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The authors propose an alternative to the USP disintegration test method. The method embraces physiological conditions of the oral cavity, as a screening tool for developing ODT products.
Orally disintegrating tablets (ODTs) are designed to dissolve or disintegrate rapidly upon contact with saliva to eliminate some common problems for oral solid-dosage forms such as difficulty in swallowing (dysphagia), the need for chewing a tablet, and the need for water intake (1). The Center for Drug Evaluation and Research's (CDER's) Data Standards Manual for Dosage Forms provides the original definition of an ODT as "a solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue (2)." Ideally, an ODT dissolves or disintegrates quickly in a few seconds it is placed on the tongue without the intake of water. ODTs can be used for incorporating additional clinical benefits such as enhancing oral absorption and bioavailability, improving patient compliance, and for business purposes such as extending patent life, product life cycle, and product differentiation (3).
Figure 1 (FIGURE COURTESY OF THE AUTHOR)
Recently, increasing numbers of active pharmaceutical ingredients (APIs) have been formulated into orally disintegrating dosage forms. The current market consists of more than 145 launched products (both branded and generic) for 92 molecules (and combinations), which is an increase of 10 molecules and more than 15 brands from 2004, including prescription and over-the-counter (OTC) segments. ODT therapies for central nervous system disorders (depression, mood disorders, migraine headaches, Alzheimer's disease, insomnia, anxiety) still dominate the market, accounting for more than 40% of the market value. Gastrointestinal (GI) ODTs increased in share to 34% by value, oncology to 10%, and diabetes to 7%. In 2005–2006, brand companies learned that patients perceived a faster onset of action with an ODT, and caregivers welcomed the ease of administration of ODTs to patients who are reluctant to comply with medical orders or who became combatant when administered their medicine. These are likely the contributing factors to the high growth in the ODT market (4).
In 1998, the definition of an orally dissolving or disintegrating tablet appeared in a compendial publication for the first time. According to the recently issued Draft Guidance for Industry of Orally Disintegrating Tablets (1), FDA specifically recommends that, in addition to the original definition for an ODT, ODTs be considered solid oral preparations that disintegrate rapidly in the oral cavity, with an in vitro disintegration time of approximately 30 s or less according to the United States Phamacopeia (USP) disintegration method or alternative. Although tablet size and weight are not explicitly included in the definition, in view of patient safety and compliance, the agency recommends that the weight of the tablet not exceed 500 mg.
Presently, neither USP nor the European Pharmacopoeia has defined a specific disintegration test for ODTs. The results from the USP disintegration test ‹701› do not provide a strong correlation with in vivo disintegration times in the mouth because the test uses a disintegration medium of about 900 mL of water and a vigorously oscillating apparatus, which provide conditions far than those found in vivo (5). According to a test method reported in the 12th Annual FDA Science Forum (6), currently there is no USPin vitro method for evaluating disintegration time for ODTs, which represents in vivo disintegration time in the mouth. Therefore, FDA recommends using a modified form of the USP disintegration test ‹701›. A quick and simple modified test was designed to help regulatory review scientists in evaluating the ODTs. Using a disposable syringe, 1 mL of water is delivered directly onto a tablet placed on a flat surface. Completeness of disintegration of the tablet is checked by the manual palpation of the tablet at the end of 30 s, which is set by FDA as the disintegration specification for ODTs. The proposed test method requires minimum equipment so that it allows review scientists to evaluate, in an office setting, the disintegration of ODTs submitted for approval. It also can serve as a quick screening tool for review scientists to decide whether a dosage form is appropriately labeled as an ODT. Incomplete disintegration may require further laboratory testing on the product or justification by the firm to label the product as an ODT.
