What is a tablet ?

Submitted by on Sun, 11/15/2009 - 22:55

What will you gain?

1.1 Why do we need to

convert an active pharmaceutical ingredient into a suitable dosage form?

1.2
What is a tablet?

1.3 Advantages and

disadvantages of tablet as a dosage form

1.1 Why do we need to convert an active pharmaceutical ingredient into

a
suitable dosage form? (1-5)

Active pharmaceutical compounds (drugs) are used for the treatment of a disease
or for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may
exist in solid, liquid or semisolid form. They are rarely prescribed to the
patients as such i.e. without adding excipients, since the desired effect
may not be obtained. Earlier, it was thought that excipients are inert in
nature but, in recent time it is well known that excipients can greatly modify
the intended effect of a drug. The API and excipients are suitably processed
in pharmaceutical industry to convert them into dosage forms such as tablet,
capsule, suspension, solution, etc. The selection of excipients and processing
of drug excipients mixture is as important as API itself.

Patient acceptability can be improved by controlling the organoleptic properties.

Dosage form provides desired therapeutic level of a drug.

1.2 What is a tablet? (1-5)

It is a solid dosage form each containing a unit dose of one or more medicament/s.
Tablets are solid, flat or biconvex discs prepared by compressing a drug or a
mixture of drugs with or without suitable excipients.

Tablets
may be swallowed whole or being chewed. Some are dissolved or dispersed in
water before administration. Some are put in oral cavity, where the active
ingredient is liberated at a predetermined rate. Implants or passeries may also
be presented in form of tablet.
Tablet may vary in shape and differ greatly in size and weight depending on
the amount of medicinal substance and the intended mode of administration.

1.3 Advantages and disadvantages of tablet as a dosage form. (1-5)

The advantages are listed below:

I.Large scale
manufacturing is feasible in comparison to other dosage forms. Therefore,
economy can be achieved.

II.Accuracy of dose
is maintained since tablet is a solid unit dosage form.

III. Tailor made release profile can be achieved.

IV. Longer expiry period and minimum microbial spillage

owing to lower moisture content.

V. As tablet is not a sterile dosage form, stringent

environmental conditions are not required in the tablet department.

VI. Ease of packaging (blister or strip) and easy

handling over liquid dosage form.

VII. Easy to
transport in bulk. Emergency supply supplies can be carried by patients.

VIII.Organoleptic
properties (taste, appearance and odour) are best improved by coating of
tablet.

IX. Product identification is easy and markings done with

the help of grooved punches and printing with edible ink.

X. Different types of tablets are available like buccal,

floating, colon targeting, effervescent, dispersible, soluble, and chewable,
etc.

XI. In composition to parenterals dosage form, a doctor

or a nurse is not required for administration. I.e. self administration is
possible.

XII. In comparison to
capsules, tablets are more tamperproof.

The disadvantages are listed below:

I.It is difficult
to convert a high dose poorly compressible API into a tablet of suitable size
for human use.

II.Difficult to
formulate a drug with poor wettability, slow dissolution into a tablet.

III. Slow onset of action as compared to parenterals,

liquid orals and capsules.

IV. The amount of liquid drug (e.g. Vitamin E,

Simethicone) that can be trapped into a tablet is very less.

V. Difficult to swallow for kids, terminally ill and

geriatric patients.

VI. Patients undergoing radiotherapy cannot swallow

tablet.

Key Phrases

Ø Reasons to go for dosage form

i) To control organoleptic properties

ii) Achieve desired therapeutic level of drug

Ø The most widely used dosage form is tablet

Ø Advantages

i) Accurate dose

ii) Tailor made release profiles

iii) Longer expiry period

iv) Stringent environmental condition is NOT required

v) Easy handling

Ø Disadvantages

i) Slow onset of action

ii) Large amount of liquid cannot be incorporated

iii) Difficulty in swallowing especially for geriatric and

pediatric patients
Types of tablets
Submitted by on Sun, 12/06/2009 - 19:49

1.4 Types of Tablets

What will you gain?

1.4.1 Oral tablets for

ingestion

1.4.2 Tablets used in the

oral cavity

1.4.3 Tablets
administered by other routes

1.4.4 Tablets used to

prepare solution

With advancement in technology and increase in awareness towards modification in

standard tablet to achieve better acceptability as well as bioavailability,
newer and more efficient tablet dosage forms are being developed. The main
reasons behind formulation of different types of tablets are to create a
delivery system that is relatively simple and inexpensive to manufacture,
provide the dosage form that is convenient from patient’s perspective and
utilize an approach that is unlikely to add complexity during regulatory
approval process. To understand each dosage form, tablets here are classified
by their route of administration and by the type of drug delivery system they
represent within that route.

