Tablet disintegration:

Effects of temperature and pH of aqueous disintegrating fluid

and influence of solubility of diluent
on the behaviour of superdisintegrants

Eija Leskinen
Seminar summary
Division of pharmaceutical technology
Department of pharmacy
University of Helsinki
31.3.2003

I Introduction................................................................................................................... 1
II Theoretical part............................................................................................................ 1
1. Mechanisms of tablet disintegration................................................................... 1
1.1.
Water uptake ............................................................................................... 2
1.2.
Swelling of disintegrant .............................................................................. 3
2. Disintegrants........................................................................................................ 4
2.1.
Hydrophilic disintegrants ............................................................................ 4
2.2.
Insoluble disintegrants................................................................................. 5
3. Other factors........................................................................................................ 5
3.1.
Effect of diluents ......................................................................................... 5
3.2.
Effect of binders.......................................................................................... 6
3.3.
Effect of surfactants .................................................................................... 6
3.4.
Effect of lubricants...................................................................................... 6
3.5.
Effect of disintegrating fluid ....................................................................... 7
III Experimental part ....................................................................................................... 7
4. Materials .............................................................................................................. 7
5. Methods............................................................................................................... 7
5.1.
Characterisation of materials....................................................................... 7
5.1.1.
Micromeritic properties....................................................................... 7
5.1.2.
Thermal analysis ................................................................................. 8
5.1.3.
Microcalorimetry................................................................................. 8
5.2.
Preparation of mixtures ............................................................................... 8
5.3.
Preparation of tablets................................................................................... 8
5.4.
Characterisation of tablets........................................................................... 8
5.4.1.
Disintegration...................................................................................... 8
5.4.2.
Mechanical strength............................................................................ 9
IV Results and discussion............................................................................................... 9
6.1.
Characterisation of materials........................................................................... 9
6.2.
Disintegration................................................................................................ 10
6.3.
Mechanical strength...................................................................................... 12
V Conclusions ............................................................................................................... 12
References

I Introduction
In pharmaceutics, disintegration usually means the process of solid form breaking up
when it comes into contact with aqueous fluid. In most cases, disintegration is a
disaggregation process of constituent particles before dissolution happens. Tablets
must disintegrate to afford acceptable dissolution rates. Availability of a drug from
tablet depends on tablets ability to disintegrate fast enough in existing dissolution
media (Ingram and Lowenthal, 1966). pH of gastrointestinal fluid affects drug
absorption by affecting its solubility and dissolution, but also tablet disintegration may
be influenced by it. This is the case when tablet contains such binders or disintegrants
the solubility of which is pH-dependent (Banker and Rhodes, 1996).
In the experimental work three grades of lactose were combined with four
superdisintegrants and tablets were prepared with different porosity levels. Also one
hygroscopic and insoluble diluent, sorbitol and dicalcium phosphate dihydrate were
used in combination with disintegrants. Disintegration and calorimetric measurements
were made in three temperatures with water and simulated gastric and intestinal fluid.
The purpose was to adjust, if the properties of diluent, such as solubility,
hygroscopicity and heat of wetting, have some influence on the disintegration time of
tablets. Also the effect of pH and temperature of disintegration fluid was investigated.
This summary concentrates mainly on the mechanisms behind tablet disintegration. At
the end, some results of the experimental work is shown.

II Theoretical part
1. Mechanisms of tablet disintegration
Complete tablet disintegration is defined by USP XXV as the state in which any
residue of the tablet, except fragments of insoluble coating, remaining on the screen is
a soft mass having no palpably fine core. The importance of tablet disintegration was
recognized already 1879, when a patent recommended that tablets should be perforated
in order to achieve better penetration rates for gastric fluid and to speed up the
disintegration (Lowenthal, 1972). In order to achieve the best formulation for desired
bioavailability we have to know the mechanisms behind the disintegration process
(Guyot-Hermann, 1992).
Disintegration has been investigated a lot for the past few decades, but there is still no
general agreement of the factors involved. One of the earliest suggested reasons was
that when fluid enters a tablet, it results in the heat of wetting of the ingredients which
causes the entrapped air in the tablet to expand and forces the tablet to disintegrate
(Matsumaru, H. (1958) Yakugaku Zasshi 78 (63) 1198 through Lowenthal and
Burruss, 1971). Later it was proposed that disintegration is caused by the water
absorption and swelling of the disintegrant (Ingram and Lowenthal, 1966). Nogami et
al. (1966) concluded that immersional wetting may be the controlling factor in tablet

disintegration. Wetting depends on many factors, such as the disintegrant and the
binder used, moisture content and particle size of compressed powder and the
compression conditions. The pores of the tablets were considered widely as a
disintegrating factor, but the tablets compressed to maximum density having a good
disintegration created question about the necessity of pores for tablet disintegration
(Lowenthal and Burruss, 1971). Whatever the mechanism is; swelling, capillary action,
heat of wetting or disintegrating particle/particle-forces, water uptake is always the
first step (Bolhuis et al., 1982; Ferrari et al., 1996; van Kamp et al., 1986c)
Nowadays there is two main mechanism proposed for disintegration (figure 1).
Disintegration takes place by the annihilation of the interparticle bonding (passive
mechanism) and by the development of separating stress due to swelling of
disintegrant by the fluid permeating into the tablet (active mechanism). (Caramella et
al., 1986; Ferrari et al., 1996; Gissinger and Stamm, 1980).

