COMMENTARY

Oral Solid Dosage Form Disintegration Testing — The Forgotten Test

JOZEF AL-GOUSOUS, PETER LANGGUTH

Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz,
Mainz D-55128, Germany

Received 18 August 2014; revised 16 November 2014; accepted 18 November 2014

Published online 24 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24303

ABSTRACT: Since its inception in the 1930s, disintegration testing has become an important quality control (QC) test in pharmaceutical
industry, and disintegration test procedures for various dosage forms have been described by the different pharmacopoeias, with har-
monization among them still not quite complete. However, because of the fact that complete disintegration does not necessarily imply
complete dissolution, much more research has been focused on dissolution rather than on disintegration testing. Nevertheless, owing
to its simplicity, disintegration testing seems to be an attractive replacement to dissolution testing as recognized by the International
Conference on Harmonization guidelines, in some cases. Therefore, with proper research being carried out to overcome the associated
challenges, the full potential of disintegration testing could be tapped saving considerable efforts allocated to QC testing and quality
assurance. C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2664–2675, 2015

Keywords: bioavailability; biopharmaceutics classification system (BCS); dissolution; excipients; formulation; gastrointestinal; in vitro
models; intestinal absorption

INTRODUCTION greater amount of publications dealing with dissolution testing

methodologies compared with those dealing with disintegration
It is a well-known fact that an immediate-release dosage form
testing methodologies (as shown in Fig. 2).
should disintegrate in order to efficiently liberate its active
Nevertheless, the greater simplicity of disintegration com-
ingredient(s) and make it available for absorption. Therefore,
pared with dissolution testing (e.g., no analytics needed, lesser
disintegration testing methods were developed.
volume of fluids required, less time-consuming) makes the idea
The first mention of a test for disintegration was in the
of putting more focus on disintegration attractive. This has
1907 Edition of Pharmacopoeia Helvetica, in the compressed
been recognized by the International Conference on Harmo-
pastilles monograph, stating that they should dissolve or disin-
nization (ICH) that allowed the use of disintegration testing
tegrate after a short time of them being placed in cold water.1
as a surrogate for dissolution testing if certain conditions are
In 1933, a disintegration test for tablets appeared in the same
met.6 Therefore, focusing more interest and research on disin-
pharmacopoeia.2 It stated that a tablet should be placed in a
tegration testing could, because of the test’s simplicity, enable
100-mL Erlenmeyer flask containing 50 mL of water, at a tem-
the QC departments of pharmaceutical companies to save ap-
perature of 37◦ C, and the flask was to be gently swirled from
preciable expenses in terms of time, efforts, and even money.
time to time.2 It was stated that the tablet had to disintegrate
In this commentary, disintegration testing is discussed and
into a powder or dissolve within 15 min.2
possible means of enhancing its potential as a QC method in
In 1948, the British Pharmacopoeia (BP) adopted a disinte-
the pharmaceutical industry are introduced. Particular focus
gration test for tablets based on observing the disintegration
will be given to its potential use as a surrogate for dissolution
behavior in test tubes.3 However, by that time, a specific disin-
testing.
tegration testing apparatus had been used for 8 years by the
laboratories of US Army Medical Department (Fig. 1),4 and
this apparatus formed the basis for the basket-rack assembly
apparatus, first adopted by the United States Pharmacopoeia DISINTEGRATION APPARATUS
(USP) in 1950,5 which is the apparatus currently used to per- A disintegration apparatus is composed of a 1-L low-form cylin-
form the vast majority of disintegration testing procedures for drical beaker, a heating system that keeps the temperature at
orally administered dosage forms. 37 ± 2◦ C, a basket-rack assembly, and a device to move the
Since then, the disintegration test has been a major qual- basket-rack assembly vertically.7–10 Two types of basket-rack
ity control (QC) test in pharmaceutical development and QC. assembly are described: apparatus A (Fig. 3) and apparatus B
However, it has been well understood that, despite disintegra- (Fig. 4). Apparatus A is described in all major pharmacopoeias:
tion being a prerequisite for acceptably rapid drug dissolution, European Pharmacopoeia (Ph Eur), BP, USP, and Japanese
complete disintegration does not necessarily imply complete Pharmacopoeia (JP), whereas apparatus B is described only in
dissolution of the active ingredient. This has contributed to the Ph Eur, BP, and the Dietary Supplements chapter of the
the much greater focus on dissolution testing methods in phar- USP, where it is required for testing tablets and capsules more
maceutical research, which can be easily noticed by the much than 18 mm in length.7–10 The chapters on disintegration test-
ing are harmonized between Ph Eur and BP.
Correspondence to: Peter Langguth (Telephone: +49-6131-392-5746;
Fax: +49-6131-392-5021; E-mail: langguth@uni-mainz.de) Both types consist of a set of open-ended transparent tubes
Journal of Pharmaceutical Sciences, Vol. 104, 2664–2675 (2015) maintained in a vertical position by two plates containing

