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 harmonization 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
C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:26642675, 2015
assurance. 
Keywords: bioavailability; biopharmaceutics classification system (BCS); dissolution; excipients; formulation; gastrointestinal; in vitro
models; intestinal absorption

INTRODUCTION
It is a well-known fact that an immediate-release dosage form
should disintegrate in order to efficiently liberate its active
ingredient(s) and make it available for absorption. Therefore,
disintegration testing methods were developed.
The first mention of a test for disintegration was in the
1907 Edition of Pharmacopoeia Helvetica, in the compressed
pastilles monograph, stating that they should dissolve or disintegrate after a short time of them being placed in cold water.1
In 1933, a disintegration test for tablets appeared in the same
pharmacopoeia.2 It stated that a tablet should be placed in a
100-mL Erlenmeyer flask containing 50 mL of water, at a temperature of 37 C, and the flask was to be gently swirled from
time to time.2 It was stated that the tablet had to disintegrate
into a powder or dissolve within 15 min.2
In 1948, the British Pharmacopoeia (BP) adopted a disintegration test for tablets based on observing the disintegration
behavior in test tubes.3 However, by that time, a specific disintegration 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
(USP) in 1950,5 which is the apparatus currently used to perform the vast majority of disintegration testing procedures for
orally administered dosage forms.
Since then, the disintegration test has been a major quality control (QC) test in pharmaceutical development and QC.
However, it has been well understood that, despite disintegration being a prerequisite for acceptably rapid drug dissolution,
complete disintegration does not necessarily imply complete
dissolution of the active ingredient. This has contributed to
the much greater focus on dissolution testing methods in pharmaceutical research, which can be easily noticed by the much
Correspondence to: Peter Langguth (Telephone: +49-6131-392-5746;
Fax: +49-6131-392-5021; E-mail: langguth@uni-mainz.de)
Journal of Pharmaceutical Sciences, Vol. 104, 26642675 (2015)

C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

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greater amount of publications dealing with dissolution testing

methodologies compared with those dealing with disintegration
testing methodologies (as shown in Fig. 2).
Nevertheless, the greater simplicity of disintegration compared with dissolution testing (e.g., no analytics needed, lesser
volume of fluids required, less time-consuming) makes the idea
of putting more focus on disintegration attractive. This has
been recognized by the International Conference on Harmonization (ICH) that allowed the use of disintegration testing
as a surrogate for dissolution testing if certain conditions are
met.6 Therefore, focusing more interest and research on disintegration testing could, because of the tests simplicity, enable
the QC departments of pharmaceutical companies to save appreciable expenses in terms of time, efforts, and even money.
In this commentary, disintegration testing is discussed and
possible means of enhancing its potential as a QC method in
the pharmaceutical industry are introduced. Particular focus
will be given to its potential use as a surrogate for dissolution
testing.

DISINTEGRATION APPARATUS
A disintegration apparatus is composed of a 1-L low-form cylindrical beaker, a heating system that keeps the temperature at
37 2 C, a basket-rack assembly, and a device to move the
basket-rack assembly vertically.710 Two types of basket-rack
assembly are described: apparatus A (Fig. 3) and apparatus B
(Fig. 4). Apparatus A is described in all major pharmacopoeias:
European Pharmacopoeia (Ph Eur), BP, USP, and Japanese
Pharmacopoeia (JP), whereas apparatus B is described only in
the Ph Eur, BP, and the Dietary Supplements chapter of the
USP, where it is required for testing tablets and capsules more
than 18 mm in length.710 The chapters on disintegration testing are harmonized between Ph Eur and BP.
Both types consist of a set of open-ended transparent tubes
maintained in a vertical position by two plates containing
the corresponding number of openings arranged in a circle

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Figure 1. Disintegration apparatus from the 1940s 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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Figure 3. Disintegration apparatus A with dimensions in millimeter.9