Figure 1. The most common explanations for the swelling of tablet in contact with
disintegrating fluid. (Guyot-Hermann and Ringard, 1981;Guyot-Hermann, 1992)

1.1. Water uptake

In tablets there usually exist three different kinds of bonds: solid bridges, mechanical
interlocking and intermolecular forces. The last one is believed to be the dominating
bonding mechanism. When the liquid with a suitable dielectric constant replaces the
air between the tablet particles, intermolecular bonds weaken and annihilate. The
liquid must penetrate into the tablet in order to produce bond weakening (Ferrari et al.,
1996).
The penetration of a liquid into a porous structure depends on the balance between
capillary and viscous forces. The liquid volume uptake with respect to time is
expressed by the Washburn equation:

V2 =

2m cos
k o

(1)

where m is the hydraulic pore radius, is the surface tension of the penetrating liquid,
is the contact angle between liquid and the pore wall, ko is a constant depending on
the pore shape and is the liquid viscosity. The liquid penetration is also dependent on
other things, such as the choice of ingredients and their hydrophilicity and tabletting
conditions (Guyot-Hermann, 1992; van Kamp et al., 1986a; Nogami et al., 1966).
There are some limitations in using the Washburn equation and the numerical values
are only suggestive, but the parameters are well accepted to those that govern the water
uptake into the tablets (Faroongsarng and Peck, 1994; Guyot-Hermann, 1992).
Some disintegrants have the ability to enhance the liquid uptake by drawing liquid into
the porous network of tablet. In these tablets the pore structure has an important role
and any hydrophobicity of tablet ingredients will affect it unfavourably. It is thus
important for these kinds of disintegrants to maintain the porous structure and have a
low interfacial tension toward aqueous fluids (Banker and Rhodes, 1996). Disintegrant
helps disintegration by creating a hydrophilic network around the drug particles.
disintegrant helps disintegration (Guyot-Hermann and Ringard, 1981).

1.2. Swelling of disintegrant

Perhaps the most widely accepted general mechanism of action for tablet disintegrants
is swelling. Almost all disintegrants swell to some extent (Banker and Rhodes, 1996;
Guyot-Hermann, 1992). There seems to be a correlation between the disintegration
time and porosity of the tablet. Tablets with low packing fraction have high porosity,
so the disintegrant has sufficient space to swell inside the tablets and no swelling force
is developed. Then the disintegration is slow. At higher packing fractions there is not
enough space to adjust the swollen disintegrant particles, so tablets disintegrate more
rapidly (figure 2). If the packing fraction is very high, fluid is unable to penetrate the
tablet well and the disintegration is again slow (Botzolakis and Augsburger, 1988;
Ferrari et al., 1995; Guyot-Hermann, 1992; Lowenthal, 1972; Kurup and Pilpel, 1977;
Mattsson et al., 2001).

Figure 2. Disintegration as a function of pore diameter and swollen disintegrant

particle diameter. (Guyot-Hermann, 1992)
3

2. Disintegrants
Disintegrants are added to tablets in order to enhance the disintegration. The purpose
of disintegrants is to counteract the action of tablet binder and the compression force
used (Visavarungroj and Remon, 1990). Two main mechanisms of action of
disintegrants are swelling in contact with disintegrating fluid and increase in the
capillary forces by a rapid uptake of aqueous fluid (Lpes-Sols and VillafuerteRobles, 2001). Faroongsarng and Peck (1994) showed that the hydrophilic nature of
excipients, like disintegrants, played a big role in water uptake into the tablet. Already
Httenrauch and Keiner (1973) determined good disintegrants as strongly hydrophilic,
water insoluble and only slightly gel-forming.

