1

1
 DISINTEGRANTS
• Disintegrating agents are substances routinely included in the tablet
formulations to aid in the break up of the compacted mass when it is
put into a fluid environment.
• They promote moisture penetration and dispersion of the tablet
matrix.
• Eg: starch, starch derivatives, clays, cellulose, cellulose derivatives, alginates ,
polyvinyl pyrrolidine ,cross linked

2
 SUPERDISINTEGRANTS

• In recent years, several newer agents have been developed known as

“Superdisintegrants”.
• These newer substances are more effective at lower concentrations
with greater disintegrating efficiency and mechanical strength.
• On contact with water the Superdisintegrants swell, hydrate, change
volume or form and produce a disruptive change in the tablet.
• Effective Superdisintegrants provide improved compressibility,
compatibility and have no negative impact on the mechanical strength
of formulations containing high-dose drugs.
• The Superdisintegrants include a particulate agglomerate of co
processed starch or cellulose and a sufficient amount of an augmenting
agent to increase the compatibility of the Superdisintegrants
• The augmented Superdisintegrants provides a fast disintegration of a
solid dosage form when incorporated in sufficient quantity therein,
without untowardly affecting the compatibility of the solid dosage
form (relative to the solid dosage form without the Superdisintegrants.

The commonly available Superdisintegrants along with their

commercial trade names are briefly described herewith.

V.M.H.P.S. College of Pharmacy

 2

MODIFIED STARCHES 2

 Sodium starch glycolate is the sodium salt of a carboxymethyl ether of

starch.
 It is effective at a concentration of 2-8%. It can take up more than 20
times its weight in water and the resulting high swelling capacity
combined with rapid uptake of water accounts for its high
disintegration rate and efficiency
 It is available in various grades i.e. Type A, B and C, which differ in
pH, viscosity and sodium content.
 Other special grades are available which are prepared with different
solvents and thus the product has a low moisture (<2%) and solvent
content (<1%), thereby being useful for improving the stability of
certain drugs.

MODIFIED CELLULOSES 2
CARBOXYMETHYLCELLULOSE AND ITS DERIVATIVE
(CROSCARMELLOSE SODIUM)

 Cross-linked sodium Carboxymethylcellulose is a white, free flowing

powder with high absorption capacity.
 It has a high swelling capacity and thus provides rapid disintegration
and drug dissolution at lower levels
 . It also has an outstanding water wicking capability and its cross-
linked chemical structure creates an insoluble hydrophilic, highly
absorbent material resulting in excellent swelling properties.
 Its recommended concentration is 0.5–2.0%, which can be used up to
5.0% L-HPC (Low substituted Hydroxyl propyl cellulose)

V.M.H.P.S. College of Pharmacy

 3

L-HPC(LOW SUBSTITUTED HYDROXY PROPYL

CELLULOSE)2

 It is insoluble in water, swells rapidly and is used in the range of 1-

5%. The grades LH- 11 and LH-21 exhibit the greatest degree of
swelling.

CROSS-LINKED POLYVINYLPYRROLIDONE 2

 It is a completely water insoluble polymer.

 It rapidly disperses and swells in water but does not gel even after
prolonged exposure
 . The rate of swelling is highest among all the Superdisintegrants and
is effective at 1-3%
 . It acts by wicking, swelling and possibly some deformation recovery.
 The polymer has a small particle size distribution that imparts a
smooth mouth feel to dissolve quickly.
 Varieties of grades are available commercially as per their particle size
in order to achieve a uniform dispersion for direct compression with
the formulation.

SOY POLYSACCHARIDE 2

 It is a natural super disintegrate that does not contain any starch or

sugar so can be used in nutritional products.

V.M.H.P.S. College of Pharmacy

 4
2
CROSS-LINKED ALGINIC ACID

 It is insoluble in water and disintegrates by swelling or wicking

action.
 It is a hydrophilic colloidal substance, which has high sorption
capacity
 It is also available as salts of sodium and potassium.

GELLAN GUM2

 It is an anionic polysaccharide of linear tetrasaccharides, derived from

Pseudomonas elodea having good Superdisintegrants
 It has the property similar to the modified starch and celluloses.

XANTHAN GUM2

 Xanthan Gum derived from Xanthomonas campestris

 It is official in USP with high hydrophilicity and low gelling tendency.
 It has low water solubility and extensive swelling properties for faster
disintegration.

CALCIUM SILICATE 2

 It is a highly porous, lightweight Superdisintegrants, which acts by

wicking action.
 Its optimum concentration range is 20-40%

V.M.H.P.S. College of Pharmacy

 5
2
ION EXCHANGE RESINS

 The INDION 414 has been used as a Superdisintegrants for ODT.

 It is chemically cross-linked polyacrylic, with a functional group of –
COO – and the standard ionic form is K+. It has a high water uptake
capacity.
 Indion 414 appears as a white-to-pale coloured powder, free from
foreign matter.