equidistantly from the center of the plate as well as from each

other.710 The two plates are fastened to each other by three
bolts passing through them.710 A stainless steel wire cloth with
square apertures (size 2.0 0.2 mm) is attached to the bottom plate.710 The thickness of the wire is specified to be 0.57
0.66 mm for apparatus A, whereas for apparatus B, it is set at
0.600.66 mm by Ph Eur and BP and 1/4 inch by the Dietary
Supplements chapter of the USP.710 Apparatus A contains six
tubes, while apparatus B contains three larger tubes.710 The
exact design of the device can be varied as long as the specifications for the tubes and the wire cloth are adhered to.710 The
JP also provides specifications for a perforated metal plate that
can be used to secure the tubes and the plates.10
Both types are supplied with transparent plastic cylindrical
disks specified to have a relative density of 1.181.20, but those
of apparatus A are smaller and, unlike those of apparatus B,
have trapezoidal-shaped planes cut into the lateral surface of
the cylinder.710 Unique to the JP is an accessory called the
auxiliary tube (Fig. 5) made up of an open-ended plastic tube
and two plastic rings, each containing an acid-resistant wire
gauze, to be attached to the tubes ends.10 A handle made of
acid-resistant wire is fitted to the tube. This auxiliary tube is
used for the disintegration testing of granules.10
The disintegration tester also includes a device for the vertical movement of the basket rack assembly.710 This vertical
movement is specified to occur at a rate of 2932 cycles per

minute through a 5357 mm distance in a smooth manner

with the speed being the same for both the upward and the
downward strokes.710 The volume of the immersion fluid in
the vessel is specified to be such that at the highest point of
the upward stroke the wire mesh remains at least 15 mm below
the surface of the fluid, and descends to not less than 25 mm
from the bottom of the vessel on the downward stroke. At
no time should the top of the basket-rack assembly become
submerged.710
The detection of the disintegration time is usually determined visually, when all of the dosage forms except insoluble fragments of coating and/or, in case of capsules, capsule
shells are a soft mass with no firm palpable core. In addition,
disks that can provide automatic detection for disintegration
time, and are recognized by the pharmacopoeias,710 are commercially available, and can be used when the use of disks
is proscribed. These disks give a signal that disintegration is
complete when they come into contact with the stainless steel
mesh and can be particularly useful when doing the test in
turbid media.
A striking aspect is lack of harmonization for certain features like the use of apparatus B. This apparatus is specified
in the Ph Eur, BP, and the Dietary Supplements chapter of
the USP, but not by the General Tests chapter of the USP and
the JP. This may lead to same dosage forms (tablets and capsules longer than 18 mm) being tested differently in different

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

laboratories, and using different apparatuses can lead to different disintegration times.11

COMPENDIAL TESTS

Figure 5. Auxiliary tube for the disintegration testing of granules

according to JP.10

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Table 1 gives a preview of the disintegration tests required

by the Ph Eur, BP, USP, and JP. The BP has its general disintegration tests harmonized with Ph Eur so the BP and Ph
Eur occupy the same column of the table. Otherwise, harmonization among pharmacopoeias concerning the disintegration
tests required for different dosage forms is clearly not complete, and many dosage forms are not mentioned in all pharmacopoeias. Moreover, in the USP, disintegration tests for different dosage forms are specified in both the general chapter on
disintegration testing and in the dietary supplements chapter,
and these two sets of tests are not identical, as is seen in the
table.

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Generally, the usage of disks is more common in the Ph

Eur and the BP. These two pharmacopoeias also often state
that if the test fails because of sticking to disks, it should be
repeated omitting them.7,8 Generally, for tests performed with
the basket-rack assembly, if one or two units fail to disintegrate (according the Ph Eur, BP, and JP) or to disintegrate
completely (USP), the test should be repeated with 12 more
units, and at least 16 out of the 18 tested units should completely disintegrate.710 A unique feature of the JP in this regard is that it allows the repetition on further 12 units when
1 or 2 units fail the acid-resistance stage of the disintegration
test for enteric-coated tablets and capsules.10 Another exceptional feature is that, for the type B apparatus, the Ph Eur and
BP state that only a total of 6 units are to be tested without
Table 1.

stating the allowance of testing 12 more units in case 1 or 2 of

the first 6 units fail to disintegrate.7,8
Concerning hard capsules, the USP specifies water as the
immersion medium in its general chapter on disintegration,
but pH 4.5 acetate buffer for dietary supplements.9 And these
two media may sometimes lead to different disintegration
performance for the same product, as shown by Almukainzi
et al.11 Another USP-specific feature is the use of a removable wire cloth attached to the upper surface of the basket-rack
assembly.9 This is a relic of the older USP editions that did not
forbid the basket-rack assembly becoming submerged, and can
be considered redundant now.
The testing methods for enteric-coated dosage forms
show some striking differences between the different

Compendial Disintegration Tests for Different Dosage Forms

Dosage Form

USP General Chapter9

USP Dietary
Supplements Chaptera9

Ph Eur and BP7,8

Uncoated tablets

Using water or specified

medium. Disks used if
proscribed by the
individual monograph.

