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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.
Aug 2, 2008
By: Jae Han Park, Kevin M. Holman, Glenn A. Bish, Donald G. Krieger, Daniel S.
Ramlose, Cliff J. Herman, Stephen H. Wu
Pharmaceutical Technology
Volume 32, Issue 8
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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.
Aug 2, 2008
By: Jae Han Park, Kevin M. Holman, Glenn A. Bish, Donald G. Krieger, Daniel S.
Ramlose, Cliff J. Herman, Stephen H. Wu
Pharmaceutical Technology
Volume 32, Issue 8
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 (1012). None of these methods provides a
good in vitroin 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.
Materials
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.
Methods
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:
Blend ODT placebo granules with taste-masked APAP granules in a V-blender for
20 min
Add 1.0% (w/w) sodium stearyl fumarate as the lubricant to the powder blend
from the first step and then mix for additional 5 min in the blender
Compress the powder blend from the previous step to making tablets using a 16-
station Manesty Betapress. The precompression force was 1300 N, and the main
compression forces were 7 kN and 13 kN, respectively, at 60 rpm in 0.4062 and
0.5625-in. dies with round, flat-faced punches with beveled edges. The resulting
tablet weights were targeted at 400 mg and 900 mg, respectively. For 900-mg
tablets, the amount of APAP is shown in Table II.
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.
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.
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 Table I: Optimum volume of
accordingly and the results were reported. the blue dye solution for a
given tablet size.
Methods
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:
Blend ODT placebo granules with taste-masked APAP granules in a V-blender for
20 min
Add 1.0% (w/w) sodium stearyl fumarate as the lubricant to the powder blend
from the first step and then mix for additional 5 min in the blender
Compress the powder blend from the previous step to making tablets using a 16-
station Manesty Betapress. The precompression force was 1300 N, and the main
compression forces were 7 kN and 13 kN, respectively, at 60 rpm in 0.4062 and
0.5625-in. dies with round, flat-faced punches with beveled edges. The resulting
tablet weights were targeted at 400 mg and 900 mg, respectively. For 900-mg
tablets, the amount of APAP is shown in Table II.
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.
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.
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 0.20.4
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 0.50.7 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 0.52.0 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.
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 24 s faster than the results from other
volunteers.
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.
Aug 2, 2008
By: Jae Han Park, Kevin M. Holman, Glenn A. Bish, Donald G. Krieger, Daniel S.
Ramlose, Cliff J. Herman, Stephen H. Wu
Pharmaceutical Technology
Volume 32, Issue 8
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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,
110 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.
Conclusions
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
.
References
1. Draft Guidance for Industry Orally Disintegrating Tablets (FDA, Rockville, MD),
http://www.fda.gov/cder/guidance/index.htm, April 2007.
7. J. Segado Ferran et al., "Orally Disintegrating Tablets and Process for Obtaining
Them," WO 103629 (2003).
8. G. Abdelbary et al., "Determination of the In Vitro Disintegration Profile of Rapidly
Disintegrating Tablets and Correlation With Oral Disintegration," Int. J. Pharm. 292
(12), 2941 (2005).
10. M.Gohel et al, "Formulation Design and Optimization of Mouth Dissolve Tablets
of Nimesulide Using Vacuum Drying Technique," AAPS Pharm. SciTech. 5 (3), 16
(2004).
11. J.M. Dor et al., "A New In Vitro Method to Measure the Disintegration Time of a
Fast-Disintegration Tablet," Proc. Intl Control. Rel. Bioact. Mater. 26, 939940
(1999).
13. J. Park and S. Wu, "Should Orally Disintegrating Tablets (ODTs) Have A Weight
Limit?," poster presentation, AAPS Annual Meeting and Exposition, San Diego, CA,
Nov. 1923, 2007.
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