2.1. Hydrophilic disintegrants

High hydrophilicity is important for a fast liquid uptake into the tablet (GuyotHermann, 1992). Ingram and Lowenthal (1966) stated that water absorption is a
qualitative measure of many disintegrants, but it does not give any quantitative
information of their effectiveness. However, Khan and Rhodes (1975) came into a
conclusion that disintegrants with the highest water uptake are generally the most
effective in tablet systems.
Starch was the first tablet disintegrant used, but when the demand for faster
disintegration and drug dissolution increased, more active agents were searched. At
first, native starches were modificated. The swelling properties were improved by
carboxymethylation, and the integrity of the starch grains was kept by a cross-linkage.
The main products of this group are Primojel and Explotab. They have a high
swelling capacity so they are very effective even at low concentrations. (Bolhuis et al.,
1984; Gebre-Mariam et al., 1996; Guyot-Hermann, 1992).
Crospovidone is a cross-linked polyvinylpyrrollidone (PVP), which is insoluble but
high hydrophilic due to its high molecular weight and cross-linked structure. It does
not swell significantly, but it is a very good disintegrant also at low consentration
(Guyot-Hermann, 1992).
Cellulose and derivates are derived by various physicochemical manipulations from
the pulp of woody plants. Carboxymethylated cellulose sodium (Carmellose sodium) is
soluble in water and because of the fibrillar structure highly hydrophilic (GuyotHermann, 1992; Wan and Prasad, 1989).
Sodium substitution causes higher hydrophilicity on the material. Cross-linked sodium
carboxy methylcellulose, Ac-Di-Sol, is nearly insoluble due to its cross-linkage. Its
high hydrophilicity results in fast fluid uptake into the tablet structure (GuyotHermann, 1992). It rapidly swells to 4-8 times its original volume in contact with fluid
and its fibrous nature allows intraparticulate and extraparticulate wicking of water
even at low concentration levels (Sunada and Bi, 2002). Because of their high
effectiveness carboxymethyl starches, Ac-Di-Sol and cross-linked PVP are listed as
superdisintegrants (Ferrero et al., 1997; Gebre-Mariam et al., 1996; Guyot-Hermann,
1992).

2.2. Insoluble disintegrants

If the solubility of disintegrant is high, also the viscosity of the penetrating fluid
increases. This slows down fluid uptake and consequently disintegration. Insolubility
of disintegrants may be increased by three methods. Cross-linkage is the most effective
one (Primojel, Explotab, Ac-Di-Sol). Other methods are salting the material by
an insolubilizing cation and increasing the degree of polymerization (Ac-Di-Sol)
(Guyot-Hermann, 1992).

3. Other factors
3.1. Effect of diluents
The solubility of diluents in tablets affects both the rate and mechanism of tablet
disintegration. Water soluble fillers tend to dissolve rather than disintegrate, while
insoluble diluents produce rapid disintegration. Investigations show that
superdisintegrants have a greater effect on disintegration time in an insoluble system
than in a soluble or partially soluble system. With soluble compounds the viscosity of
penetrating fluid increases and pores of tablet widen rapidly. This reduces the
effectiveness of strongly swelling disintegrant agents (Chebli and Cartilier, 1998;
Mattsson et al., 2001, Roche-Johnson et al., 1991). The soluble excipients will also
compete for the locally available water thus inhibiting the action of disintegrant
(Gordon and Chowhan, 1987; Lpes-Sols and Villafuerte-Robles, 2001).
Lactose is a common tablet diluent, which exists in various grades differing in
crystallinity and hydration and consequently in solubility. Contradicting results have
been reported about the effect of lactose on the disintegration of tablets when used as a
major component. Ferrari et al. (1995) considered it to hinder the development of
disintegration force and to tend to dissolve rather than disintegrate, while insoluble
materials produce rapidly disintegrating tablets with an adequate amount of
disintegrant. The similar conclusions were made by Chebli and Cartilier (1998) and
Mattsson et al. (2001). They, however, stated that soluble -lactose monohydrate and
crystalline -lactose act as passive disintegrants because of hydrogen bond
annihilation. Anhydrous -lactose has no ability to disintegrate at all in contact with
disintegrating fluid. The reason may be its transformation from anhydrous to
monohydrate form and reduction of the pore diameter during the penetration process
(van Kamp et al., 1986b). On the contrary, in older studies tabletted anhydrous lactose
showed relatively fast disintegration (Batuyios, 1966; Bolhuis and Lerk, 1973). Chebli
and Cartilier (1998) observed that tablets made by spray-dried lactose disintegrate
more slowly than the tablets made by crystalline lactose monohydrate. Spray-dried
lactose is very soluble owing to its amorphicity and has no solid planes on which the
swelling force of the disintegrant can be exerted. This slows down the disintegration.

3.2. Effect of binders

Besides the demand for fast disintegration, it is desirable that the tablets have adequate
tensile strength. Normally this is adjusted by adding binder to the tablet formulation.
The bond promoting properties of binder may, however, counteract rapid
disintegration (Mattsson et al., 2001). Binders can have a significant effect on
disintegration. If the binder concentration is high enough, delayed drug release is
obtained (Lowenthal, 1972).