There are several modified disintegration test methods for ODTs. In one involving a Petri dish, a given volume of water is used as a medium to mimic physiological conditions. A 10-cm diameter Petri dish is filled with 10 mL of water containing eosin, a water soluble dye. A 10-cm diameter circular tissue paper is placed in the Petri dish. The tablet is carefully placed in the center of the dish and the time for the tablet to completely disintegrate into fine particles is noted as the disintegration time (7). Another popular in vitro method involves a texture analyzer instrument to accurately determine the disintegration time. In this test, a flat-ended cylindrical probe penetrates into the disintegrating tablet immersed in a defined volume of water. As the tablet disintegrates, the instrument is set to maintain a small force for a determined period of time. The plot of the distance traveled by the probe generated with the instrument's software provides a disintegration profile of the tablet as a function of time. The plot facilitates calculation of the start and end point of the tablet disintegration (8, 9). Other modified disintegration test methods for ODTs have been suggested (10–12). None of these methods provides a good in vitro–in vivo correlation (IVIVC) for the disintegration time of an ODT. The main reason is that the experimental conditions used do not simulate the wet tongue surface condition or the amount of saliva in the mouth at a given time. Therefore, it is very desirable to develop a simple alternative method for evaluating the disintegration time of ODTs with these specific attributes:
In this article, the authors propose a new alternative in vitro disintegration test method closely simulating placing an ODT on the tongue as compared with the current USP disintegration test method. We also compared our proprietary ODT formulations with the commercial ODT products using the proposed test. Although we do not have extended in vivo data for all ODTs discussed in this study to fully demonstrated IVIVC, the limited in vivo evaluation results of selected preparations in the study indicated the feasibility and usefulness of the alternative test method.
FD&C blue no.1 powder (lot AM1351) was provided as a research sample by Sensient (Milwaukee, WI). Taste-masked acetaminophen (80% paracetamol and 20% ethyl cellulose) was purchased from Schwarz Pharma (Milwaukee, WI). Spray-dried mannitol (Pearlitol 100SD, lot E172P) was purchased from Roquette (Keokuk, IA). Two grades of talc (lots H10016 and B6179N1) were obtained from Mineral and Pigment Solutions, Inc. (MPSI, Park Hills, MO). Crospovidone XL-10 (lot 3500145826) was purchased from SPI Pharma (New Castle, NE) for use as a super disintegrant. Sodium stearyl fumarate (PRUV, lot 102) was purchased from JRS Pharma. (Cedar Rapids, IA). Milli-Q water was used throughout the experiments. Claritin Reditabs, Alavert, and Zicam were purchased through a local Walgreens pharmacy store (St. Louis, MO). Excedrin QuickTabs were purchased through an online vendor. Parcopa and Prevacid SoluTab were obtained through McKesson.
Preparation of Covidien ODTs. Covidien (Mansfield, MA) ODT placebo granules consist of four components described in the "Materials" section. The granules were prepared by using a top-spray fluid-bed granulation process. The ODT placebo granules were mixed with 1.0% (w/w) sodium stearyl fumarate in a V-blender for 5 min. The lubricated placebo granules were then made into placebo tablets for disintegration comparison or used for preparing ODTs containing a high dose of acetaminophen (APAP). The APAP-containing tablets were prepared by the following steps:
Hardness test. The tablet crushing load, which is the force (kilopond, kp) required to break a tablet into halves by compression in the diametrical direction, was measured with a hardness tester (Varian Hardness Tester, VK-200).
Friability test. The friability test method was performed using a Varian Friabilator according to the USP 25 tablet friability method described in General Chapter ‹1216› Tablet Friability.
Evaluation of disintegration times
In vitro test using the USP disintegration method (5). The disintegration times of the Covidien 400 mg and 900 mg APAP-containing ODTs and representative commercial ODT products were determined according to the USP 29, test number 701 (5). The disintegration time was determined when the last tablet fully disintegrated and all particles passed through the screen.
