Académique Documents
Professionnel Documents
Culture Documents
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)
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).
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.
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.
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.
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
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
Lactose anhydrous / pH
1.2
Lactose anhydrous / pH
7.4
10
( s e c )
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).
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 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
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.
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
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