SUPERDISINTEGRANTS WITH COMMERCIAL

AVAILABLE BRANDS2

 Although there are many Superdisintegrants, which show superior

disintegration
 Researchers are experimenting with modified natural products, like
formalincasein, chitin, chitosan, polymerized agar acrylamide, xylan,
smecta, key-jo-clay, crosslinked carboxymethylguar and modified
tapioca starch.
 Water insoluble Superdisintegrants show better disintegration property
than the slightly water soluble agents, since they do not have a
tendency to swell.
 Superdisintegrants that tend to swell show slight retardation of the
disintegration property due to formation of viscous barrier.
 . The Superdisintegrants may be used alone or in combination with
other Superdisintegrants.
 Commercially available Superdisintegrants are listed in the table
given below

V.M.H.P.S. College of Pharmacy

 6

Thus, an overview of various types of Superdisintegrants which are

available have been discussed. The ease of availability of these
agents and the simplicity in the direct compression process suggest
that their use would be a more economic alternative in the
preparation of ODT than the sophisticated and patented techniques.

V.M.H.P.S. College of Pharmacy

 7
There are two methods of incorporating disintegrating agents into the tablet:

I.Internal Addition (Intragranular)

II.External Addition (Extragranular)

III.Partly Internal and External

In external addition method, the disintegrant is added to the sized granulation

with mixing prior to compression. In Internal addition method, the
disintegrant is mixed with other powders before wetting the powder mixtures
with the granulating fluid. Thus the disintegrant is incorporated within the
granules. When these methods are used, part of disintegrant can be added
internally and part externally. This provides immediate disruption of the tablet
into previously compressed granules while the disintegrating agent within the
granules produces further erosion of the granules to the original powder
particles. The two step method usually produces better and more complete
disintegration than the usual method of adding the disintegrant to the
granulation surface only.

V.M.H.P.S. College of Pharmacy

 8
DEFINITION
Process of a solid form breaking up upon contact with water or gastrial fluids.

IMPORTANCE
• Pre – requisite for bioavailability efficacy.
• Pharmacopeial requirement for dissolution rate.
• Pharmacopeial requirement for disintegration time.

DIFFERENT SUPERDISINTEGRANT AND

CHARACTERIZATION

Sr. No. Product Brand Dosage Characteristic

1 Sodium starch Primojel, 1-6% Cost effective
glycol ate glycolys, swelling type
Explotab
2 Croscarmellos Primellose, Ac- 1-6% Cellulose base,
e Di-Sol water penetration
high
3 X-povidone Kollidon, 1-6% Hygroscopic, water
polyplasdone penetration rate
high

V.M.H.P.S. College of Pharmacy

 9
3
DISINTEGRATION MECHANISM(1)

Swelling is important

DISINTEGRATION MECHANISM(2) 3
Water penetration

V.M.H.P.S. College of Pharmacy

 10

Although disintegrants are important components in solid dosage their

mechanisms of action has not been clearly elucidated. The mechanisms
proposed in the past include water wicking, swelling, deformation recovery,
repulsion, and heat of wet-ting. It seems likely that no single mechanism can
explain the complex behavior of the disintegrants. However, each of these
proposed mechanisms provides some understanding of different aspects of
disintegrant action.

V.M.H.P.S. College of Pharmacy

 11

WATER WICKING4
The ability of a disintegrant to draw water into the porous network of a tablet
is essential for effective disintegration. For crospovidone water wicking has
been thought to be the main mechanism of disintegration. On served that
crospovidone swells very little, yet rapidly absorbs water into its network.
Even the extensively swelling Sodium Starch Glycolate shows improved
disintegration when the molecular structure was altered to improve water
uptake, as observed by Rudnic et al. Unlike swelling, which is mainly a
measure of volume expansive with accompanying force generation, water
wicking is not necessarily accompanied by a volume increase.

The ability of a system to draw water can be summarized by the Washburn

equation.

V.M.H.P.S. College of Pharmacy

 12

(
2 ycosθ
L = 2n ) rt
This equation is too simplistic to apply to a dynamic tablet-disintegration
process, but it does show that any change in the surface tension (y), pore size
(r), solid-liquid contact angel (0), or liquid viscosity (n) could change the
water wicking efficiently (L-Length of water penetration in the capacity, t =
time) for example, when Rudnic et al. evaluated the disintegration efficiency
of crospovidone of different particle sizes, the samples with the largest particle
sizes probably yielded greater pore size and altered the shape of the pore.
Indeed, fiber length increased by greater particle size could improve the
capillary uptake of water into the dosage from matrix.
Super disintegrants draw water into the matrix system at faster rate and to a
greater extent when compared to traditional starch. Van Kamp et al, utilizing a
water uptake measurement device, showed that tablets that demonstrate
greater uptake volume and rate, such as those containing Sodium Starch
Glycol ate, disintegrated more rapidly, although the hydrophobic lubricant,
magnesium stearate, seemed o negatively affect the wicking process, those
containing Sodium Starch Glycolate were less affected by the detrimental
effect of mixing with the hydrophobic lubricant. Lerk et al also observed a
lower rate of wetting when disintegrants were mixed with magnesium Stearate
for various mixing times. The decrease in the rate of wetting was proportional
to the time of mixing. Most likely, this observation reflects a greater
delamination of magnesium stearate at longer mixing times.