Simulated wetting test (13). The wetting time of the ODTs was evaluated using the method described below. The method is called the "Simulated Wetting Test" (SWT). One Whatman filter paper disk (21 mm in diameter) was placed in each well of a Corning 12-well polystyrene microplate (22 mm in diameter). A given volume (see Table I) of 0.1% (w/w) Sensient Blue #1 dye solution was then added into each well in various amounts based on tablet size using an automatic pipettor. An ODT was carefully placed on the surface of the wet paper disk in each well using a pair of forceps. The flat tablet face was in contact with the filter paper, and the level of the dye solution did not cover the tablet. The total wetting time was measured, defined as the time required for the blue dye solution to diffuse through the tablet and completely cover the surface. The wetting time was recorded as the simulated disintegration time.
Table I: Optimum volume of the blue dye solution for a given tablet size.
Limited in vivo disintegration test in the mouth. An in vivo test of 900-mg placebo ODTs was conducted on four volunteers (three volunteers for 400-mg placebo ODTs). Each volunteer received 10 900-mg placebo ODTs, or 10 400-mg placebo ODTs, respectively. A placebo ODT was placed on the tongue of a volunteer, and the time for disintegration was measured by using a stopwatch. The ages of volunteers were between 20 and 60 years old. The participants were allowed to move the ODT against the upper roof of the mouth with their tongues and to cause gentle movement on the tablet without chewing it or tumbling the tablet from side to side. Immediately after the tablet disintegrated completely into small particles, the stopwatch was stopped and the time recorded. Forty 900-mg tablets and 30 400-mg tablets were evaluated accordingly and the results were reported.
Results and discussion
Optimization of the blue dye solution in the simulated wetting test. The average volume of saliva and the condition of the tongue surface play a key role in assessing the disintegration time of an ODT in the mouth. The rate of saliva secretion is 0.2–0.4 mL/min when resting and can increase to as much as 2 mL/min when stimulated. Therefore, the average rate of saliva secretion is about 0.5–0.7 mL/min (14), and the tongue surface is generally wet. These two factors were specifically considered in developing the new alternative disintegration test method (SWT) for ODTs. The optimum volume of the test medium (blue dye solution) must be adjusted within a range of 0.5–2.0 mL, mimicking the in vivo conditions in the mouth according to various tablet weights. Table I shows the recommended volume of the blue dye solution for various tablet sizes. The optimum volume of dye solution was established by correlating limited in vivo disintegration times of Covidien placebo ODTs and APAP-containing ODTs with the wetting times of the respective tablet sizes.
Physical properties of the tested ODT products. Table II lists the physical properties of three Covidien ODT preparations and six ODT commercial products. In general, the hardness values of all six commercial ODT products were between 1.8 and 7.9 kp for tablet weights in the range of 27–1400 mg. Therefore, most of the currently commercial products were packed in blister packs because of relatively low tablet hardness. However, Covidien ODTs were mechanically stronger and suitable for a conventional HDPE bottle packaging with both tablet sizes (400 mg and 900 mg). The ODT products in Table II are representative for understanding how the disintegration time of an ODT is influenced by the respective tablet size.
Table II: Physical properties of Covidien ODTs and commercial ODTs .
ODT disintegration times. The disintegration times for both the 400-mg and 900-mg placebo ODTs were determined using three different methods: conventional USP disintegration test method as recommended by the FDA, limited in vivo disintegration test in the mouth, and SWT method proposed in this study.
Table III shows that the average disintegration times of the ODTs according to the USP method were about 9 s for the 400-mg tablets and 12 s for the 900-mg tablets. The average disintegration times of 400-mg and 900-mg placebo ODT tablets using the SWT method were about 14 and 25 s, which are closer to the respective data of the limited in vivo test. The average disintegration times of both the 400-mg and 900-mg placebo ODT tablets in the mouth were about 16 and 24 s, respectively. Thus the USP disintegration times showed a poorer correlation with the limited in vivo disintegration times, but the results from the SWT method showed a stronger correlation with the limited in vivo disintegration times. The SWT method further showed the larger differences in the disintegration times for two tablet sizes.