3.3. Effect of surfactants

During the disintegration process, the first step is always taken through the interaction
between tablet and liquid. The wettability of solid may be influenced by many factors
as contact angle and surface tension (Nogami et al., 1966). Surfactants may be
included in tablet formulation to increase the wetting of the powder mass and enhance
drug dissolution (Banker and Rhodes, 1996).
The effect of surfactants on tablet disintegration has been reported to decrease or to
increase the disintegration time (Lowenthal, 1972). It was also stated that surfactants
decrease disintegration time only if both contact angle and surface tension are
decreased. The effect of surfactant is noticeable if the contact angle before adding is
greater than 90 degrees. According to Lowenthal and Burruss (1971) this may help to
explain the contradicting results regarding to the effect of surfactant on tablet
disintegration.

3.4. Effect of lubricants

Lubricating agents are added to tablets to prevent sticking of the powder mass or the
finished tablets to the machinery. Most lubricants, especially the most effective ones,
are very hydrophobic and act by particle coating (Banker and Rhodes, 1996).
Lubricant particles are generally smaller than other particles in the mixture. When the
mixture is mixed, lubricant particles may adhere to the surface of the other particles.
Formed hydrophobic coating inhibits the wetting and consequently tablet
disintegration. A common lubricant magnesium stearate may cleave as a result of a
stress during mixing. A lot of smaller particles develops from primary particles and
they coat the other particles more completely strongly hindering water penetration
(Guyot-Hermann, 1992).
Lubricant has a strong negative effect on the water uptake if tablet contains no
disintegrant or even a lot of slightly swelling disintegrants. On the contrary, the
disintegration time is hardly affected if there is some strongly swelling disintegrant in
the tablet (Bolhuis et al., 1982).

3.5. Effect of disintegrating fluid

It has been noted that superdisintegrants can behave differently in acidic and neutral
dissolution media (Gordon et al., 1993). Botzolakis and Augsburger (1988) reported
that when fluid is changed from acidic to water, the liquid uptake and efficiency of
superdisintegrants is altered. Vadas et al. (1984) used Ac-Di-Sol as disintegrant in
spray-dried lactose tablets and showed that the disintegrant was least effective at pH
1.5 and almost equally efficient at pH 6.0 and 7.5. Also Visavarungroj and Remon
(1990) reported that superdisintegrants tended to promote faster dissolution in a
neutral fluid than in an acidic fluid.

III Experimental part

4. Materials
The diluents used were sorbitol (Merck, Darmstad, Germany), dibasic calcium
phosphate dihydrate (Emcompress, FMC Intern, Cork, Ireland), -lactose
monohydrate (Pharmatose 90M), anhydrous -lactose (Pharmatose DCL 21), and
spray dried -lactose monohydrate (Pharmatose DCL 11). All lactoses were
manufactured by FMC Intern. The diluents were sieved to a size fraction of 300-106
m and mixed with four different kind of superdisintegrants, sodium starch glycolate
(Primojel), croscarmellose sodium (Ac-Di-Sol), carboxymethylcellulose sodium
(Carmellose sodium) and cross-linked polyvinylpyrrolidone (Crospovidone) after
sieving them to a fraction of < 75m. Magnesium stearate (1% w/w) silicon dioxide
(0,5% w/w) were used as lubricating and flow agents.
All the powdered materials were dried at 40 C for 24 hours and then stored at room
temperature at 52% relative humidity in desiccator containing salt solution of
Mg(NO3 )2 . After drying bulk and true densities and particle size were measured.

5. Methods
5.1. Characterisation of materials
5.1.1. Micromeritic properties
The bulk density (b) was measured in a 50 ml cylinder and true density was
determined with an air comparison pycnometer (Beckmann, Model 930, catalogue
number 93001). Particle size was measured by using an image processing and analysis
system (Quantimed 500, Leica, Cambridge, UK). At least 200 particles were analysed
under different magnifications in paraffin oil.

5.1.2. Thermal analysis

The purpose with thermal analysis was to have an idea of heat of solution of all the
powders used. In a thermostated bath there were two vessels, another one for the
examined powder and another for the deionised water, which was used to solute the
powders. In the vessel with the powder there was a sensor connected to computer.
When the water was added on the powder, the changes in the temperature due to
solution of the materials were recorded using Labview (version 6.0, National
Instruments, USA). Thermal analyses were made at 37 C temperature.
5.1.3. Microcalorimetry
Calorimetry is a suitable technique for the study of all the solid liquid interactions
and for the quantitative evaluation of water affinity from the heat of immersion. That is
why it seemed reasonable to compare the disintegration of tablets containing diluents
of different solubility and heat of solution in presence of disintegrants of different heat
of immersion applying calorimetry. The heat of solution was measured using a
Setaram C80 Calvet-type micro calorimeter, operating isothermally in the range of 0300 C.