Table.1. Various Types Of Tablets

1.4.1 ORAL 1.4.1.1 Standard

TABLETS FOR compressed tablets
INGESTION
1.4.1.2 Multiple
compressed tablets

I. Compression coated tablet

II. Layered tablet

III. Inlay tablet

1.4.1.3 Modified Release tablet

 1.4.1.4 Delayed action tablet

1.4.1.5 Targeted tablet

I. Floating tablet

II. Colon targeting tablet

1.4.1.6 Chewable tablet

1.4.1.7 Dispersible tablet

1.4.2 TABLETS 1.4.2.1 Lozenges and
USED IN THE ORAL troches
CAVITY
1.4.2.2 Sublingual tablet

1.4.2.3 Buccal tablet

1.4.2.4 Dental cones

1.4.2.5 Mouth dissolved

tablet
1.4.3 TABLETS 1.4.3.1 Vaginal tablet
ADMINISTERED BY
OTHER ROUTES 1.4.3.2 Implants
1.4.4 TABLETS 1.4.4.1 Effervescent
USED TO PREPARE tablet
SOLUTION
1.4.4.2 Hypodermic tablet

1.4.4.3 Soluble tablet

1.4.1 Oral tablets for ingestion (1-3)

These tablets are meant to be swallowed intact along with

a sufficient quantity of potable water. Exception is chewable tablet. Over 90%
of the tablets manufactured today are ingested orally. This shows that this
class of formulation is the most popular world wide and the major attention
of the researcher is towards this direction.

1.4.1.1 Standard compressed tablets

These are the standard uncoated tablets made by either direct compression
or wet granulation or dry granulation or double compaction.
1) Figure.1. Standard Compressed Tablet

They may be used for local action in gastro-intestinal tract or systemic action.
When the tablet exert local action, they are formulated as more water insoluble
by means of selecting slow dissolving excipients and thus provides local action
for long time period. e.g., antacids and adsorbents. The drugs that produce
systemic action have some aqueous solubility and designed to disintegrate and
dissolve quickly so that the drug can be quickly absorbed and produce systemic
action. Generally, an API exhibits bioavailability depending upon Biopharmaceutical
Class, which is based on water solubility and gastro-intestinal membrane permeability
criteria. But, it can be altered by appropriate selection of excipients and
processing technology.

1.4.1.2 Multiple compressed tablets

The tablets in this category are prepared for two reasons: to separate physically
or chemically incompatible ingredients and to produce repeat action/ prolonged
action tablet.

The tablet manufacturing machine is generally operated at relatively lower

speed than for standard compression tablet. There are three categories under
this class:

I.Layered tablets – two to three component system.

II.Compression coated tablets – tablet within a tablet.

III.Inlay tablet – coat partially surrounding the core.

The layered tablet is preferred over compression coated tablet as the surface
contact is less and the production is simple and more rapid.

I. Multilayered tablets

When two or more active pharmaceutical ingredients

are needed to be administered simultaneously and they are incompatible, the
best option for the formulation pharmacist would be to formulate multilayered
tablet. It consists of several different granulations that are compressed to
form a single tablet composed of two or more layers and usually each layer is
of different colour to produce a distinctive looking tablet. Each layer is fed
from separate feed frame with individual weight control. Dust extraction is
essential during compression to avoid contamination. Therefore, each layer
undergoes light compression as each component is laid down. This avoids
granules intermixing if the machine vibrates.

For example, admixture containing Phenylephedrin HCL

and Ascorbic Acid with Paracetamol.

Paracetamol + phenylephedrine Hydrochloride → one layer

Paracetamol + ascorbic acid → another layer.

Figure.2. Multilayered Tablet

2) II. Compression coated tablets

This type of tablet has two parts, internal core and surrounding coat. The
core is small porous tablet and prepared on one turret. For preparing final
tablet, a bigger die cavity in another turret is used in which first the coat
material is filled to half and then core tablet is mechanically transferred,
again the remaining space is filled with coat material and finally compression
force is applied. This tablet readily lend itself in to a repeat action tablet
as the outer layer provides the initial dose while the inner core release the
drug later on. But, when the core quickly releases the drug, entirely different
blood level is achieved with the risk of over dose toxicity. To avoid immediate
release of both the layers, the core tablet is coated with enteric polymer so
that it will not release the drug in stomach while, the first dose is added
in outer sugar coating. Even so, coating operation requires interpretation while
manufacturing and dawdling the manufacturing process. Sometimes, inner core
may be of liquid formulation to provide immediate release of core after the
coat gets dissolved.