SWELLING4

V.M.H.P.S. College of Pharmacy

 13
Although water penetration is a necessary first step for disintegration,
swelling is probably the most widely accepted mechanism of action for tablet
disintegrants. In-deed, most disintegrants do swell to some extent, but the
variability of this property between disintegrants reduces its plausibility as a
sole mechanism.
The earliest attempt to measure swelling was to measure the
sedimentation volume of slurries. Nogami et al. developed a reliable test to
measure both swelling and water uptake. Gissinger and Stamm modified this
apparatus and found a positive correlation between the rate of swelling and the
disintegrant action for some disintegrants. List and Muazzam later adapted
this apparatus to measure both the rate of swelling and the swelling force by
the application of force and displacement transducers. They found that
disintegrants which generate large swelling forces are generally more
effective.
For swelling to be effective as a mechanism of disintegraton, there must
be a superstructure against which the disintegrant swells. Swelling of the
disintegrant against the matrix leads to the development of a swelling force. A
large internal porosity in the dosage form in which much of the swelling can
be accommodated reduces the effectiveness of the disintegrant. At the same
time, a matrix which yields readily through plastic deformation may partly
accommodate any disintegrant swelling if swelling does not occur at sufficient
rapidly.

The swelling of some disintegrants is dependent on the pH of the media.

Sangraw et al. reported that sedimentation volumes of anionic cross-linked
starches and celluloses are altered in acidic media. Polyplasdone XL and

V.M.H.P.S. College of Pharmacy

 14
Starch 1500 were unchanged. In a separate study, Chen el al. showed that
acetaminophen tablets containing primojel and Ac-Di-Sol have longer
disintegration and dissolution times in acidic than in neutral medium. Those
containing Polyplasdone XL showed no such differences. The remarkable
swelling capacity of some super disintegrants by exposing individual particles
deposited on slides to high humidities and observing their degree of swelling
through a microscope.
On the other hand, when Caramella et al. evaluated different
disintegrants for their ability to sell, no correlation could be observed between
the maximum disintegrating force and the degree of particle swelling.
However, they did observe a correlation between the rate of disintegrating
force development and the disintegration time. Therefore, these authors
suggested that the rate of development of a disintegrating force is all-
important. Swelling capable of rapid force development may be preferred
since a slowly developing force could hypothetically allow tablets to relieve
the stress generated without bond disruption

V.M.H.P.S. College of Pharmacy

 15
.

DEFORMATION RECOVERY4
The deformation recovery theory implies that the shapes of the disintegrant
particles are distorted during compression, and that the particles return to their
precompression shape upon wetting, thereby causing the tablet to break apart.
Hess, with the aid of photomicrographs, showed that deformed starch particles
returned to their original shape when exposed to moisture.
Fassihi concluded that at higher compression forces, disintegration may
be come dependent on mechanical activation of the tablet, resulting from the
stored energy imparted by the compression process. He examined the

V.M.H.P.S. College of Pharmacy

 16
disintegration times of tablets made of Emdex powder, magnesium stearate,
and 5% disintegrant. Regard less of the disintegrant used (sodium starch
glycolate, microcrystalline cellulose, corscarmellose sodium, or starch), the
disintegration time increased with increasing compression force then
decreased again when the compression force was above 120 MNm2.

Research on deformation and its recovery in situ as a disintegration

mechanism is incomplete. However, such a mechanism may be an important
aspect of the mechanism of action of disintegrates such as crospovidone and
starch which appear to exhibit little or no swelling. The efficacy of such
disintegrants is likely to be dependent on the relative yield strength of the
disintegrant and of the matrix in which it is compressed, since disintegration
efficiency would surely depend on how much deformation is sustained by the
disintegrant particles. Time-dependent stress relaxation could also be a factory
in the aging of such tablets, in that any deformation induced into the
disintegrants which cannot be sustained by intraparticulate bonding may
gradually recover as the matrix relaxes.

REPULSION THEORY4

Guyot Hermann and Ringard have proposed a particle- particle repulsion

theory to explain the observation that particles which do not swell extensively,
such as starch, could still promote disintegration. According to this theory,
water penetrates into the tablet through hydrophilic pores and a continuous
starch network which conveys water from one particle to the next, imparting a
significant hydrostatic pressure. The water then penetrates between starch

V.M.H.P.S. College of Pharmacy

 17
grains because of its affinity for starch surfaces, thereby breaking hydrogen
bonds and other forces holding the tablet together. At present, this theory is
not supported by adequate data.