5.2. Preparation of mixtures

Diluents were mixed with superdisintegrants in the proportions of 98/2%, 96.5/3.5%
and 95/5% in order to produce 3 mixtures between every diluent and superdisintegrant.
Excipients including also magnesium stearate and silicon dioxide were mixed for 20
minutes in a Turbula mixer (Type 2TC, Willy A. Bachofen AG Maschinenfabrik,
Basel, Switzerland). True densities of the mixtures were defined before tabletting.

5.3. Preparation of tablets

Mixtures were compressed on a single-punch tablet machine (Kilian, type KIS, KlnNiehl, Germany) equipped with a 10 mm diameter die and flat-faced punches. The
setting of punches was varied corresponding to a 2.5 mm distance at closest position in
order to change weight of the tablets to attain three different levels of packing fractions
for all the powder mixtures tabletted.

5.4. Characterisation of tablets

5.4.1. Disintegration
The disintegration time of the tablets was measured in three different media, deionised
water (pH 6.5) and simulated gastric (pH 1.2) and intestinal fluid (pH 7.4).
Measurements were made using the USP XXIII disintegration test apparatus (Erweka
ZT 3U, Erweka Apparatebau, GmbH, Heusenstamm, Germany) without discs.
Simulated gastric fluid (without pepsin) and simulated intestinal fluid (without
pancreatin) were prepared according to USPXXI. The tablets were considered
completely disintegrated, when all the particles had passed through the mesh.

5.4.2. Mechanical strength

The diametrical breaking strength and deformation of the tablets were measured by
placing them on the edge and compressing them between the two platens of a tensile
tester (CT5, Engineering System, Nottingham, England). The rate of the upper platen
movement was 1.5 mm/sec. The force applied to each tablet and the corresponding
relative displacement of the platens due to tablet deformation was monitored
continually. From the collected data were calculated several parameters, which were
the area under the load-displacement curve, the normalized work of failure, the
toughness area-ratio, tensile strength and the apparent tablet failure viscosity
(Malamataris and Rees, 1993).

IV Results and discussion

6.1. Characterisation of materials
In table 1. some physicomechanical properties of diluents and disintegrants are
summarized. It can be seen that the particle size of disintegrants is much smaller than
the particle size of diluents. This makes it possible for disintegrants to set up a
continuous hydrophilic network around the diluent particles (Guyot-Hermann, 1982).
The heat of solution of diluents exhibited an exothermic response, while the heat of
solution of disintegrants was endothermic. However, the net measured response for the
entalphy of solution is a summation of numerous component parts. That is why the
single number for the entalphy of solution must be considered with some caution
(Hogan and Buckton, 2000).

Table 1. Physicomechanical properties of diluents and disintegrants

Material
Diameter
Moisture
Bulk
True
content
density
density
(m)
3
(%w/w)
mean sd
(g/cm )
(g/cm 3 )
115.8 59.1
Sorbitol
0.57 (0.572) 1.49 (1.492)
-lactose
0.75 (0.762) 1.54 (1.542)
monohydrate 137.0 64.8
-lactose
111.5 40.5
0.60 (0.612) 1.54
spray-dried
-lactose
63.7 16.4
0.66 (0.672) 1.58 (1.582)
anhydrous
Emcompress 142.8 45.3
0.78 (0.862) 2.35
51.8 12.7
0.44 (0.482) 1.6
Ac-Di-Sol
62.2 21.5
Carm Na
0.46 (0.481) 1.6
Crospovidone 44.7 6.7
0.33 (0.241) 1.26
37.2 10.6
Primojel
0.73 (0.761) 1.55
1Rudnic et al. (1982)
2Handbook of pharmaceutical excipients (1984)

Heat of
solution
(J/g) in 37C
-111.8 0.01
-57.3 0.05
-54.0 0.07
-20.5 0.36
7.7 0.42
11.7 0.74
45.8 0.04
3.1 0.87

6.2. Disintegration
The purpose was to investigate, if the properties of the diluent and temperature and pH
of disintegrating fluid have impact on the efficiency of disintegrant. In figure 3. Ac-DiSol is combined with different grades of lactose. Temperature is constant but
disintegrating fluid varies. It can be seen that tablets made of anhydrous -lactose
disintegrated very slowly. In fact they rather dissolved than disintegrated, due to high
initial solubility of anhydrous -lactose (van Kamp et al. 1986b). Porosity level had a
great influence on the disintegration behaviour of tablets containing anhydrous lactose. If the porosity was high, disintegration was rather fast, but with decreasing
porosity level the disintegration time increased considerably and with very low
porosities tablets dissolved completely instead of disintegrating.
Tablets made of -lactose monohydrate disintegrated fast regardless of porosity level.
From the lactoses used, -lactose monohydrate had the lowest initial solubility (van
Kamp et al. 1986b) and because of that the disintegrant acts effectively in tablets.
Tablets containing spray-dried lactose disintegrated almost as fast as -lactose
monohydrate tablets. Disintegration was slower only at higher packing fractions where
porosity level is quite low. Spray-dried lactose contains approximately 15%
amorphous lactose and 85% -lactose monohydrate. When the amorphous substance
comes in contact with water, the outer layer of the tablet dissolves and forms a viscous
gel. This inhibits fluid to get inside the tablet and also slows down the disintegration
(Vromans et al. 1987).
As can be seen from all the graphs in figure 3, pH of the fluid does not have a
significant effect on disintegration. Plots in figures 4, 5 and 6 show that the
disintegration profiles does not change much although the pH of disintegrating fluid is
changed.