Figure.3. Compression Coated Tablet

III. Inlay tablets (4)

A type of layered tablet in which instead the core

tablet being completely surrounded by coating, top surface is completely
exposed. While preparation, only the bottom of the die cavity is filled with
coating material and core is placed upon it. When compression force is applied,
some coating material is displaced to form the sides and compress the whole
tablet. It has some advantages over compression coated tablets:

i)Less coating
material is required.

ii)Core is visible,
so coreless tablets can be easily detected.

iii)Reduction in coating forms a thinner tablet and thus freedom from capping
of top coating.
Figure.4. Inlay Tablets

1.4.1.3 Modified Release tablets

The main aim behind formulation of this dosage form is to release the medicament
slowly for long time duration after administration of a single tablet.

Figure.5. Graphical Comparison Of Blood Concentration

V/S Time

A widespread use of this type of tablet is seen in present scenario, as well

as many researchers have concentrated their attention in this direction. This
is mainly because of improvement in patient’s compliance as the dosage frequency
is reduced, patient can take an undisturbed sleep at night, it’s also beneficial
for psychiatric patients who forget to take their tablets regularly and the
dose related side effects and toxicities are reduced. Any adjuvant that can
alter water uptake rate, swelling and gelling characteristics of Matrixing agents
can alter the release rate of API e.g., electrolytes in HPMC matrix tablet.
It’s also possible to achieve pulsed drug release. Weakly basic drugs exhibit
good solubility at low pH while less soluble at high pH conditions, which can
result in incomplete drug release for sustained release formulations. The drug
release can be modified by providing suitable micro environmental pH in the
tablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkaline
polymers results in desirable drug release of acidic drugs. On the other hand,
formulation of this type of dosage form presents challenge for the formulator:
increases the cost of manufacturing, chances of burst drug release and drop
in drug release rate in terminal phase and thus incomplete release on API. In
case of accidental poisoning, the doctor has to deal with special treatment
problems. Due to large size, patient may feel difficulties in swallowing as
the matrixing agent to drug ratio is high. Classic approaches are usually based
on adaptation of either film coated or multiparticulate technologies or those
involving slow release matrices.

Coating technology (6)

It combines semi permeable coatings and osmotic tablet cores to produce “zero
order release” technology. Attention is also focused to trigger drug release
at critical time point e.g., to achieve drug release 1 -2 hours before the patient
awakens. Alza’s prolific research activities have yielded a technology called
“Ringcap” which is based on a tablet, preferentially film coated, partially
coated with a series of rings whose respective thickness provides the means
of moderating the rate at which the drug is released from final dosage form.

Figure.6. Ringcap (Coated) Tablet

Matrix technology

Classically matrix products exhibit first order (or perhaps square-root-of-time)

drug release characteristics. In order to achieve zero order release characteristics,
it’s necessary to employ specially designed materials or strategies that seek
to manipulate tablet structure or geometry. Combination of conventional HPMC
matrix technology with upper and lower layer. This helps to moderate drug release
by increase in surface area with concomitant reduction in drug concentration
within the device.

Figure.7. Matrix Tablet

Release of medicament can follow

various mechanisms (2)

i) Diffusion is rate limiting

Diffusion is driving force where the movement of drug molecules occurs from
high concentration in the tablet to lower concentration in gastro intestinal
fluids. This movement depends on surface area exposed to gastric fluid, diffusion
pathway, drug concentration gradient and diffusion coefficient of the system.

Figure.8. Diffusion Release Pattern

In practice, we can follow either of the two methods,

1.The drug is formulated in an insoluble matrix; the gastric fluid penetrates

the dosage form and dissolves the medicament and release the drug through diffusion.

2.The drug
particles are coated with polymer of defined thickness so as the portion of
drug slowly diffuse through the polymer to maintain constant drug level in
blood.

ii)
Dissolution is rate limiting

The drugs with poor water solubility (BCS class 2 and

4) are inherently sustained release forms. While for water soluble drugs, it’s
possible to incorporate a water insoluble carrier to reduce dissolution of the
drug particles are coated with this type of materials e.g. Polyethylene Glycol.
One may skip the use of disintegrating agent to promote delayed release.

iii) Osmotic pressure is rate limiting

Osmosis is a phenomenon in which the flow of liquid

occurs from lower concentration to higher concentration through a semi
permeable membrane which allows transfer of liquid only. The whole drug is
coated with a semi permeable membrane with a hole on one end of tablet made by
a laser beam. The gastric fluid penetrates through the membrane, solubilizes
the drug and increases the internal pressure which pumps the drug solution out
of the aperture and releases the drug in gastric environment. The delivery rate
is constant provided that the excess of drug present inside the tablet. But, it
declines to zero once the concentration drops below saturation.