HEAT OF WETTING4

Matsumara noticed that starch particles exhibit slight exothermic properties

during wetting, which was thought to cause localized stress resulting from the
expansion of air retained in the tablet matrix. Unfortunately, this explanation,
if valid, would be limited to a few substances such as aluminium silicate and
kaolinite. List and Muazzam found that exothermic wetting reactions were not
exhibited by all disintegrants and that even when a significant heat of wetting
was generated, disintegration time did not always decrease. Caramella et al.
observed that an increase in temperature, which should cause air expansion,
did not enhance maximum force generation in several formulations.
Therefore, they concluded that expansion of air in pores due to heat of wetting
could not be supported by the data. More recently, Luangtana-anaii el al.
examined the heat of swelling of powders and tablets of magnesium carbonate
and Emcompress Magnesium carbonate tablets with significantly higher heat
of wetting disintegrated more readily than the Encompress tablets. Indeed, a
thermodynamic approach would be an interesting way to develop a model for
the mechanism of tablet disintegration. However, heat of wetting alone is
probably inadequate to explain disintegration.

V.M.H.P.S. College of Pharmacy

 18

The newer disintegrants may be organized as follows

1) SODIUM STARCH GLYCOLATE5

Non proprietary name

BP: Sodium Starch Glycolate.
USP: Sodium Starch Glycolate.

Synonyms

Carboxymethyl starch, sodium salt: Explotab, primojel

Structural formula

V.M.H.P.S. College of Pharmacy

 19

Primojel

Is a sodium starch glycolate, produced by cross- linking and carboxymethy

lization of pharma grade Potato starch.

Functional category
Tablet and capsule disintegrant.

Description

Sodium Starch Glycolate is a white to off-white, odorless, tasteless, free-

flowing powder. It consists of oval or spherical granules, 30-100 micrometer
in diameter with some less-spherical granules ranging from 10-35 micro meter
in diameter.

Applications in pharmaceutical formulation or technology

Sodium Starch Glycolate is widely used in oral pharmaceuticals as a

disintegrant in capsule and tablet formulations. It is commonly used in tablets
prepared by either direct-compression or wet-granulation processes. The usual

V.M.H.P.S. College of Pharmacy

 20
concentration employed in a formulation is between 2-8%, with the
optimum concentration about 4% although in many cases 2% is sufficient.
Disintegration occurs by rapid uptake of water followed by rapid and
enormous swelling.

Method of Manufacture

Sodium starch glycolate is a substituted and cross linked derivative of potato

starch. Starch is carboxymethylated by reacting it with sodium choloroacetate
in an alkaline medium followed by neturalization with citric, or some other
acid. Cross linking may be achieved by either physical methods or chemically
by using reagents such as phosphorus oxytrichloride or sodium
trimetaphosphate.

Handling precautions

Observe normal precautions appropriate to the circumstances and quantity of

material handled. Sodium starch glycolate may be irritant to the eyes; eye
protection and gloves are recommended. A dust mask or respirator is
recommended for processes that generate a large quantity of dust.

Related substances

Pregelatinized starch; starch

V.M.H.P.S. College of Pharmacy

 21

2) CARBOXYMETHYLCELLULOSE SODIUM5

Nonproprietary names

BP: Carmellose sodium.

USP: Carboxymethylcellulose sodium.

Synonyms

Acucel; aquasorb; blanose; cekol; cellulosegum; CMC sodium; finnix;

nymcel; sodium carboxymethyl cellulose; sodium cellulose glycolate.

Structural formula

V.M.H.P.S. College of Pharmacy

 22

Functional category

Coating agent; tablet and capsule disintegrant; tablet binder; stabilizing agent;
suspending agent; viscosity-increasing agent; water absorbing agent.

Description

Carboxymethylcellulose sodium occurs as a white to almost white colored,

odorless, granular powder.

Applications in pharmaceutical formulation or technology

Carboxymethylcellulose sodium is widely used in oral and topital

pharmaceutical formulations primarily for its viscosity-increasing properties.
Viscous aqueous solutions are used to suspend powders intended for either
topital application or oral and parenteral administration. Carboxy
methylcellulose sodium may also be used as a tablet binder and disintegrant,
and to stabilize emulsions.

V.M.H.P.S. College of Pharmacy

 23
Higher concentrations, usually 3-6%, of the medium viscosity grade are

Use Concentration (%)

Emulsifying agent 0.25-1.0
Gel-forming agent 3.0-6.0
Injections 0.05-0.75
Oral solutions 0.1-1.0
Tablet binder 1.0-6.0
used to produced gels which can be used as the base for applications and
pastes; glycols are often included in such gels to prevent drying out.
Carboxymethylcellulose sodium is additionally one of the main ingredients of
self-adhesive ostomy, wound care, and dermatological patches where it is used
to absorb wound exudates or Transepidermal water and sweat.
Carboxymethylcellulose sodium is also used in cosmetics, toiletries,
incontinence, personal hygiene, and food products.

Method of manufacture

Alkali cellulose is prepared by steeping cellulose obtained from wood pulp or

cotton fibers in sodium hydroxide solution. The alkali cellulose is then reacted
with sodium monochloroaccetate to produce carboxymethylcellulose sodium.
Sodium chloride and sodium glycolate are obtained as by-products of this
etherification.