C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association the corresponding number of openings arranged in a circle

2664 Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015

 COMMENTARY 2665

Figure 1. Disintegration apparatus from the 1940’s before becoming official in the USP.4

Figure 2. Hits when searching for the terms “Disintegration Test” and “Dissolution test” within the date ranges shown on the x-axis in PubMed.
Accessed June 23, 2014.

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2666 COMMENTARY

Figure 3. Disintegration apparatus A with dimensions in millimeter.9

equidistantly from the center of the plate as well as from each minute through a 53–57 mm distance in a smooth manner
other.7–10 The two plates are fastened to each other by three with the speed being the same for both the upward and the
bolts passing through them.7–10 A stainless steel wire cloth with downward strokes.7–10 The volume of the immersion fluid in
square apertures (size 2.0 ± 0.2 mm) is attached to the bot- the vessel is specified to be such that “at the highest point of
tom plate.7–10 The thickness of the wire is specified to be 0.57– the upward stroke the wire mesh remains at least 15 mm below
0.66 mm for apparatus A, whereas for apparatus B, it is set at the surface of the fluid, and descends to not less than 25 mm
0.60–0.66 mm by Ph Eur and BP and 1/4 inch by the Dietary from the bottom of the vessel on the downward stroke. At
Supplements chapter of the USP.7–10 Apparatus A contains six no time should the top of the basket-rack assembly become
tubes, while apparatus B contains three larger tubes.7–10 The submerged.”7–10
exact design of the device can be varied as long as the specifi- The detection of the disintegration time is usually deter-
cations for the tubes and the wire cloth are adhered to.7–10 The mined visually, when all of the dosage forms except insolu-
JP also provides specifications for a perforated metal plate that ble fragments of coating and/or, in case of capsules, capsule
can be used to secure the tubes and the plates.10 shells are a soft mass with no firm palpable core. In addition,
Both types are supplied with transparent plastic cylindrical disks that can provide automatic detection for disintegration
disks specified to have a relative density of 1.18–1.20, but those time, and are recognized by the pharmacopoeias,7–10 are com-
of apparatus A are smaller and, unlike those of apparatus B, mercially available, and can be used when the use of disks
have trapezoidal-shaped planes cut into the lateral surface of is proscribed. These disks give a signal that disintegration is
the cylinder.7–10 Unique to the JP is an accessory called the complete when they come into contact with the stainless steel
“auxiliary tube” (Fig. 5) made up of an open-ended plastic tube mesh and can be particularly useful when doing the test in
and two plastic rings, each containing an acid-resistant wire turbid media.
gauze, to be attached to the tube’s ends.10 A handle made of A striking aspect is lack of harmonization for certain fea-
acid-resistant wire is fitted to the tube. This auxiliary tube is tures like the use of apparatus B. This apparatus is specified
used for the disintegration testing of granules.10 in the Ph Eur, BP, and the Dietary Supplements chapter of
The disintegration tester also includes a device for the ver- the USP, but not by the General Tests chapter of the USP and
tical movement of the basket rack assembly.7–10 This vertical the JP. This may lead to same dosage forms (tablets and cap-
movement is specified to occur at a rate of 29–32 cycles per sules longer than 18 mm) being tested differently in different

Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015 DOI 10.1002/jps.24303
 COMMENTARY 2667

Figure 4. Disintegration apparatus B with dimensions in millimeter.9

laboratories, and using different apparatuses can lead to dif-

ferent disintegration times.11

COMPENDIAL TESTS
Table 1 gives a preview of the disintegration tests required
by the Ph Eur, BP, USP, and JP. The BP has its general dis-
integration tests harmonized with Ph Eur so the BP and Ph
Eur occupy the same column of the table. Otherwise, harmo-
nization among pharmacopoeias concerning the disintegration
tests required for different dosage forms is clearly not com-
plete, and many dosage forms are not mentioned in all phar-
macopoeias. Moreover, in the USP, disintegration tests for dif-
ferent dosage forms are specified in both the general chapter on
disintegration testing and in the dietary supplements chapter,
Figure 5. Auxiliary tube for the disintegration testing of granules and these two sets of tests are not identical, as is seen in the
according to JP.10 table.

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2668 COMMENTARY

Generally, the usage of disks is more common in the Ph stating the allowance of testing 12 more units in case 1 or 2 of
Eur and the BP. These two pharmacopoeias also often state the first 6 units fail to disintegrate.7,8
that if the test fails because of sticking to disks, it should be Concerning hard capsules, the USP specifies water as the
repeated omitting them.7,8 Generally, for tests performed with immersion medium in its general chapter on disintegration,
the basket-rack assembly, if one or two units fail to disinte- but pH 4.5 acetate buffer for dietary supplements.9 And these
grate (according the Ph Eur, BP, and JP) or to disintegrate two media may sometimes lead to different disintegration
completely (USP), the test should be repeated with 12 more performance for the same product, as shown by Almukainzi
units, and at least 16 out of the 18 tested units should com- et al.11 Another USP-specific feature is the use of a remov-
pletely disintegrate.7–10 A unique feature of the JP in this re- able wire cloth attached to the upper surface of the basket-rack
gard is that it allows the repetition on further 12 units when assembly.9 This is a relic of the older USP editions that did not
1 or 2 units fail the acid-resistance stage of the disintegration forbid the basket-rack assembly becoming submerged, and can
test for enteric-coated tablets and capsules.10 Another excep- be considered redundant now.
tional feature is that, for the type B apparatus, the Ph Eur and The testing methods for enteric-coated dosage forms
BP state that only a total of 6 units are to be tested without show some striking differences between the different

Table 1. Compendial Disintegration Tests for Different Dosage Forms

USP Dietary
Dosage Form USP General Chapter9 Supplements Chaptera9 Ph Eur and BP7,8 JP10

Uncoated tablets Using water or specified Using water or specified Using water as the Using water or specified
medium. Disks used if medium with a 30-min medium. Fifteen medium and a 30-min
proscribed by the time limit. Disks used minute time limit. time limit unless
individual monograph. if proscribed by the Disks are used. otherwise specified.
individual monograph. Disks used if
proscribed by the
individual monograph.
Plain-coated Same as uncoated. Same as uncoated, but For tablets other than Using water or specified
tablets sugar-coated tablets film-coated tablets, use medium and a 30-min
should be immersed in water with disks for time limit unless
water for 5 min at 60 min unless otherwise specified.
room temperature otherwise justified or Disks are used if
before the start of the authorized. If any of proscribed by the
test. the tablets fails to individual monograph.
disintegrate, repeat
with six more tablets
using 0.1 M HCl. For
film-coated tablets, use
the same procedure
but for 30 min
unless otherwise
justified or authorized.
Pills Using water or specified
medium and a 60-min
time limit. Disks are
used if proscribed by
the individual
monograph. If they
contain a crude drug,
use the first fluid for
disintegration.b If any
residue remains, a
successive 60-min test
with the second fluidb
for disintegration is
carried out.
Delayed release One-hour acid stage with One-hour acid stage with Two-hour acid stage (or Two-hour stage in first
tablets SGF, followed by 1-h SGF, followed by 1-h other time duration if fluid for disintegration
SIF stage without SIF stage without justified or authorized followed by 1-h stage
disks. In case a sugar disks. In case a sugar but not less than 1 h) in the second fluid for
coating is present, coating is present, with 0.1 M HCl disintegration.b
immerse in water for immerse in water for without disks followed
5 min at room 5 min at room by an 1-h stage in
temperature. temperature. phosphate buffer pH
6.8 R with disks.