500

Lactose monohydrate /
water

Disintegration time (sec)

450

Lactose monohydrate /
pH 1.2

400
350

Lactose monohydrate /
pH 7.4

300
250

Lactose spray-dried /
water

200

Lactose spray-dried / pH
1.2

150

Lactose spray-dried / pH
7.4

100

Lactose anhydrous /
water

50
0
0.94

0.87

0.8

Packing fraction of tablets

Lactose anhydrous / pH
1.2
Lactose anhydrous / pH
7.4

Figure 3. Disintegration times of different lactose (98%) tablets in temperature of

37C. Ac-Di-Sol (2%) used as disintegrant.

10

( s e c )

Lactose monohydrate + Ac-Di-Sol in pH 1,2

Lactose monohydrate + Ac-Di-Sol in pH 7,4

20

(sec)
time

40
98

20

0.92

96

0.90
0.88
0.86

Pack
ing fr
action

0.84

95

0
0.92

0.88
0.86

Pack
ing fr
actio
n

0.84

95

40
30
98

20

97

10
0

96

0.90

50

Co
nc
en
tra
tio
n

Co
nc
en
tra
tio
n

97

60

97
0.92

96

0.90
0.88
0.86

Pack
ing fr
action

0.84

95

Figures 4, 5 and 6. Disintegration profiles of -lactose monohydrate tablets with AcDi-Sol as disintegrant. pH of disintegrating fluid varies.

The effect of temperature of disintegrating fluid is quite clear (figures 7 and 8). Highly
soluble and insoluble diluent are compared. Emcompress tablets disintegrate very fast
while tablets containing anhydrous -lactose disintegrate slowly. The difference in
disintegration times is more significant when a strongly swelling disintegrant is used
(figure 7). When the main mechanism of disintegrant is not swelling, the solubility of
diluent does not have that great impact on disintegration (figure 8).

Disintegration time (sec)

700
600
Emcompress 27

500

Emcompress 37

400

(%
)

of
dil
ue
nt

98

(%
)

40

60

of
dil
ue
nt

60

70

Emcompress 47

300

Lactose anhydrous 27

200

Lactose anhydrous 47

Co
nc
en
tra
tio
n

on

80

80

80

on

100

Disintegrati

time

100

Disintegrati

r a t i o n
D i s i n t e g

120

of
dil
ue
nt
(%
)

(sec)

t i m e

Lactose monohydrate + Ac-Di-Sol in water

Lactose anhydrous 37

100
0
0.94
0.86
0.75
Packing fraction of tablets

Figure 7. Disintegration times of tablets made from two different diluent (98%) and
strongly swelling Ac-Di-Sol (2%) as disintegrant. Disintegration times are determined
in three different temperatures, 27C, 37C and 47C.

11

Disintegration time (sec)

1000
900
800
700
600
500
400
300
200
100
0

Emcompress 27
Emcompress 37
Emcompress 47
Lactose anhydrous 27
Lactose anhydrous 37
Lactose anhydrous 47

0.92
0.85
0.74
Packing fraction of tablets
Figure 8. Disintegration times of tablets made from two different diluent (98%) and
slightly swelling Crospovidone (2%) as disintegrant. Disintegration times are
determined in three different temperatures, 27C, 37C and 47C.

6.3. Mechanical strength

The results of tablet hardness measurement still need some more work, so they are not
presented in this summary. It can be said, however, that tensile strength increased with
the decrease in particle size of diluents and with the decrease in tablet porosity.

V Conclusions
Results showed that the choice of tablet excipients can have a great influence in
disintegration time. As the dissolution of drug is dependent on the disintegration rate
of tablet, it is thus important to pay attention to diluent and disintegrant used in order
to achieve the desired availability for the drug. When choosing the excipients to tablet
formulation also the mechanical strength properties should be considered besides the
disintegration properties.