Handling precautions

Carboxymethylcellulose sodium may be irritant to the eyes. Eye protection is

recommended.

V.M.H.P.S. College of Pharmacy

 24
Related substances

Carboxymethylcellulose calcium; carboxymethylcellulose sodium 12;

croscarmellose sodium.

3) CORSPOVIDONE5

Nonproprietary Names

BP: Crospovidone.
USP: Crospovidone.

Structural formula

(C6H9NO)x

Functional category

Tablet disintegrant.

Description

Crospovidone is a white to creamy-white, finely divided, free flowing,

practically tasteless, odorless or nearly odorless, hygroscopic powder.

V.M.H.P.S. College of Pharmacy

 25
Application in pharmaceutical formulation or technology

Crospovidone is a water-insoluble tablet disintegrant used at 2-5%

concentration in tablets prepared by direct compression or wet and dry
granulation methods. It rapidly exhibits high capillary activity and pronounced
hydration capacity with little tendency to form gels.

Method of manufacture

Acetylene and formaldhyde are reacted in the presence of a highly active

catalyst to form butynediol which is hydrogenated to butanediol and then
cyclodehydrogenated to form butyrolactone. Pyrrolidone is produced by
reacting butyrolactone with ammonia. This is followed by a vinylation
reaction in which pyrrolidone and acetylene are reacted under pressure. The
monomer vinylpyrrolidone is then polymerized, in solution, using a ‘catalyst.
Crospovidone is prepared by a popcorn polymerization’ process.

Handling precautions

Observe normal precautions appropriate to the circumstances and quantity of

material handled. Eye protection, gloves, and a dusk mask are recommended.

Related substance

Povidone.

V.M.H.P.S. College of Pharmacy

 26

4) ALGINIC ACID5

Nonproprietary names
BP: Alginic acid
PhEur: Acidum alginicum
USPNF: Alginic acid
Synonyms
E400; Kelacid; L-gulo-D-mannogylcuronan; polymannuronic acid; Protacid;
Satialgine H8.
Structural formula
The PhEur 2002 describes alginic acid as a mixture of polyuronic acids
[(C6H8O6)n] composed of residues of D-mannuronic and L-glucuronic acid,
and is obtained mainly from algae belonging to the Phaeophyceae. A small
proportion of the carboxyl groups may be neutralized.
Functional category
Stabilizing agent; suspending agent; tablet binder; tablet disintegrant;
viscosity- increasing agent.

V.M.H.P.S. College of Pharmacy

 27
Description
Alginic acid is a tasteless, practically odorless, white to yellowish-white,
fibrous powder.

Applications in pharmaceutical formulation or Technology

Alginic acid is used in a variety of oral and topical pharmaceutical
formulations. In tablet and capsule formulations, alginic acid is used as both a
binder and disintegrating agent at concentrations of 1-5% w/w. Alginic acid is
widely usedas a thickening and suspending agent in a variety of pastes,
creams, and gels, and as a stabilizing agent for oil-in-water emulsions. Alginic
acid has also recently been investigated for use in an ocular formulation of
carteolol.

Therapeutically, alginic acid has been used as an antacid. In combination with

an H -receptor antagonist, it has also been utilized for the management of

2
gastroesophageal reflux. Chemically modified alginic acid derivatives have
been researched for their anti-inflammatory, antiviral, and antitumoral
activities.

In the area of controlled release, the preparation of indo-methacin sustained-

release microparticles from alginic acid (alginate)-gelatine hydrocolloid
coacervate systems has been investigated. In addition, as controlled-release
systems for liposome-associated macromolecules, microspheres have been

V.M.H.P.S. College of Pharmacy

 28
produced encapsulating liposomes coated with alginic acid and poly-L-
lysine membranes. Mechanical properties, wateruptake, and permeability
properties of a sodium salt of alginic acid have been characterized for
controlled-release applications. In addition, sodium alginate has been
incorporated into an ophthalmic drug delivery system for pilocarpine nitrate.
Also used generally as a hydrophilic matrix agent for controlled-release
applications.

Method of manufacture
Alginic acid is a hydrophilic colloid carbohydrate that occurs naturally in the
cell walls and intercellular spaces of various species of brown seaweed
(Phaeophyceae). The seaweed occurs widely throughout the world and is
harvested, crushed, and treated with dilute alkali to extract the alginic acid.

Handling precautions
Observe normal precautions appropriate to the circumstances and
quantity of material handled. Alginic acid may be irritant to the eyes or
respiratory system if inhaled as dust. Eye protection, gloves, and a dust
respirator are recommended. Alginic acid should be handled in a well-
ventilated environment.