Using water or specified

medium with a 30-min
time limit. Disks used
if proscribed by the
individual monograph.

Using water as the

medium. Fifteen
minute time limit.
Disks are used.

Plain-coated
tablets

Same as uncoated.

Same as uncoated, but

sugar-coated tablets
should be immersed in
water for 5 min at
room temperature
before the start of the
test.

For tablets other than

film-coated tablets, use
water with disks for
60 min unless
otherwise justified or
authorized. If any of
the tablets fails to
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

Delayed release
tablets

One-hour acid stage with

SGF, followed by 1-h
SIF stage without
disks. In case a sugar
coating is present,
immerse in water for
5 min at room
temperature.

One-hour acid stage with

SGF, followed by 1-h
SIF stage without
disks. In case a sugar
coating is present,
immerse in water for
5 min at room
temperature.

Two-hour acid stage (or

other time duration if
justified or authorized
but not less than 1 h)
with 0.1 M HCl
without disks followed
by an 1-h stage in
phosphate buffer pH
6.8 R with disks.

JP10
Using water or specified
medium and a 30-min
time limit unless
otherwise specified.
Disks used if
proscribed by the
individual monograph.
Using water or specified
medium and a 30-min
time limit unless
otherwise specified.
Disks are used if
proscribed by the
individual monograph.

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.
Two-hour stage in first
fluid for disintegration
followed by 1-h stage
in the second fluid for
disintegration.b

Continued
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Table 1.

2669

Continued

Dosage Form

USP General
Chapter9

USP Dietary
Supplements Chaptera9

Effervescent
tablets

Soluble tablets
Dispersible
tablets
Orodispersible
tablets
Hard capsules

Same as uncoated
tablets, but with
a removable wire
cloth attached to
the surface of the
upper plate of the
basket.

Similar to the General

Chapter but using
0.05 M acetate buffer
at a pH of 4.5 as the
immersion medium,
and with a 30-min
time limit.

Uncoated soft
shell capsules

Same as hard
capsules

A rupture test is
performed in water
using USP type II
dissolution
apparatus.

Delayed release
capsules

Granules and
dried syrups

Delayed release
granules

Only soft shell capsules

are mentioned.
Similar to delayed
release tablets but
with disks during the
SIF stage.

Ph Eur and BP7,8

Six tablets, one at a time,
are tested in a beaker
containing 200 mL of
water at 15 C25 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.
Using water at 15 C25 C
for 3 min.
Using water at 15 C25 C
for 3 min.
Should disintegrate within
3 min. No other features
specified.
Using water as the medium.
When justified and
authorized, 0.1 M HCl or
artificial gastric juice may
be used. If the capsules
float on the surface of the
water, a disk may be
added. A 30-min time
limit, unless otherwise
justified and authorized.
Similar to hard capsules but
disks are to be used even
if the capsules do not
float. In case the fill liquid
attacks the disks, they
may be omitted.
Covers both hard and soft
capsules. Same as delayed
release tablets, with an
additional statement
allowing the use of
pancreatin when justified
or authorized during the
buffer stage.

JP10

Using water or specified

medium and a 20-min time
limit unless otherwise
specified. Disks used if
proscribed by the individual
monograph.

Same as hard capsules

Same as tablets

Shake on a 500-:m sieve, and

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.
Similar to immediate release,
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

Buccal tablets
Sublingual tablets

USP Dietary Supplements

Chaptera9

USP General Chapter9

Dosage Form

Same as for uncoated tablets but

with a 4-h time limit.
Same as for uncoated tablets with
the time limit being specified in
the individual monograph.

Ph Eur and BP7,8

JP10

Same as in the General Chapter.

Same as in the General Chapter.