12

References
Banker, G.S. and Rhodes, C.T. (1996): Modern pharmaceutics. 3rd ed. Marcel Dekker, New
York. pp. 42, 135-136, 348-354, 426-427, 385.
Batuyios, N.H. (1966): Anhydrous lactose in direct tablet compression. J. Pharm. Sci. 55 (7),
727-730.
Bolhuis, G.K. and Lerk, C.F. (1973): Comparative evaluation of excipients for direct
compression, I. Pharm. Weekblad, 108, 469-481.
Bolhuis, G.K., van Kamp, H.V., Lerk, C.F. and Sessink, F.G.M. (1982): On the mechanism of
action of modern disintegrant. Acta Pharm. Tech. 28 (2), 111-114.
Bolhuis, G.K., van Kamp, H.V., Lerk, C.F., Gielen, J.W., Arends, A.W. and Stuut, G.J.
(1984): Effect of variation of degree of substitution, crosslinking and purity on the
disintegration efficiency of sodium starch glycolate. Acta Pharm. Tech. 30 (1), 24-32.
Bolhuis, G.K., Zuurman, K. and te Wierik, G.H.P. (1997): Improvement of dissolution of
poorly soluble drugs by solid deposition on a super disintegrant. II. The choice of super
disintegrants and effect of granulation. Eur. J. Pharm. Sci. 5, 63-69.
Botzolakis, J.E. and Augsburger, L.L. (1988): Disintegrating agents in hard gelatin capsules.
Part II: Swelling efficiency. Drug Dev. Ind. Pharm. 14 (9), 1235-1248.
Caramella, C., Colombo, P., Conte, U., Ferrari, F., and la Manna, A. (1986) Water uptake and
disintegration force measurements: Towards a general understanding of disintegration
mechanism. Drug Dev. Ind. Pharm. 12 (11-13), 1749-1766.
Chebli, C. and Cartilier, L. (1998): Croos-linked cellulose as a tablet excipient: A binding /
disintegrating agent. Int. J. Pharm. 171, 101-110.
Faroongsarng, D. and Peck, G.E. (1994): The role of liquid water uptake by an insoluble tablet
containing a disintegrant. Drug Dev. Ind. Pharm. 20 (10), 1777-1794.
Ferrari, F., Bertoni, M., Bonferoni, M.C., Rossi, S., Gazzaniga, A., Conte, U. and Caramella,
C. (1995): Influence of porosity and formula solubility on disintegrant efficiency in tablets.
S.T.P. Pharma Sci. 5 (2), 116-121.
Ferrari, F., Bertoni, M., Bonferoni, M.C., Rossi, S., Caramella, C. and Nystrm, C. (1996):
Investigation on bonding and disintegration properties of pharmaceutical materials. Int. J.
Pharm. 136, 71-79.
Ferrero, C., Muos, N., Velasco, M.V., Muos-Ruiz, A. and Jimnes-Castellanos, R. (1997):
Disintegrating efficiency of croscarmellose sodium in a direct compression formulation. Int. J.
Pharm. 147, 11-21.
Gebre-Mariam, T., Winnemller, M. and Schmidt, P.C. (1996): An evaluation of the
disintegration efficiency of a sodium starch glycolate prepared from enset starch in
compressed tablets. Eur. J. Pharm. Biopharm. 43 (2), 124-132.
Gissinger, D. and Stamm, A. (1980): A comparative evaluation of the properties of some tablet
disintegrants. Drug Dev. Ind. Pharm. 6 (5), 511-536.

