevaluated using the same procedures as the initial studies.
Triangle mouthfeel study of ODTs. Sensory science is a scientific method used to measure, analyze, and interpret human responses to products as perceived through their senses of touch, taste, sight, smell, or sound (10). There are many different types of sensory tests. For example, attribute difference tests measure certain qualities or trait differences between samples. Affective sensory tests measure consumer acceptance of a product. Overall difference tests measure sensory differences between samples. A triangle test is a type of overall difference test to determine if there is a sensory difference between two products. Here, the triangle mouthfeel test was performed to determine if there were any mouthfeel differences between ODTs that contain 2% Ac-Di-Sol (crosslinked croscarmellose sodium, XL-CMC, FMC, Philadelphia, PA) and ODTs that contain 5% PVP XL-10 (Crospovidone, ISP, Wayne, NJ), when all the other ingredients remain the same. Ac-Di-Sol and PVP XL-10 were chosen for study because they are the two most popular superdisintegrants and very effective at their optimal use level. These tablets were all compressed at 8kN.
ODTs that contained 2% Ac-Di-Sol were coded with two different three-digit numbers (e.g., 767, 189). ODTs that contained 2% PVP XL-10 were coded with two different sets of three-digit numbers (e.g., 312, 570). In each set of the study, three coded ODT samples were presented to a panelist. For example, the three samples could be numbered 767-312-189, which represented two identical ODTs that contain 2% Ac-Di-Sol plus one ODT that contains 5% PVP XL-10; or numbered 570-312-189, which represented two identical ODTs that contain 5% PVP XL-10 plus one ODT that contains 2% Ac-Di-Sol. Each panelist was informed that he or she received three coded samples—two were identical, and one was different. To further reduce influencing the panelists' decisions, coded samples were presented in a random order to different panelists. Each panelist was asked to test the ODT samples from left to right, and each rinsed his or her mouth with water between each test. Each panelist identified one sample he or she felt was different from the other two in terms of mouthfeel and was asked to describe the difference in the comments section. The difference in mouthfeel may have been described as disintegration time, taste, or texture. A total of 34 ODT sample sets (102 tablets) were tested by 34 panelists. Responses were collected and used to draw a statistical conclusion.
Texture analyzer evaluation of ODTs. A texture analyzer (TA-XT2i, Texture Technologies, Scarsdale, NY) was used to monitor the disintegration process of ODTs in shallow water. The settings were "measure distance in compression, hold until time" with a 5-kg load cell, ½-in. diameter clear, cylindrical probe. The automatic surface detection trigger was set to 1 g, with a pretest speed of 1 mm/s and a test speed of 0.1 mm/s. For each test, a small weighing boat with 2 mL of deionized water was placed under the probe with a height set at 7 mm. The ODT to be tested was put into the 2mL water, and the test started simultaneously.
Results and discussion
Characterization of ODTs. Figure 2 is an overview of tablet disintegration time. The different graphs represent different disintegrant use levels, from 0.5% to 20%. Within each graph, the x-axis is the four disintegrants studied, the y-axis is the five compaction forces (4kN–12kN), and the z-axis is tablet disintegration time. In the first graph, a control sample without any disintegrant was included. The results indicated that Ac-Di-Sol disintegrates ODTs much faster than crospovidone (both PVP XL-10 and Kollidon CL-SF (crospovidone, BASF, Ludwigshafen, Germany)) and Glycolys (sodium starch glycolate, Roquette, Lestrem, France) at a low use level (≤2%). Crospovidone starts to perform at 5% and beyond. Glycolys is less potent than Ac-Di-Sol at low use level and less potent than crospovidone at a high level.
In fact, at a low use level (0.5–2%), Ac-Di-Sol was the only disintegrant among the three types that could effectively disintegrate tablets at all compaction force ranges. Even when the use level increased to 2%, Ac-Di-Sol was still the only disintegrant that could provide ODTs that meet the USP-required 30 s disintegration time at all compaction force ranges (see Figure 3).
Figure 3: Tablet disintegration time at 2% disintegrant use level. Ac-Di-Sol is crosslinked croscarmellose sodium, PVP XL-10 is crospovidone, Kollidon CL-SF is crospovidone, and Glycolys is sodium starch glycolate.
Figure 4 provides an overview of tablet-crushing strength for all disintegrants at different use levels (0.5%–20%) and compaction forces (4kN–12kN). Within each graph, the z-axis is the tablet-crushing strength. Results showed that disintegrants had no impact on tablet-crushing strength when the disintegrant use level was ≤ 5%, as the tablet-crushing strength was similar to the control sample at all compaction force ranges. However, tablet-crushing strength started to decrease when the disintegrant use level was ≥ 8%; the tablets became softer. In addition, tablet friability data (see Figure 5) further confirmed the tablet-crushing strength conclusions (e.g., tablet became friable if the disintegrant use level reached or exceeded 8%).
Figure 4: Tablet-crushing strength overview.
For each disintegrant, an optimal use level was identified. The optimal use level is defined as the lowest use level that can achieve the fastest disintegration time over the range of compaction forces studied for that particular disintegrant. The optimal use level for Ac-Di-Sol is 2%, for PVP XL-10 and Kollidon CL-SF is 5%, and for Glycolys is 5%. Figure 6 is a summary graph of the optimal disintegrant use level versus disintegration time for tablets with a 70–80N crushing strength. In general, at each disintegrant's optimal use level, 2% Ac-Di-Sol could disintegrate tablet at the same fast speed as 5% PVP XL-10 and 5% Kollidon CL-SF, and they all outperformed 5% Glycolys.