Oral lyophilizates

Using a beaker containing

200 mL of water at
15 C25 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

contains much higher phosphate concentration than those specified by the USP and the JP leading to faster disintegration in
the Ph Eur/BP buffer by virtue of its higher buffer capacity and
ionic strength (Fig. 6).12 On the basis of what is known about
GI fluid composition, the USP and JP media can be considered
less bioirrelevant than the Ph Eur/BP medium.12 In addition,
for delayed-release tablets, the USP, contrary to the Ph Eur and
the BP, states that disks should be omitted.79

DISINTEGRATION AS A DISSOLUTION SURROGATE

ICH Q6A Decision Tree 7
It is a well-known fact that complete disintegration does not
necessarily imply complete dissolution, making dissolution
testing necessary even when disintegration testing is successful. However, in some cases, a disintegration test may act as a
surrogate for dissolution testing.
According to the ICH Q6A Decision Tree 7 (Fig. 7), a disintegration test can be used as a surrogate for a dissolution test
if the following conditions are met6 :

2. The drug has a dose/solubility ratio not less than 250 mL

over a pH range of 1.26.8.
3. More than 80% of the dose is dissolved within 15 min at
pH values of 1.2, 4.0, and 6.8.
4. A relation has been determined between dissolution and
disintegration.
This means that disintegration testing may replace dissolution 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.
However, fulfilling the above-listed conditions, the fourth one
in particular, may be not an easy task as the dissolution rate
of solid oral dosage forms is often not determined by their disintegration (in particular when the disintegration is rapid) as
shown by Radwan et al.13 (Fig. 8). For instance, among 12 tablet
formulations of Verapamil hydrochloride prepared by Gupta
et al.,14 only one was identified as being suitable for having
the dissolution test replaced by a disintegration test showcasing the need of a thorough investigation to ascertain that the
formulation meets the required criteria.
Liquid-Filled Capsules

1. The dosage form does not exhibit modified release characteristics.

Liquid-filled capsules may be a dosage form for which a

disintegration test provides an appropriate surrogate for a

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Figure 7. ICH Q6A decision tree 7.6

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

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Figure 8. Relationship between disintegration time and percent drug

dissolved at 30 min for different trospium chloride tablet products.13
Zone A shows that, for rapidly disintegrating products, disintegration
time has little impact on dissolution rate, whereas in zone B, as disintegration becomes slower, dissolution rate is slowed down. In zone C, the
disintegration time is greater than 30 min, so, naturally, no relation
can be determined with the parameter percent dissolved at 30 min.

Challenges of the Pharmacopoeial Disintegration Test

Using disintegration testing as a dissolution testing surrogate
offers clear benefits but also various challenges that need to be
addressed.
A particular aspect of the hydrodynamics in a disintegration tester is problematic, as far as determining a relationship
between dissolution and disintegration results is concerned.
As the hydrodynamic conditions are milder in a typical paddle dissolution apparatus than in a disintegration tester,16 it is
theoretically conceivable that situations may arise where the
disintegration may determine the dissolution rate in a paddle
apparatus, but it will not exhibit such a relation with the dissolution results when performed in a disintegration tester owing
to its being faster there.
However, many other challenges need to be addressed too
for the proper use of disintegration testing as a dissolution test
surrogate. First of all, the specifications outlined for the disintegration tester are not sufficiently narrow to prevent variations, which still fall within the specifications, from resulting
in significantly different test results. For example, in a study
by Almukainzi et al.,11 the use of two different beaker sizes,
which both fall within the USP specifications, resulted in significantly different disintegration times for some dietary supplement products.
Moreover, the biorelevance of the hydrodynamics and the
media used for disintegration testing, in addition to the mechanical stresses involved, is questionable. This may potentially lead to scenarios in which deviations from the expected
in vivo release behavior of the batch may not be detected by in
vitro testing. This problem is present in dissolution testing too
and so is not disintegration testing-specific, but still needs to
be addressed.
For example, Radwan et al.,17 showed that the fluid velocity
around the tablets in a disintegration tester is much higher
than the estimated fluid velocity in the stomach, and they sug-