Continued

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 COMMENTARY 2669

Table 1. Continued

USP General USP Dietary

Dosage Form Chapter9 Supplements Chaptera9 Ph Eur and BP7,8 JP10

Effervescent Six tablets, one at a time,

tablets are tested in a beaker
containing 200 mL of
water at 15◦ C–25◦ C.
When the evolution of gas
ceases, the tablet has
disintegrated, being
either dissolved or
dispersed in the water so
that no agglomerates of
particles remain. A 5-min
time limit is specified.
Soluble tablets Using water at 15◦ C–25◦ C
for 3 min.
Dispersible Using water at 15◦ C–25◦ C
tablets for 3 min.
Orodispersible Should disintegrate within
tablets 3 min. No other features
specified.
Hard capsules Same as uncoated Similar to the General Using water as the medium. Using water or specified
tablets, but with Chapter but using When justified and medium and a 20-min time
a removable wire 0.05 M acetate buffer authorized, 0.1 M HCl or limit unless otherwise
cloth attached to at a pH of 4.5 as the artificial gastric juice may specified. Disks used if
the surface of the immersion medium, be used. If the capsules proscribed by the individual
upper plate of the and with a 30-min float on the surface of the monograph.
basket. time limit. water, a disk may be
added. A 30-min time
limit, unless otherwise
justified and authorized.
Uncoated soft Same as hard A rupture test is Similar to hard capsules but Same as hard capsules
shell capsules capsules performed in water disks are to be used even
using USP type II if the capsules do not
dissolution float. In case the fill liquid
apparatus. attacks the disks, they
may be omitted.
Delayed release Only soft shell capsules Covers both hard and soft Same as tablets
capsules are mentioned. capsules. Same as delayed
Similar to delayed release tablets, with an
release tablets but additional statement
with disks during the allowing the use of
SIF stage. pancreatin when justified
or authorized during the
buffer stage.
Granules and Shake on a 500-:m sieve, and
dried syrups transfer 100 mg of the residue
to each of the auxiliary tubes.
Use water as immersion
medium unless otherwise
specified. A 30-min time limit
for plain and a 60-min one for
coated granules unless
otherwise specified.
Delayed release Similar to immediate release,
granules but a two-stage approach (1 h
in the first fluid for
disintegration and 30 min in
the second fluid for
disintegrationb ). In the first
stage, not more than 15
particles should fall from the
gauze.

Continued

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Table 1. Continued

USP Dietary Supplements

Dosage Form USP General Chapter9 Chaptera9 Ph Eur and BP7,8 JP10

Buccal tablets Same as for uncoated tablets but Same as in the General Chapter.
with a 4-h time limit.
Sublingual tablets Same as for uncoated tablets with Same as in the General Chapter.
the time limit being specified in
the individual monograph.
Oral lyophilizates Using a beaker containing
200 mL of water at
15◦ C–25◦ C. Six units tested,
1 at a time. It should
disintegrate within 3 min.
a
Under dietary supplements in USP, disks are generally proscribed for vitamin-mineral dosage forms (unless otherwise proscribed in the individual monograph),
whereas in botanical and other dosage forms, disks are generally omitted unless otherwise proscribed in the individual monograph.
b
First and second fluids for disintegration of JP are the same as the SGF and SIF of the USP, respectively, but without enzymes.