V.M.H.P.S. College of Pharmacy

 29

2
1. PARTICLE SIZE

Both the rate and force of disintegrant action may be dependent upon the
particle size of the disintegrant. Smallenbrock et al. found that starch grains
with relatively large particle size were more efficient than the smaller particle
size grades. This is probably because the continuous hydrophilic network of
disintegrants is more efficiently built up by the bigger particles. Rudnic et al.
also found that coarser grades of crospovidone (50-100 μm, Grade B; 50-300
μm, Grade C) were more efficient than the finer particles (<15 μm. Grade A).
The differences in disintegration efficiency between Grades B and C were not
clear, however. When List and Muazzam evaluated two different grades of
crospovidone particles (100-200 μm and >315 μm), the efficiencies between
the two grades were similar Results for the other disintegrants, Amberlite
IRP88 and potato starch, support that coarser particle sizes allow more
efficient disintegration than finer particles. For disintegrants that swell
extensively, this can be explained by the observed force development. Indeed,
larger particles of sodium starch glycolate swelled more rapidly and to a
greater extent than the smaller particles.

V.M.H.P.S. College of Pharmacy

 30

2
2. MOLECULAR STRUCTURE

Disintegrants can vary in molecular structure based on how they are

manufactured or processed. Corn starch, for example, contains different
proportions of two sugar fractions, amylose and amylopectin. Schwartch and
Selinski concluded that the linear polymer amylose was responsible for the
disintegrant properties associated with starch whereas the branched polymer
amylopectin was responsible for the gummy property. Varying the amylose to
amylopectin ratio did not affect the porosities of the resulting tablets. Rudnic
et al evaluated the effects of cross-linking and carboxymethyl substitution in
Sodium Starch Glycolate and concluded that the swelling of the disintegrant
was largely inversely proportional to the degree of cross linking. Swelling
also was inversely proportional to the level of substitution, but to a lesser
degree Shah et al found that carboxymethyllulose, having high molecular
weight and low levels carboxymethylation, was best for tablet disintegration.

V.M.H.P.S. College of Pharmacy

 31

3. EFFECT OF COMPRESSION FORCE2

Compression force affects disintegration time in different ways. First it

governs the penetration of dissolution fluids into the matrix by controlling the
porosity of the compact. Low compression force can lead to relatively high
tablet porosity and rapid penetration of water. However, it has often been
observed that tablets containing Starch exhibit disintegration times that tend to
pass through a minimum as compression force increase. At low compression
forces, any possible swelling or deformation recovery that may take place may
be more or less accommodated by the porosity, whereas at intermediate
compression forces a maximal disintegrating effect may develop. At high
compression forces, fluid penetration may be impeded by a further reduction
of porosity while particle deformation of the disintegrants becomes more
important. In general, List and Muazzam found increased swelling pressures
at higher compression forces when various amberlite resins, starches, and
crospovidones were used at 2.5% concentration in dicalcium phosphate matrix
tablets.
In two different studies, Khan and Rhodes observed that tablets containing
sodium starch glycol ate disintegrate relatively slowly at low compression
force, fast at intermediate compression force, and slowly again at high

V.M.H.P.S. College of Pharmacy

 32
compression force. However, the effects of compression force on the
disintegration time of other types of disintegrants, such as cation exchange
resin, calcium sodium alginate, and various forms of starches, varied widely.
Perhaps the effect of compression force on the disintegration time depends on
the nature of the disintegrants, such as their mechanism of disintegration and
deformation characteristics.

Munoz et al. found that the effect of compression pressure of disintegration

time depended on the concentration of the super disintegrant Explotab used,
the figure (3) shows that the shortest disintegration time could be achieved at
ca 7% disintegrant concentration. At this concentration, compression force
has little effect on disintegration time. The disintegration time was more
affected by compression force at low disintegrant concentration, being shortest
at intermediate compression force. This type of biphasic effect of
compression force on disintegration time also was observed for Ac-Di-Sol
with a surface-response curve similar to that of Explolab. When disintegration
times were-studies at 5 and 10% disintegrant, 5% Ac-Di-Sol yielded the
lowest porosity, lowest yield pressure in Heckle analysis, and shortest
disintegration time. At 10% disintegrant concentration, the tablets showed a
slight expansion after compression, which could explain a slightly increased
disintegration time compared to the 5% concentration.
The effect that compression force can have on the disintegration efficiency
seems, therefore, largely dependent on the mechanism of the disintegrant
action. The effectiveness of swelling or structure recovery may well be
dependent on attaining a compression force that achieves a critical porosity in
the matrix. On the other hand, the capillary uptake of liquid, which is a

V.M.H.P.S. College of Pharmacy

 33
necessary precursor to these mechanisms, could be compromised if the
tablet matrix is compressed to porosity too low.