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 probably lower than in the GI tract, which may be of particular
concern for enteric-coated products as, at least in theory, potential in vivo disintegration in the stomach may not be necessarily 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 disintegration 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
and the in vivo time to peak plasma vitamin C concentrations
(Tmax ) (Fig. 9). The disintegration data showed an appreciable degree of correlation with the in vivo Tmax for the first three
products (R2 value of 0.9375 when only those three products are
included); however, they overdiscriminated between the slowest and the second slowest formulations worsening the overall
correlation.
The disintegration test, in that study, was performed in distilled water, and the difference between the slowest and the second slowest formulations was that the slowest formulation contained much more stearic acid and magnesium stearate (with
the hardness being similar).19 Therefore, a possible (at least
partial) explanation could be that pure water overdiscriminated
between the two formulations as it could not penetrate throughout the lipophilic structure of the slowest formulations tablet
as fast as GI fluids, which contain surface-active substances,
could. Moreover, the surface-active materials in human GI fluids could help in partially dispersing the stearic acid, which was
not the case with pure water. And, furthermore, as there is the
possibility that the disintegration of the slowest formulations
tablet was completed in the intestine, intestinal fluid, by virtue
of its pH, could have partially solubilized the stearic acid, thus
aiding disintegration and dissolution. This shows the need for
considering the use of media of better biorelevance. In addition,
in the same study, higher values of vitamin C bioavailability
extent were achieved with the slower disintegrating tablets,19
which the authors explained by higher saturation degree of
the transporters involved in vitamin C transport with the
faster-releasing formulations, thus showcasing the need for further research in order to better tailor the compendial requirements for the formulations of certain active ingredients to their
properties.
In another study, both disintegration and dissolution testing
failed to predict the rank order of the speed of absorption of
paracetamol from three different solid oral formulations.20 And
yet in another study, performed by Whiting and Pluhator,21
disintegration testing exhibited a higher degree of correlation
than dissolution testing with urinary calcium excretion rate
increase during the interval of 24 h after administration of
calcium carbonate tablets. These examples, indicate that,
though far from being perfect, the use of disintegration testing as dissolution surrogate, could prove useful provided that
further work is performed to enhance the biorelevance of both
dissolution and disintegration testing methodologies. This will

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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

that correlate well with both dissolution testing and in vivo
product performance.
In addition to biorelevance issues, another potential challenge is the definition of a protocol that shows a relationship
between dissolution and disintegration. For tablets, this can
be performed by compressing the tablet formulation to different hardness levels using different compression forces (similar
to what was performed by Gupta et al.14 ), and establishing a
relationship between disintegration time and a dissolution parameter, such as percent of dose released at suitable time intervals or times required to achieve certain percent of dose release
values. Further research to characterize the nature of the dissolution versus disintegration correlation would be helpful in
this regard.
For capsules, the picture is a bit more complicated. If the
capsule was filled with a powder or a liquid, the opening of the
shell will be the critical step for disintegration, unless powder
clumping occurs. But in case the capsule is filled with a plug,
or powder clumping occurs, plug/clump disintegration may be
the critical step for capsule disintegration.
When the shell opening is the critical disintegration step,
the disintegration behavior of the product can be varied by
shell cross-linking (an example using formaldehyde vapor is
described by Han and Gallery15 ), and in case plug disintegration is the critical step, then compressing the plug to
different hardness levels may be the procedure to be applied. However, first of all, it needs to be ascertained whether
plug or shell disintegration is the critical disintegration step.
This can be carried out by performing both the plug hardening and the shell hardening procedures and comparing
the resulting effects on disintegration times. If it is difficult to make a judgment, then it will be better to perform
the dissolutiondisintegration correlation protocol using both
procedures.
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Combining Disintegration with Pooled Dissolution

A disintegration tester can be potentially used for pooled dissolution testing provided that the active ingredient has sufficient
solubility to maintain sink conditions. It may be argued, however, that similar advantages may be obtained by performing
a pooled dissolution for six tablets in one dissolution vessel
instead of pooling the samples, but, in some cases, a pooled
dissolution test result might be combined with a disintegration
test result to give a surrogate for a normal dissolution test and
thus saving some analytics-associated effort. This may work,
in particular, for some enteric-coated products.
A combined disintegration-pooled dissolution testing scheme
for enteric-coated products may be proposed as follows:
1. At the end of the acid resistance stage, observe for any
visible signs of leakage, cracking and the like. In case
they are not observed, take a sample of the immersion
fluid and then move on to the buffer stage and observe
the disintegration.
2. In case the units successfully disintegrate in the buffer
within the set time limit, and the amount released into
the acid at the end of the acid resistance stage is below
the set tolerance level, the batch is considered to have
passed the test.
Such an approach may be allowed when:
1. The active ingredient is sufficiently soluble in the buffer
so that sink conditions could be maintained.
2. The dissolution in the buffer is known to be fast.
3. A relation has been determined between disintegration
and dissolution in the buffer.
4. The intra-batch variability has been repeatedly shown to
be low.

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Table 2.