Table III: Disintegration times of Covidien placebo ODTs.
Furthermore, volunteers were asked to collect saliva in a 10-mL graduate cylinder for three minutes to see how the disintegration time was influenced by the production rate of saliva per minute. The disintegration time of the tablets in the mouth of a volunteer with more saliva produced in a minute was 2–4 s faster than the results from other volunteers.
Table IV shows both the wetting time as a simulated disintegration time and the disintegration time from the USP test of APAP-ODT (900-mg ODT containing 562.5mg Schwarz Pharma taste-masked APAP, or 450-mg APAP, and Covidien ODT placebo granules). Although the tablet containing acetaminophen is bigger than 500 mg, both the in vitro disintegration times from the SWT method and the USP disintegration method were less than 30 s.
Table IV: Disintegration times of Covidien APAP-containing ODTs.
Table V shows the comparison between the wetting time using the SWT method and the disintegration time using the standard USP method for six commercial ODT products. The USP disintegration times were consistently shorter than the wetting times for all ODTs in this study, regardless of tablet size. For example, the disintegration time of 800 mg Zicam tablets using the SWT method was greater than 3 min, which is much closer to in vivo test results, but the USP disintegration time of a Zicam tablet was as fast as 45 s. Similarly the 1000-mg PARCOPA tablet product showed the same trend (147 versus 51 s). The wetting time of 1400-mg Excedrin QuickTabs using the SWT method and the disintegration time obtained from the USP disintegration method were less than 30 s. The data in Table V also suggest that the magnitude of the values obtained in the SWT test seem more differentiating than the magnitude of the values obtained from the USP test.
Table V: Disintegration times of selected ODT products.
Overall, the results showed there was a strong correlation between the limited in vivo disintegration time and the in vitro wetting time using the proposed alternative method (SWT) for 400-mg and 900-mg Covidien placebo ODT tablets. The disintegration times obtained from the SWT method are more closely mimicking the physiological conditions in the mouth. Advantages of the SWT method include minimal requirement of equipment (Corning 12-well polystyrene plates, Whatman glass fiber paper disks, 1–10 mL auto pipettor, stopwatch, and a water-soluble blue dye solution). This test can serve as a simple, consistent, and reproducible screening tool for evaluating disintegration time of ODTs to better estimate the disintegration time in the mouth. As shown in Table III, the standard USP test did not sufficiently differentiate the disintegration time of a smaller size tablet from the results of a larger size tablet. But the SWT method discriminated the disintegration times of two tablet sizes and closely agreed with their respective disintegration times in the mouth in the limited in vivo test.
The proposed simple in vitro simulated wetting test (SWT), which embraces the physiological conditions of the mouth, for ODTs in this study showed a strong correlation with the limited in vivo disintegration test in the mouth. The USP disintegration method for ODTs does not closely estimate the disintegration time of ODTs in this study in the oral cavity, and it does not provide a realistic testing condition for evaluating an ODT. The results for commercial ODTs and Covidien APAP containing ODTs using the proposed method indicated that the SWT can better differentiate the disintegration times of the tested samples. We propose that the SWT method as described in this study should be considered as a standard USP test method for evaluating the disintegration time of ODTs in the future providing that the in vitro data are further validated with additional available in vivo disintegration times of the commercial ODT products to establish a strong IVIVC.
Jae Han Park, PhD,* is a senior research associate. Kevin M. Holman, Glenn A. Bish, and Donald G. Krieger are formulation scientists. Daniel S. Ramlose is a senior research chemist. Cliff J. Herman, PhD, is a senior director. Stephen H. Wu, PhD, is a technical fellow, all at Pharmaceutical R&D of Mallinckrodt Pharmaceutical, Covidien, 385 Marshall Ave., Webster Groves, MO 63119, tel. 314.654.2762, Jaehan.Park@Covidien.com.
*To whom all correspondence should be addressed.
Submitted: Feb. 29, 2008. Accepted: April 2, 2008.
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