V.M.H.P.S. College of Pharmacy

 34
Fig(3)-Surface response of disintegration time as functions of
compression pressure and percentage disintegrant

4. MATRIX SOLUBILITY2

The disintegrant mechanism seems to depend not only on the disintegrant

itself but also on the matrix. Disintegrants work most effectively in insoluble
matrices. Insoluble matrices, such as those containing calcium phosphate do
not disintegrate adequately without disintegrants. On the other hand, tablets
and capsules that primarily consist of water-soluble fillers or drugs tend to
dissolve rather than to disintegrate, even in the presence of disintegrating
agents. It has been suggested that during the dissolving process, the water acts
as a plasticizer which can potentially reduce the development of disintegrating
force. In addition, soluble materials that tend to swell can form viscous plugs
which may impede further penetration of moisture into the Matrix. However,
the addition of disintegrants almost predicably shortens disintegration lime,
despite the solubility of the matrix

V.M.H.P.S. College of Pharmacy

 35

5. INCORPORATION IN GRANULATION2

The method of incorporating disintegrants in granulation has been

controversial. Should the disintegrant be all extra granular, all intragranular,
or divided between these two location? Maize starch, sodium calcium
alginate, alginic acid, and other disintegrants gave more rapid disintegration
when incorporated extra granularly than intragranularly in a sulfadiazine
granulation. They also reported that the latter method gave a linear dispersion
and they concluded that the best compromise was to use both intra and extra
granular disintegrants.
Van kamp evaluated the method of incorporation of Primojel, Ac-Di-Sol, and
Polyplasdone XI, in prednisone tablets formed from lactose granules. Whether
the incorporation of the super disintegrant was intragranular, extra granular or
evenly distributed in both sites, they found little or no different in
disintegration time, crushing strength, or dissolution of prednosone.

V.M.H.P.S. College of Pharmacy

 36
Interestingly, their results with potato starch showed discrepancies with the
earlier work of Shotton and Leonard in that intragranular starch was more
effective than extra granular starch. Naproxen, a poorly soluble drug at gastric
pH, dissolved faster when Ac-Di-Sol was incorporated intragranularly,
compared to extra granularly or evenly distributed between the intra and extra
granular portions. More recently, a study reported by Khattab et al. showed
that the combined incorporation of intra and extra granular disintegrating
agents (Sodium Starch glycol ate, croscarmellose sodium, or crospovidone) in
a paracetamol granulation resulted in faster disintegration and dissolution than
extra granular or intragranular incorporation alone.

More studies are necessary to elucidate the effect of other factors, such as the
type of binder, the type of filler, and the solubility of the matrix, which may
significantly influence the effectiveness of disintegrants in different modes of
incorporation. For example, Becker et al. found that extra granular
crospovidone was more effective in an acetaminophen tablet with a binder of
maltodextrin (Licab DSH), pregelatinized maize starch (Lycab PGS), or low-
substituted hydroxypropyl cellulose (L-HPC) than with a
polyvinylpyrrolidone or hydroxypropyl methylcellulose binder. In addition,
the difference seen in the effectiveness of starch in different modes of
incorporation between the Shotton and the Van Kamp studies may be related
to the absence or presence of lactose, a soluble filler. Unlike Shotton, Van
Kamp et al. used lactose as soluble filler, which might have reduced the
relative effectiveness of extra granular starch, making the intragranular
incorporation more favorable.

V.M.H.P.S. College of Pharmacy

 37
The observations summarized in Table (1) make it difficult to generalize
that one method of incorporation of disintegrant in granulation is better than
another. However, when all of the data are taken together, it would appear that
the combined addition of disintegrants both extra granularly and
intragranularly would provide the best opportunity for optimal disintegrant
effectiveness.

TABLE (1) EFFECT OF DISINTEGRANT INCORPORATION IN GRANULES ON

TABLET PROPERTIES

Crushing strength (Kgf) Disintegration time (S)

Disintegrant Intra Equal Extra Intra Equal Extra

Control 6.5 664
4% primojel 5.3 5.0 5.8 38 41 49
4% Ac-Di-Sol 3.8 4.8 5.7 110 126 148
4% Nymcel 16 4.0 4.3 6.5 499 540 488
4% Polyplasdone 5.8 6.0 6.1 31 40 43
20%Potato starch 3.3 3.4 2.1 69 80 110

6. EFFECT OF REWORKING2

The effect of recompressing a wet-massed microcrystalline cellulose matrix

containing super disintegrants on swelling force kintetics also has been
investigated. When the disintegrants were placed extra granularly, only
Explolab among those considered retained good efficiency after reworking.
When placed intragranularly, all disintegrants had reworking efficiencies

V.M.H.P.S. College of Pharmacy

 38
equivalent to that of the nondisintegrant control. Adding 2% disintegrant
extra granularly prior to the second compression restored disintegrant activity
for Polyplasdone XL but only partially for Ac-Di-Sol. In further work
reworked tablets containing 2% disintegrant extra granularly were studied.
The data in Table (2) illustrate that maximal swelling forces were reduced in
all cases, but there was no correlation with tablet disintegration time.