Figure 6. Difference between the disintegration times of placebo soft gelatin capsules coated to different levels with shellac enteric coat when
using the Ph Eur and the USP disintegration tests.12

pharmacopoeias. The buffer used by the Ph Eur and the BP 2. The drug has a dose/solubility ratio not less than 250 mL
contains much higher phosphate concentration than those spec- over a pH range of 1.2–6.8.
ified by the USP and the JP leading to faster disintegration in 3. More than 80% of the dose is dissolved within 15 min at
the Ph Eur/BP buffer by virtue of its higher buffer capacity and pH values of 1.2, 4.0, and 6.8.
ionic strength (Fig. 6).12 On the basis of what is known about 4. A relation has been determined between dissolution and
GI fluid composition, the USP and JP media can be considered disintegration.
less bioirrelevant than the Ph Eur/BP medium.12 In addition,
for delayed-release tablets, the USP, contrary to the Ph Eur and This means that disintegration testing may replace dissolu-
the BP, states that disks should be omitted.7–9 tion testing as a routine QC test for some formulations of BCS
class I and III drugs, which carries the advantage of making
routine QC testing easier because of reasons mentioned before.
DISINTEGRATION AS A DISSOLUTION SURROGATE However, fulfilling the above-listed conditions, the fourth one
ICH Q6A Decision Tree 7 in particular, may be not an easy task as the dissolution rate
of solid oral dosage forms is often not determined by their dis-
It is a well-known fact that complete disintegration does not integration (in particular when the disintegration is rapid) as
necessarily imply complete dissolution, making dissolution shown by Radwan et al.13 (Fig. 8). For instance, among 12 tablet
testing necessary even when disintegration testing is success- formulations of Verapamil hydrochloride prepared by Gupta
ful. However, in some cases, a disintegration test may act as a et al.,14 only one was identified as being suitable for having
surrogate for dissolution testing. the dissolution test replaced by a disintegration test showcas-
According to the ICH Q6A Decision Tree 7 (Fig. 7), a disin- ing the need of a thorough investigation to ascertain that the
tegration test can be used as a surrogate for a dissolution test formulation meets the required criteria.
if the following conditions are met6 :
Liquid-Filled Capsules
1. The dosage form does not exhibit modified release char- Liquid-filled capsules may be a dosage form for which a
acteristics. disintegration test provides an appropriate surrogate for a

Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015 DOI 10.1002/jps.24303
 COMMENTARY 2671

Figure 7. ICH Q6A decision tree 7.6

dissolution test for routine QC, in case the liquid fill is a so- An interesting case study for liquid-filled capsules is de-
lution from which no precipitation of drug occurs after dis- scribed by Han and Gallery,15 where the FDA approved the use
integration and contact with appropriate release media. This of disintegration testing instead of dissolution testing for an
may save time and costs associated with the elaborate sample encapsulated oily solution product of a poorly soluble drug not
preparation steps/equipment that are often needed for the dis- exhibiting rapid release on the grounds of complicated analytics
solution testing of such products, particularly when the liquid resulting in too much variability leading to a strong potential
fill is a lipid-based formulation—with self-emulsifying systems for overdiscrimination. A thoughtful point of argument made in
providing a particular challenge as it is difficult to distinguish the new drug application was that if the product was dosed in a
the drug within the emulsion droplets from the released drug. spoon instead of a capsule, no dissolution test would have been
For enteric-coated liquid-filled capsules, however, there is a risk required.15 This case study shows that some ICH criteria can
of the active ingredient diffusing undetected across the cap- be, sometimes, waived to allow the use of disintegration test-
sule shell and the coat into the immersion medium during the ing as a surrogate for dissolution testing, when an appropriate
acid stage of a disintegration test, making its use as a dis- scientific reasoning is presented, and it is another example on
solution test surrogate for enteric-coated liquid-filled capsules the value of disintegration testing for QC testing of liquid-filled
questionable. capsules.