Figure 5: Tablet friability overview.
Figure 7 is an overview of tablet stability in terms of its disintegration time. The x, y, z axis are the same as Figure 2. Bar graphs and cylinder graphs represent 24-hour and 4-month disintegration time data, respectively. Overall, disintegration time of all tablets slightly increased after 4 months of storage in ambient conditions within sealed plastic bags. However, no stability difference was found among different disintegrants. The slight disintegration time increase came from case hardening of the model mannitol tablet. All tablets became harder over storage (e.g., tablet-crushing strength increased for all tablets).
Figure 6: Tablet disintegration time comparison at optimal use level (tablet-crushing strength: 70~80 N).
Triangle mouthfeel study of ODTs. In terms of mouthfeel of ODTs that contain 2% Ac-Di-Sol versus ODTs that contain 5% PVP XL-10, 15 panelists provided the correct judgment out of the 34 panelists. This means 15 panelists picked out the correct odd sample, while the other 19 panelists picked out one of the two identical samples instead of the real, different one. According to the statistical table provided by Meilgaard et al. (10), a minimum of 17 correct judgments was required to establish significance at 95% probability level. A minimum of 19 correct judgments was required to establish significance at 99% probability level. The conclusion from this triangle mouthfeel study, therefore, was that there is no significant statistical difference between ODTs that contain 2% Ac-Di-Sol and ODTs that contain 5% PVP XL-10 in terms of mouthfeel.
Figure 7: Stability study of tablet disintegration time: 24 h (bar graph) versus 4 months (cylinder graph).
Texture analyzer evaluation of ODTs. USP's disintegration test method is well established to differentiate traditional tablets' disintegration time, but it does not reflect the disintegration environment of ODTs, which typically has a small amount of water available. To mimic the ODTs disintegrating or softening process in an oral cavity, a method was developed on a texture analyzer to monitor the disintegrating process of ODTs in 2 mL of deionized water.
Figure 8 compares tablet disintegration process between ODTs that contain 2% Ac-Di-Sol and ODTs that contains 5% PVP XL-10 from the texture analyzer, in commonly used ODT hardness ranges. The three graphs are for tablets that were compressed at 4kN, 6kN, and 8kN, respectively. Each graph shows the probe travel distance as a function of tablet immersion time in shallow water. The plateau portion of each curve indicates the tablet was cohesive enough to withstand the slight compressive force before it further disintegrated. The steep vertical portion of each curve indicates that the tablet had disintegrated further and the probe distance increased in search of the target force. The test came to an end when the probe touched the bottom of the weighing boat.
Figure 8: Tablet disintegration process demonstrated by texture analyzer.
One interesting finding from this texture analyzer study was that 2% Ac-Di-Sol and 5% PVP XL-10 provided different ODT disintegration patterns. Ac-Di-Sol-containing tablets showed an alternative in plateau and vertical portion on the disintegration curve, indicating a gradual softening or disintegration process. On the other hand, PVP XL-10-containing tablets displayed an initial longer portion of plateau followed by a big vertical portion, indicating an initial delay in tablet softening or disintegration, followed by a sudden tablet softening or disintegration. This finding partially explained the triangle-mouthfeel study results. For example, in the triangle study, out of the total panelists that made the correct judgment, 80% commented that Ac-Di-Sol containing ODTs provided a preferred mouthfeel to PVP XL-10 containing ODTs such as a smoother mouthfeel with faster disintegration for Ac-Di-Sol-containing ODTs. This difference could be attributed to the gradual disintegration pattern of Ac-Di-Sol-containing ODTs.
The selection of superdisintegrants is critical to ensure rapid tablet disintegration of ODTs that were prepared from the DC process. This study showed that all three types of commercial superdisintegrants, XL-CMC, crospovidone, and SSG, can be used in ODT applications at common ODT tablet-hardness ranges. An optimal use level was identified for each superdisintegrant, which is 2% for Ac-Di-Sol, 5% for PVP XL-10, 5% for Kollidon CL-SF, and 5% for Glycolys. Ac-Di-Sol is the most effective among all three types of superdisintegrant. It achieved rapid tablet disintegration time at the lowest use level and it more effectively disintegrated harder tablets. In general, ODTs that contain 2% Ac-Di-Sol had the same mouthfeel as ODTs that contain 5% PVP XL-10; however, 2% Ac-Di-Sol and 5% PVP XL-10 disintegrated tablets in different pattern when only a small amount of water was available such as in the oral cavity.
Yeli Zhang* is a senior research associate, Amy Wrzesinski is an associate chemist, Marley Moses is a research technician, and Holly Bertrand is a research chemist, all in the pharmaceutical department of FMC, 801 PrincetonSouth Corporate Center, Ewing, NJ 08628, tel. 609.963.6236, fax 609.963.6241, firstname.lastname@example.org.
*To whom all correspondence should be addressed.
Submitted: Dec. 16, 2009. Accepted: Mar. 8, 2010.
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