Gordon, M.S. and Chowhan, Z.T. (1987): Effect of tablet solubility and hygroscopicity on
disintegrant efficiency in direct compression tablets in terms of dissolution. J. Pharm. Sci. 76
(12), 907-909.
Gordon, M.S., Rudraraju, V.S., Dani, K.D. and Chowhan, Z.T. (1993): Effect of the mode of
super disintegrant incorporation on dissolution in wet granulated tablets. J. Pharm. Sci. 82 (2),
220-226.
Guyot-Hermann, A.M. and Ringard, J. (1981): Disintegration mechanisms of tablets
containing starches. Hypothesis about the particle-particle repulsive force. Drug Dev. Ind.
Pharm. 7 (2), 155-177.
Guyot-Hermann, A.M. (1992): Tablet disintegration and disintegrant agents. S.T.P. Pharma
Sci. 2 (6), 445-462.
Hogan, S.E. and Buckton, G. (2000): The quantification of small degrees of disorder in lactose
using solution calorimetry. Int. J. Pharm. 207, 57-64.
Httenrauch, R. and Keiner, I. (1973): Neues hochwirksames Sprengmittel fr Komprimate.
Pharmazie 28, H.2, 137.
Ingram, J.T. and Lowenthal, W. (1996): Mechanism of action of starch as a tablet disintegrant
I. Factors that affect the swelling of starch grains at 37 . J. Pharm. Sci. 55 (6), 614-617.
van Kamp, H.V., Bolhuis, G.K., de Boer, A.H., Lerk, C.F. and Lie-A-Huen, L. (1986a): The
role of water uptake on tablet disintegration. Pharm. Acta Helv. 61 (1), 22-29.
van Kamp, H.V., Bolhuis, G.K., Kussendrager, K.D. and Lerk, C.F. (1986b): Studies on
tableting properties of lactose. IV. Dissolution and disintegration properties of different types
of lactose. Int. J. Pharm. 28, 229-238.
van Kamp, H.V., Bolhuis, G.K. and Lerk, C.F. (1986c): Studies on tableting properties of
lactose. V. Effects of both lubrication and addition of disintegrants on properties of tablets
prepared from different types of crystalline lactose. Acta Pharm. Suec. 23 (4), 217-30.
Khan, K.A. and Rhodes, C.T. (1975): Disintegration properties of calcium phosphate dibasic
dihydrate tablets. J. Pharm. Sci. 64 (1), 166-168.
Kitamori, N. and Shimamoto, T. (1976): Influence of tablet dimensions on the disintegration
time. Chem. Pharm. Bull. 24 (8), 1789-1794.
Kurup, T.R.R. and Pilpel, N. (1977): The tensile strength and disintegration of griseofulvin
tablets. Powder Technol. 16, 179-188.
Lpes-Sols, J. and Villafuerte-Robles, L. (2001): Effect of disintegrants with different
hygroscopity on dissolution of Norfloxacin/Pharmatose DCL 11 tablets. Int. J. Pharm. 216,
127-135.
Lowenthal, W. and Burruss, R. A. (1971): Mechanism of action of starch as a tablet
disintegrant IV: effect of medicaments and disintegrants on mean pore diameter and porosity.
J. Pharm. Sci. 60 (9), 1325-1332.
Lowenthal, W. (1972): Disintegration of tablets. J. Pharm. Sci. 61 (11), 1695-1711.

Malamataris, S. and Rees, J.E. (1993): Viscoelastic properties of some pharmaceutical

powders compared using creep compliance, extended Heckel analysis and tablet strength
measurements. Int. J. Pharm. 92, 123-135.
Mattsson, S., Bredenberg, S. and Nystrm, C. (2001): Formulation of high tensile strength
rapidly disintegrating tablets. Evaluation of the effect of some binder properties. S.T.P. Pharma
Sci. 11 (3), 211-220.
Nogami, H., Nagai, T. and Ushida, H. (1966): Studies on powdered preparations. XIV.
Wetting of powder bed and disintegration time of tablet. Chem. Pharm. Bull. 14 (2), 152-158.
Roche-Johnson, J., Wang, L-H, Gordon, M.S. and Chowhan, Z.T. (1991): Effect of
formulation solubility and hygroscopicity on disintegrant efficiency in tablets prepared by wet
granulation, in terms of dissolution. J. Pharm. Sci. 80 (5), 469-471.
Rudnic, E.M., Rhodes, C.T., Welch, S. and Bernardo, P. (1982): Evaluations of the mechanism
of disintegrant action. Drug Dev. Ind. Pharm. 8 (1), 87-109.
Sunada, H. and Bi, Y. (2002): Preparation, evaluation and optimization of rapidly
disintegrating tablets. Powder Technol. 122, 188-198.
USP XXV: <701> Disintegration, p.2010. United States Pharmacopeial Convention inc. 2001.
Vadas, E.B., Down, G.R.B. and Miller, R.A. (1984): Effect of compressional force on tablets
containing cellulosic disintegrators I: Dimensionless disintegration values. J. Pharm. Sci. 73
(6), 781-783.
Visavarungroj, N. and Remon, J.P. (1990): Crosslinked starch as a disintegrating agent. Int. J.
Pharm. 62, 125-131.
Vromans, H., Bolhuis, G.K., Lerk, C.F., Kussendrager, K.D. and Bosch, H. (1986): Studies on
tableting properties of lactose. VI. Consolidation and compaction of spray dried amorphous
lactose. Acta Pharm. Suec. 23 (4), 231-40.
Vromans, H., Bolhuis, G.K., Lerk, C.F. and Kussendrager, K.D. (1987): Studies on tableting
properties of lactose. VIII. The effect of variations in primary particle size, percentage of
amorphous lactose and addition of a disintegrant on the disintegration of spray-dried lactose
tablets. Int. J. Pharm. 39, 201-206.
Wale, A. and Weller, P.J. (1984): Handbook of pharmaceutical excipients, 2nd ed., American
Pharmaceutical association, Washington D.C. and the Pharmaceutical Society of Great Britain,
London. p.56-60, 78-81, 141-144, 252-261, 462-466, 477-480.
Wan, L.S.C. and Prasad, K.P.P. (1989): Uptake of water into tablets with low-substitued
carboxymethyl cellulose sodium as disintegrant. Int. J. Pharm. 55, 115-121.