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2672 COMMENTARY

gested decreasing the speed of the vertical movement of the

basket-rack assembly as a way to overcome this problem. On
the other hand, Kamba et al.,18 showed that the mechanical
destructive force within the disintegration apparatus is prob-
ably lower than in the GI tract, which may be of particular
concern for enteric-coated products as, at least in theory, po-
tential in vivo disintegration in the stomach may not be neces-
sarily detected in vitro, and the typical paddle dissolution test
provides even milder hydrodynamic conditions, making it even
more unlikely for a dissolution test to detect this phenomenon.
This shows the importance of conducting disintegration testing
despite the presence of dissolution testing.
As for how do the results of pharmacopoeial in vitro disin-
tegration testing, indeed, correlate with in vivo performance
in humans, a study by Bhagavan and Wolkoff,19 for example,
provided disintegration time data and pharmacokinetic data
obtained from human volunteers for four different vitamin C
tablet formulations. We did correlate the disintegration times
Figure 8. Relationship between disintegration time and percent drug and the in vivo time to peak plasma vitamin C concentrations
dissolved at 30 min for different trospium chloride tablet products.13 (Tmax ) (Fig. 9). The disintegration data showed an apprecia-
Zone A shows that, for rapidly disintegrating products, disintegration ble degree of correlation with the in vivo Tmax for the first three
time has little impact on dissolution rate, whereas in zone B, as disinte- products (R2 value of 0.9375 when only those three products are
gration becomes slower, dissolution rate is slowed down. In zone C, the included); however, they overdiscriminated between the slow-
disintegration time is greater than 30 min, so, naturally, no relation est and the second slowest formulations worsening the overall
can be determined with the parameter percent dissolved at 30 min. correlation.
The disintegration test, in that study, was performed in dis-
tilled water, and the difference between the slowest and the sec-
Challenges of the Pharmacopoeial Disintegration Test
ond slowest formulations was that the slowest formulation con-
Using disintegration testing as a dissolution testing surrogate tained much more stearic acid and magnesium stearate (with
offers clear benefits but also various challenges that need to be the hardness being similar).19 Therefore, a possible (at least
addressed. partial) explanation could be that pure water overdiscriminated
A particular aspect of the hydrodynamics in a disintegra- between the two formulations as it could not penetrate through-
tion tester is problematic, as far as determining a relationship out the lipophilic structure of the slowest formulation’s tablet
between dissolution and disintegration results is concerned. as fast as GI fluids, which contain surface-active substances,
As the hydrodynamic conditions are milder in a typical pad- could. Moreover, the surface-active materials in human GI flu-
dle dissolution apparatus than in a disintegration tester,16 it is ids could help in partially dispersing the stearic acid, which was
theoretically conceivable that situations may arise where the not the case with pure water. And, furthermore, as there is the
disintegration may determine the dissolution rate in a paddle possibility that the disintegration of the slowest formulation’s
apparatus, but it will not exhibit such a relation with the disso- tablet was completed in the intestine, intestinal fluid, by virtue
lution results when performed in a disintegration tester owing of its pH, could have partially solubilized the stearic acid, thus
to its being faster there. aiding disintegration and dissolution. This shows the need for
However, many other challenges need to be addressed too considering the use of media of better biorelevance. In addition,
for the proper use of disintegration testing as a dissolution test in the same study, higher values of vitamin C bioavailability
surrogate. First of all, the specifications outlined for the dis- extent were achieved with the slower disintegrating tablets,19
integration tester are not sufficiently narrow to prevent vari- which the authors explained by higher saturation degree of
ations, which still fall within the specifications, from resulting the transporters involved in vitamin C transport with the
in significantly different test results. For example, in a study faster-releasing formulations, thus showcasing the need for fur-
by Almukainzi et al.,11 the use of two different beaker sizes, ther research in order to better tailor the compendial require-
which both fall within the USP specifications, resulted in sig- ments for the formulations of certain active ingredients to their
nificantly different disintegration times for some dietary sup- properties.
plement products. In another study, both disintegration and dissolution testing
Moreover, the biorelevance of the hydrodynamics and the failed to predict the rank order of the speed of absorption of
media used for disintegration testing, in addition to the me- paracetamol from three different solid oral formulations.20 And
chanical stresses involved, is questionable. This may poten- yet in another study, performed by Whiting and Pluhator,21
tially lead to scenarios in which deviations from the expected disintegration testing exhibited a higher degree of correlation
in vivo release behavior of the batch may not be detected by in than dissolution testing with urinary calcium excretion rate
vitro testing. This problem is present in dissolution testing too increase during the interval of 2–4 h after administration of
and so is not disintegration testing-specific, but still needs to calcium carbonate tablets. These examples, indicate that,
be addressed. though far from being perfect, the use of disintegration test-
For example, Radwan et al.,17 showed that the fluid velocity ing as dissolution surrogate, could prove useful provided that
around the tablets in a disintegration tester is much higher further work is performed to enhance the biorelevance of both
than the estimated fluid velocity in the stomach, and they sug- dissolution and disintegration testing methodologies. This will

Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015 DOI 10.1002/jps.24303
 COMMENTARY 2673

Figure 9. Relationship between the in vivo Tmax values and the disintegration times of four tablet formulations studied by Bhagavan and
Wolkoff.19

make it more possible to obtain disintegration test methods Combining Disintegration with Pooled Dissolution
that correlate well with both dissolution testing and in vivo
A disintegration tester can be potentially used for pooled disso-
product performance.
lution testing provided that the active ingredient has sufficient
In addition to biorelevance issues, another potential chal-
solubility to maintain sink conditions. It may be argued, how-
lenge is the definition of a protocol that shows a relationship
ever, that similar advantages may be obtained by performing
between dissolution and disintegration. For tablets, this can
a pooled dissolution for six tablets in one dissolution vessel
be performed by compressing the tablet formulation to differ-
instead of pooling the samples, but, in some cases, a pooled
ent hardness levels using different compression forces (similar
dissolution test result might be combined with a disintegration
to what was performed by Gupta et al.14 ), and establishing a
test result to give a surrogate for a normal dissolution test and
relationship between disintegration time and a dissolution pa-
thus saving some analytics-associated effort. This may work,
rameter, such as percent of dose released at suitable time inter-
in particular, for some enteric-coated products.
vals or times required to achieve certain percent of dose release
A combined disintegration-pooled dissolution testing scheme
values. Further research to characterize the nature of the dis-
for enteric-coated products may be proposed as follows:
solution versus disintegration correlation would be helpful in
this regard.
For capsules, the picture is a bit more complicated. If the 1. At the end of the acid resistance stage, observe for any
capsule was filled with a powder or a liquid, the opening of the visible signs of leakage, cracking and the like. In case
shell will be the critical step for disintegration, unless powder they are not observed, take a sample of the immersion
clumping occurs. But in case the capsule is filled with a plug, fluid and then move on to the buffer stage and observe
or powder clumping occurs, plug/clump disintegration may be the disintegration.
the critical step for capsule disintegration. 2. In case the units successfully disintegrate in the buffer
When the shell opening is the critical disintegration step, within the set time limit, and the amount released into
the disintegration behavior of the product can be varied by the acid at the end of the acid resistance stage is below
shell cross-linking (an example using formaldehyde vapor is the set tolerance level, the batch is considered to have
described by Han and Gallery15 ), and in case plug disin- passed the test.
tegration is the critical step, then compressing the plug to
different hardness levels may be the procedure to be ap- Such an approach may be allowed when:
plied. However, first of all, it needs to be ascertained whether
plug or shell disintegration is the critical disintegration step. 1. The active ingredient is sufficiently soluble in the buffer
This can be carried out by performing both the plug hard- so that sink conditions could be maintained.
ening and the shell hardening procedures and comparing 2. The dissolution in the buffer is known to be fast.
the resulting effects on disintegration times. If it is diffi- 3. A relation has been determined between disintegration
cult to make a judgment, then it will be better to perform and dissolution in the buffer.
the dissolution–disintegration correlation protocol using both 4. The intra-batch variability has been repeatedly shown to
procedures. be low.