7. INCORPORATION IN HARD GELATIN CAPSULES2

In utility and performance of super disintegrants in direct-fill powder

formulations for hard-shell capsules filled on tamping machines are roughly
analogous to those of direct compression tablet formulation. I a study where
capsules were filled under controlled tamping force conditions using an
instrumented Zanasi LZ 64 dosator machine, dicalcium phosphate-based
formulations containing hydrochlorothiazide and different super disintegrants
were tested for dissolution times. The croscarmelloses were found to be more
effective than sodium starch glycol ate in promoting hydrochlorothiazide
dissolution, whereas crospovidone gave the poorest results. In a follow-up
multifactorial study all main parameters, including disintegrant type,
compression force, level of lubricant, and filler type, were found to have
significant effects on dissolution. At lower disintegrant concentration,
increasing

TABLE (2) REWORK EFFICIENCY (% RE) OF SUPER DISINTEGRANTS*

V.M.H.P.S. College of Pharmacy

 39
Disintegrant Relative Fb
35% porosity 40% porosity % RE
(2%)
Control 0.842 0.848 45
Polyplasdone 0.941 0.926 64
XL
Explotab 0.737 0.863 86
Ac-Di-Sol 1.015 0.951 45

Ref Formula Maximum Swelling Force (1st Compression)

= ------------------------------------------------------
Maximum Swelling Force (2nd Compression)

& RE AUC (1st Compression)

= ----------------------------- x 100
AUC (2nd Compression)

the tamping force improved the dissolution of hydrochlorothiazide, most

likely due to reduced porosity. When the lactose filler was replaced by
dicalcium phosphate, the magnitude and order of effectiveness of the
disintegrants changed.
Like with tablets, the effect of disintegrants in rapidly soluble capsule matrices
is lower than in water insoluble matrices. Perhaps doubling the concentration
normally required for tablets is needed for efficient disintegration and
significantly increases dissolution. This need for higher disintegrant
concentration is reflected in the higher porosity of capsule plugs compared to
compressed tablets. At equivalent concentrations in model lactose or
dicalcium phosphate-based systems, sodium starch glycolate and
croscarmellose sodium were more effective than crospovidone in promoting

V.M.H.P.S. College of Pharmacy

 40
dissolution of hydrochlorothiazide from capsules manufactured with the
same tamping force.
For either filler, disintegration times and swelling correlated well with
dissolution.

I. JRS SUPERDISINTEGRANTS7
1. EXPLOTAB®: The first superdisintegrant made from sodium starch
glycolate, JRS Pharma now manufactures and markets this
superdisintegrant to ensure consistent quality, availability and the
premier technical support for which we are known.
2. VIVASTAR®: This sodium starch glycolate superdisintegrant has
great disintegration power and cost savings. VIVASTAR PSF
(Pharmaceutical Solvent Free) is innovative in that it can improve
stability of certain drugs.
3. VIVASOL®: This Croscarmellose Sodium starch free
superdisintegrant offering excellent results at low use levels.
4. EMCOSOY®: An all natural, soy polysaccharides superdisintegrant,
which does not contain starch or sugar. Being a dietary fiber, it has
excellent application in nutritional products.
5. SATIALGINE H8®: A pharmaceutical grade alginic acid that offers
rapid swelling in an aqueous medium. It can be moistened and dried
without significant loss in disintegration and combines both a wicking
and swelling mechanism to promote disintegration in either wet or dry
granulations.

II. ROQUETTE SUPERDISINTEGRANTS8

V.M.H.P.S. College of Pharmacy

 41
ROQUETTE has for many years produced a carboxymethyl starch (sodium
starch glycolate) used as a superdisintegrant. This superdisintegrant has in the
past been distributed by PENWEST (ex MENDELL) under the distributor’s
trademark, EXPLOTAB. The distributorship arrangement is ending on a
phased basis, and ROQUETTE will now sell this product directly under its
own trademark: GLYCOLYS. The process and specification of GLYCOLYS
remain unchanged. GLYCOLYS therefore completes the broad high quality
range of excipients developed by and available directly from ROQUETTE

1. Tablet disintegration has received considerable attention as an

essential step in obtaining fast drug release.
2. Disintegration remains a powerful influence and precursor for drug
absorption.
3. Disintegration of tablet or capsule is depending upon the type and
quantity of disintegrants.
4. The development of fast dissolving or disintegrating tablets provides
an opportunity to take an account of tablet disintegrants.
5. Therefore, there is a huge potential for the evaluation of new
disintegrants or modification of an existing disintegrants into
superdisintegrants, so as to formulate fast dissolving dosage form
6. Many companies are involved in manufacturing of other
superdisintegrants

V.M.H.P.S. College of Pharmacy

 42

1. Leon Lachman,Herbert.A. Liebermann and Joseph.L.Kanig

Theory and Practice of Industrial Pharmacy

Page no.328
2. www.pharminfo.net

3. www.dmv-international-pharm.com

4. www.pharmpedia.com

5. Raymond.C.Rowe, Paul.J.Sheskey and Paul J. Weller

Handbook of pharmaceutical excepients

Page No.16-18,97-99,181-185,581-583
6. Encyclopedia of Pharmaceutics Vol 7
by Mark and Becker
7. www.pharmaceutical-technology.com

8. www.Roquette-pharma.com

V.M.H.P.S. College of Pharmacy

 43

V.M.H.P.S. College of Pharmacy