Alternative Disintegration Test Methods for ODTs

Apparatus
Modified USP
dissolution
apparatus 2
Wire cloth method

Charged couple
device camera
(CCD) method
Shaking water
bath method

Rotary shaft
method

Texture analyzer

ElectroForce 3100

Methodology
Operated at 100 rev/min, 900 mL dissolution
medium. Time required by the ODT to pass
through sinker screen is determined.
Water dropped at a rate of 4 mL/min over the
ODT placed in wire cloth no. 10. Time
taken for the ODT to pass through the wire
cloth considered as disintegration time
Disintegration of ODT placed on a grid placed
over a stirring element contained in a
dissolution medium. Disintegration time
monitored by a CCD camera
ODT placed in glass cylinder with a 10 mesh.
The unit is immersed in a shaking water
bath at 150 rev/min. Time for the ODT to
pass through the 10-mesh screen
considered as disintegration time
Mouth dissolving tablet placed on a wire
gauze immersed in the medium is
compressed by a rotary shaft. Rotation
speed and mechanical stress control the
disintegration time
Constant penetration force using flat-ended
probe is applied to the mouth dissolving
tablet concomitantly while immersing in
the aqueous medium. Time for the probe to
penetrate into the ODT is measured
Application of very low force (10 mN) to the
ODT placed on holder followed by an
addition of 5 mL of aqueous medium. Small
displacements of the piston and
disintegration rate are measured

Such a testing scheme can be particularly useful for liquidfilled enteric-coated capsules, especially if the filling liquid is a
solution that does not exhibit precipitation upon contact with
release media. This would allow us to save the costs and times
associated with analyzing dissolution samples of the buffer into
which the liquid fill has been released.
In case concerns about intra-batch variability and/or maintaining sink conditions in the acid stage arise, this stage could
be performed in a dissolution apparatus, with the buffer stage
being performed in a disintegration device.

ALTERNATIVE APPARATUSES
The design of the disintegration testing apparatus has basically
remained unaltered for several decades. Twenty-five years ago,
Catellani et al.22 published an interesting article about a disintegration device that could measure both the disintegrating
force developing within the tablet as well as the water uptake
kinetics, helping to provide insights into disintegrantwater interactions and to compare the action and efficiency of different
disintegrants. This apparatus was further adapted to also measure the mass of the disintegrated tablets debris alongside the
disintegrating force versus time profile.23 This test was found
promising for optimizing tablet disintegrant levels,23 and it exhibited the ability to discriminate between the effects of tablet
structure changes that could not be discriminated by conventional pharmacopoeial disintegration and dissolution tests.24

However, as it is carried out in a static mode, such a test, though

being potentially highly useful in the context of understanding
the work and effects of different formulation and/or processing
variables and designing the formulation and/or the manufacturing process accordingly, may not reflect the situation in the
human stomach and/or intestine where the tablet is far from
being static, thus potentially limiting its effectiveness as an in
vivo performance predictor. But, in this regard, it could fit into
the framework of testing the disintegration of orally disintegrating tablets (ODTs), where static disintegration testing has
found its place among the disintegration testing methods proposed as alternatives to the pharmacopoeial test. Actually, the
bulk of the proposed alternative disintegration testing designs
are centered on disintegration testing of ODTs as the large fluid
volumes and the agitation intensity used do not reflect the conditions the tablet is subjected to in the oral cavity.25 Kraemer
et al., in their review on dissolution testing for ODTs, have
listed a few examples on alternative apparatuses for disintegration testing of these dosage forms (Table 2).25
For soft shell capsules, the Dietary Supplements chapter of
the USP specifies a rupture test using a type II dissolution
apparatus instead of a typical disintegration test (USP). Almukainzi et al.26 compared this rupture test with a disintegration test and found no advantage for a rupture test compared
with a disintegration test.

CONCLUSION
Despite its limitations, owing to its simplicity, disintegration
testing remains an important QC tool in the pharmaceutical
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 pharmaceutical industry significant costs. But, in order to enhance
this aspect, clear guidance should be established and additional
research should be performed to make the test more biopredictive. In addition, more harmonization among pharmacopoeias
is still desirable with regard to disintegration testing.

ACKNOWLEDGMENTS
We would like to thank Dr. Simone Wengner for the
helpful discussion. The German Academic Exchange Service (DAAD) is acknowledged for providing a stipend to
J.A-G. This work was contributed to the OrBiTo project
(http://www.imi.europa.eu/content/) as sideground.

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