At first we have to know about disintegrate.......
WHAT ARE DISINTEGRATES?
Disintegrates are agents
added to tablet (and some encapsulated) formulations to promote the breakup of
the tablet (and capsule “slugs’) into smaller fragments in an aqueous
environment thereby increasing the available surface area and promoting a more
rapid release of the drug substance.
There are three major mechanisms and factors affecting
tablet disintegration as follows:
A: Swelling:
Although not all effective disintegrates swell in contact with water, swelling is believed to be a mechanism in which certain disintegrating agents (such as starch) impart the
disintegrating effect. By swelling in contact with water, the adhesiveness of
other ingredients in a tablet is overcome causing the tablet to fall apart.
B: Porosity and Capillary Action:
Effective disintegrates that
do not swell are believed to impart their disintegrating action through porosity and capillary action. Tablet porosity provides pathways for the
penetration of fluid into tablets. The disintegrate particles (with low
cohesiveness & compressibility) themselves act to enhance porosity and
provide these pathways into the tablet. Liquid is drawn up or “wicked” into
these pathways through capillary action and rupture the inter-particulate bonds
causing the tablet to break apart.
C: Deformation:
Starch grains are generally
thought to be “elastic” in nature meaning that grains that are deformed under
pressure will return to their original shape when that pressure is removed.
But, with the compression forces involved in tableting, these grains are
believed to be deformed more permanently and are said to be “energy rich” with
this energy being released upon exposure to water. In other words, the ability
for starch to swell is higher in “energy rich” starch grains than it is for
starch grains that have not been deformed under pressure.
It
is believed that no single mechanism is responsible for the action of most disintegrates. But rather, it is more likely the result of inter-relationships
between these major mechanisms.
The
classical example of the earliest known disintegrant is Starch. Corn Starch or
Potato Starch was recognized as being the ingredient in tablet formulations
responsible for disintegration as early as 1906 (even though tablet
disintegration was itself not given much importance in tablet formulations
until much later).
Until fairly recently, starch
was the only excipient used as a disintegrant. To be effective, corn starch has
to be used in concentrations of between 5-10%. Below 5%, there is insufficient
“channels” available for wicking (and subsequent swelling) to take place. Above
10%, the incompressibility of starch makes it difficult to compress tablets of
sufficient hardness.
Although
the connection between bio-availability of drug and tablet disintegration took
some time to become appreciated, it is now accepted that the role of the disintegrate is extremely important.
Other factors which
affect the dissolution of Drugs from tablets are:
- Type and Concentration of Active Ingredient
- Type and Concentration of Binder Used
- Type and Concentration of Fillers Used
(soluble vs. insoluble)
- Type and Concentration of Lubricant Used
- Type of Dissolution testing Used (Apparatus,
Speed, Media)
- Manufacturing Process (wet granulation vs.
compaction vs. direct compression)
In
a direct compression process, drug is blended with a variety of
excipients, subsequently lubricated and directly compressed into a tablet. A
disintegrant used in this type of formulation, simply has to break the tablet
apart to expose the drug substance for dissolution.
In
a wet granulation process, the drug substance is combined with other
excipients and processed with the use of a solvent (aqueous or organic) with
subsequent drying and milling to produce granules. The resulting granules are
then blended with additional excipients prior to being compressed into a
tablet. {Dry compaction is similar. But compression and milling are used
(rather than solvents) to make the granules}
A disintegrant used in
granulated formulation processes can be more effective if used both
“intragranularly” and “extragranularly” thereby acting to break the tablet up
into granules and having the granules further disintegrate to release the drug
substance into solution. However, the portion of disintegrant added
intragranularly (in wet granulation processes) is usually not as
effective as that added extragranularly due to the fact that it is exposed to
wetting and drying (as part of the granulation process) which reduces the
activity of the disintegrant. Since a compaction process does not involve
its exposure to wetting and drying, the disintegrant used intragranularly tends
to retain good disintegration activity.
The
following are some of the disintegrates which were available prior to the use
of the formulation.....
Pregelatinized Starch (Starch 1500)
[[[
Pregelatinized starch is a directly
compressible form of starch consisting of intact and partially hydrolyzed
ruptured starch grains. Pregelatinized starch has multiple uses in formulations
as a binder, filler and disintegrate. As a disintegrate, its effective
use concentration is between 5-10%. It’s major mechanism of action as a disintegrate is thought to be through swelling.
Micro-crystalline Cellulose (Avicel)
Like
pregelatinized starch, micro-crystalline cellulose is widely used in
formulations because of its excellent flow and binding properties. It is also
an effective tablet disintegrant when used in a concentration of between
10-20%.
Others
Sodium Bicarbonate in combination with citric or tartaric acids is used
as an “effervescent” disintegrant.
Alginic Acid at a concentration of between 5-10% is an effective,
but very expensive disintegrant.
Ion Exchange Resins (Amber-lite 88) has disintegrant properties at a
concentration of between 1-5%. But this type of disintegrant is rarely used.
SUPER DISINTEGRANTS:
Because of the increased
demands for faster dissolution requirements, there are now available, a new
generation of “Super Disintegrates”
Three
major groups of compounds have been developed which swell to many times their
original size when placed in water while producing minimal viscosity effects:
1. Modified Starches- Sodium Carboxymethyl Starch (Chemically treated Potato Starch)
i.e. Sodium Starch Glycolate
(Explotab, Primogel)
Mechanism
of Action: Rapid and extensive swelling with minimal gelling.
Effective
Concentration: 4-6%. Above 8%, disintegration times may actually increase due
to gelling and its subsequent viscosity producing effects.
2. Cross-linked polyvinylpyrrolidone- water insoluble and
strongly hydrophilic.
i.e. crospovidone
(Polyplasdone XL, Kollidon CL)
Mechanism
of Action: Water wicking, swelling and possibly some deformation recovery.
Effective Concentration:
2-4%
3. Modified
Cellulose- Internally
cross-linked form of Sodium carboxymethyl cellulose.
i.e. Ac-Di-Sol
(Accelerates Dissolution), Nymcel
Mechanism of Action: Wicking due to fibrous
structure, swelling with minimal gelling.
Effective Concentrations: 1-3% (Direct
Compression), 2-4% (Wet Granulation)
ADVANTAGES:
- Effective in lower
concentrations than starch
- Less effect on
compressibility and flow ability
- More effective
intragranularly
DISADVANTAGES:
- More hygroscopic
(may be a problem with moisture sensitive drugs)
- Some are anionic and
may cause some slight in-vitro binding with cationic drugs (not a problem in-vivo.)
SUMMARY
OF DISINTEGRANTS:
- Disintegrants are an
essential component to tablet formulations. While rapidly disintegrating
tablets do not necessarily ensure fast bioavailability, slowly disintegrating
tablets almost always assure slow bioavailability.
- The ability to interact strongly with water
is essential to disintegrant function.
- Combinations of
swelling and/or wicking and/or deformation are the mechanisms of
disintegrant action.
- Super disintegrants
offer significant improvements over starch. But hygroscopicity may be a
problem in some formulations.