DOI 10.1002/jps.24303 Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015
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Table 2. Alternative Disintegration Test Methods for ODTs However, as it is carried out in a static mode, such a test, though
being potentially highly useful in the context of understanding
Apparatus Methodology
the work and effects of different formulation and/or processing
Modified USP Operated at 100 rev/min, 900 mL dissolution variables and designing the formulation and/or the manufac-
dissolution medium. Time required by the ODT to pass turing process accordingly, may not reflect the situation in the
apparatus 2 through sinker screen is determined. human stomach and/or intestine where the tablet is far from
Wire cloth method Water dropped at a rate of 4 mL/min over the being static, thus potentially limiting its effectiveness as an in
ODT placed in wire cloth no. 10. Time vivo performance predictor. But, in this regard, it could fit into
taken for the ODT to pass through the wire
the framework of testing the disintegration of orally disinte-
cloth considered as disintegration time
grating tablets (ODTs), where static disintegration testing has
Charged couple Disintegration of ODT placed on a grid placed
device camera over a stirring element contained in a found its place among the disintegration testing methods pro-
(CCD) method dissolution medium. Disintegration time posed as alternatives to the pharmacopoeial test. Actually, the
monitored by a CCD camera bulk of the proposed alternative disintegration testing designs
Shaking water ODT placed in glass cylinder with a 10 mesh. are centered on disintegration testing of ODTs as the large fluid
bath method The unit is immersed in a shaking water volumes and the agitation intensity used do not reflect the con-
bath at 150 rev/min. Time for the ODT to ditions the tablet is subjected to in the oral cavity.25 Kraemer
pass through the 10-mesh screen et al., in their review on dissolution testing for ODTs, have
considered as disintegration time listed a few examples on alternative apparatuses for disinte-
Rotary shaft Mouth dissolving tablet placed on a wire
gration testing of these dosage forms (Table 2).25
method gauze immersed in the medium is
For soft shell capsules, the Dietary Supplements chapter of
compressed by a rotary shaft. Rotation
speed and mechanical stress control the the USP specifies a rupture test using a type II dissolution
disintegration time apparatus instead of a typical disintegration test (USP). Al-
Texture analyzer Constant penetration force using flat-ended mukainzi et al.26 compared this rupture test with a disintegra-
probe is applied to the mouth dissolving tion test and found no advantage for a rupture test compared
tablet concomitantly while immersing in with a disintegration test.
the aqueous medium. Time for the probe to
penetrate into the ODT is measured
ElectroForce 3100 Application of very low force (10 mN) to the CONCLUSION
ODT placed on holder followed by an
addition of 5 mL of aqueous medium. Small Despite its limitations, owing to its simplicity, disintegration
displacements of the piston and testing remains an important QC tool in the pharmaceutical
disintegration rate are measured industry. And, with proper research performed, its use can be
expanded allowing it to serve as a release test surrogate in
some instances, thus saving the QC departments of the phar-
Such a testing scheme can be particularly useful for liquid- maceutical industry significant costs. But, in order to enhance
filled enteric-coated capsules, especially if the filling liquid is a this aspect, clear guidance should be established and additional
solution that does not exhibit precipitation upon contact with research should be performed to make the test more biopredic-
release media. This would allow us to save the costs and times tive. In addition, more harmonization among pharmacopoeias
associated with analyzing dissolution samples of the buffer into is still desirable with regard to disintegration testing.
which the liquid fill has been released.
In case concerns about intra-batch variability and/or main-
taining sink conditions in the acid stage arise, this stage could ACKNOWLEDGMENTS
be performed in a dissolution apparatus, with the buffer stage We would like to thank Dr. Simone Wengner for the
being performed in a disintegration device. helpful discussion. The German Academic Exchange Ser-
vice (DAAD) is acknowledged for providing a stipend to
J.A-G. This work was contributed to the OrBiTo project
ALTERNATIVE APPARATUSES (http://www.imi.europa.eu/content/) as sideground.
The design of the disintegration testing apparatus has basically
remained unaltered for several decades. Twenty-five years ago,
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DOI 10.1002/jps.24303 Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015