Jerajani Final Copy

DISINTEGRANTS 1

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

SUPERDISINTEGRANTS 2

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

1

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)


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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.


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CROSS-LINKED ALGINIC ACID 2

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 GUM 2

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 GUM 2

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%


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ION EXCHANGE RESINS 2

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 BRANDS 2

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


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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.


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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.


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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

glycol ate

Primojel,

glycolys,

Explotab

1-6% Cost effective

swelling type

2 Croscarmellose Primellose, Ac-

Di-Sol

1-6% Cellulose base,

water penetration

high

3 X-povidone Kollidon,

polyplasdone

1-6% Hygroscopic, water

penetration rate

high


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DISINTEGRATION MECHANISM(1) 3

Swelling is important

.

DISINTEGRATION MECHANISM(2) 3

Water penetration


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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.


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11

2n

WATER WICKING 4

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.

L2=(ycosθ) rt


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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.

SWELLING 4

Although water penetration is a necessary first step for disintegration,

swelling is probably the most widely accepted mechanism of action for tablet


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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

Starch 1500 were unchanged. In a separate study, Chen el al. showed that


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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


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.

DEFORMATION RECOVERY 4

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

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.


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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 THEORY 4

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

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.


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HEAT OF WETTING 4

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.


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The newer disintegrants may be organized as follows

1) SODIUM STARCH GLYCOLATE 5

Non proprietary name

BP: Sodium Starch Glycolate.

USP: Sodium Starch Glycolate.

Synonyms

Carboxymethyl starch, sodium salt: Explotab, primojel

Structural formula


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Primojel

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

lization of pharma grade Potato starch.

Functional categoryTablet 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

concentration employed in a formulation is between 2-8%, with the optimum

concentration about 4% although in many cases 2% is sufficient.


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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


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2) CARBOXYMETHYLCELLULOSE SODIUM 5

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


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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.

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


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Carboxymethylcellulose sodium is also used in cosmetics, toiletries,

incontinence, personal hygiene, and food products.

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

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.


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

recommended.

Related substances

Carboxymethylcellulose calcium; carboxymethylcellulose sodium 12;

croscarmellose sodium.


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3) CORSPOVIDONE 5

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.

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


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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.


Observe normal precautions appropriate to the circumstances and quantity of

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

Related substance

Povidone.


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4) ALGINIC ACID 5

Nonproprietary namesBP: Alginic acid

PhEur: Acidum alginicum

USPNF: Alginic acid

SynonymsE400; Kelacid; L-gulo-D-mannogylcuronan; polymannuronic acid; Protacid;

Satialgine H8.

Structural formulaThe 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 categoryStabilizing agent; suspending agent; tablet binder; tablet disintegrant;

viscosity- increasing agent.

Description


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Alginic acid is a tasteless, practically odorless, white to yellowish-white,

fibrous powder.

Applications in pharmaceutical formulation or TechnologyAlginic 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 H2-receptor antagonist, it has also been utilized for the management

of 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

produced encapsulating liposomes coated with alginic acid and poly-L-lysine


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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 manufactureAlginic 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 precautionsObserve 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.


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1. PARTICLE SIZE 2

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.


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2. MOLECULAR STRUCTURE 2

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.


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3. EFFECT OF COMPRESSION FORCE 2

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


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force, fast at intermediate compression force, and slowly again at high

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


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necessary precursor to these mechanisms, could be compromised if the tablet

matrix is compressed to porosity too low.


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Fig(3)-Surface response of disintegration time as functions of

compression pressure and percentage disintegrant

4. MATRIX SOLUBILITY 2

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


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5. INCORPORATION IN GRANULATION 2

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


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evenly distributed in both sites, they found little or no different in

disintegration time, crushing strength, or dissolution of prednosone.

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


37

relative effectiveness of extra granular starch, making the intragranular

incorporation more favorable.

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 REWORKING 2


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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

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 CAPSULES 2

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


39

significant effects on dissolution. At lower disintegrant concentration,

increasing

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

Disintegrant

(2%)

Relative Fb

35% porosity 40% porosity % RE

Control 0.842 0.848 45

Polyplasdone

XL

0.941 0.926 64

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


40

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

dissolution of hydrochlorothiazide from capsules manufactured with the same

tamping force.

For either filler, disintegration times and swelling correlated well with

dissolution.

I. JRS SUPERDISINTEGRANTS 7 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.


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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 SUPERDISINTEGRANTS 8

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.


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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

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

Theory and Practice of Industrial Pharmacy

Page no.328

2. www.pharminfo.net


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http://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


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http://www.pharmpedia.com/

http://www.dmv-international-pharm.com/

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