Figure.9. Osmotic Release Pattern

iv) Release is controlled by ion exchange

Ion exchangers are water insoluble resinous materials

containing salt forming anionic or cationic groups. While manufacturing, the
drug solution is mixed with resin and dried to form beads which are tableted.
The drug release depends upon high concentration of charged ions in gastro
intestinal tract where, the drug molecules are exchanged and diffused out of
the resin into the surrounding fluid. This mechanism relies upon the ionic
environment of resin and not pH or enzyme on absorption site.

1.4.1.4 Delayed action tablets

Enteric coated tablet is such an example of delayed action tablet. This

formulation is preferred when,

i)The API
irritates gastric mucosa e.g., aspirin or strong electrolytes

ii)Drugs that produce nausea and vomiting.

iii)API is sensitive to low pH e.g., erythromycin

iv)When it’s necessary to release the drug undiluted. e.g.,

intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc.

The commonly used coating agents are: Cellulose

acetate phthalate, Hydroxy methyl propyl phthalate, polyvinyl acetate
phthalate, Eudragit®, etc. This dosage form is intended to hydrate
and begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pH
increases to 7 to 8. The presence of esterases or bile salts like surface
active agents plays a role in drug release.

1.4.1.5 Targeted tablets

When we need to release the API at a specific site in

the elementary tract, targeted drug delivery is a preferred option. Depending
upon the composition and release mechanism of a tablet, the drug is delivered
to a particular region. Under this category, we have two types of tablet:

I. Gastro retentive Tablet

This type of dosage form is to be opted when API

release is desired in stomach (Antacids, APIs used against H.pylori infection)
or site of absorption is either stomach or upper part of small intestine.

Figure.10. Floating Tablet

To retain the drug for longer time period in stomach,

following approaches can be used:
i) Low density tablet (effervescent or non
effervescent)

ii) Tablets that can expand in gastric

environment (swelling or by unfolding) and thus increasing the size so that it
cannot cross the pyloric sphincter.

iii) Using mucoadhesive

polymers that stick to mucosa of stomach and provide slow drug release.

Supine position is to be
avoided and also high level of fluid is necessary or if the swelling
formulation leaves stomach before it swells it’s ineffective. Drugs like Diazepam,
Levodopa, Benserazide,
and Ciprofloxacin are successfully marketed in this formulation.

II. Colonic tablets (7,8)

When the aim is to deliver the drug into colon

without dilution in other regions of gastrointestinal tract or the drug has
poor absorption in stomach or small intestine, colonic drug delivery is an
answer of choice. The pH in this region varies from 6.4 - 7 and presence of
microbial flora plays as important role in drug release especially in this
region. Various mechanisms are adopted for drug release in this area are coating with
pH sensitive
polymer e.g., Eudragit®S100, Eudragit® L100,
biodegradable polymer like polymers which are sensitive to colonic bacteria,
bioadhesive polymers which selectively sticks to colonic mucosa e.g.,
polycarbophils or polyethans, redox sensitive polymers that respond to redox
potential in colon which expresses the total metabolic and bacterial action.

1.4.1.6 Chewable tablets

The patients who have difficulty in swallowing

tablets whole or for children who have not yet learnt to swallow a tablet,
chewable tablet serves as an attractive alternative. The added advantage of
this medication is that it can be taken at any time or when water is not available.
Mannitol is normally used as a base due to low hygroscopy and more importantly,
it gives pleasant, cooling sensation. Antacid tablets are invariably prepared
as chewable to obtain quick ingestion relief as well as the antacid dose is too
large to swallow and the activity is related to particle size. Another example
is multivitamin tablet which a patient can take as a daily dose.

1.4.1.7 Dispersible tablet (9)

These tablets disintegrate either rapidly in water,

to form a stabilized suspension, or disperse instantaneously in the mouth to be
swallowed without the aid of water. So, it’s preferred for pediatric patients
who cannot swallow a solid dosage form and the API is unstable if formulated in
liquid formulation. Also helpful for patients having prolonged illness who are
prone to nauseatic sensations if they have to swallow a tablet. The added
advantage of this formulation is faster onset of action as compared to standard
compressed tablet. The properties of the water dispersible tablet, such as porosity,
hardness, disintegration time and increase in viscosity after dispersion are
necessary to investigate during manufacturing which decides the product
performance. The common examples of API formulated in this dosage form are
analgesics e.g., aspirin, ibuprofen, etc.

1.4.2 Tablets used in the oral cavity (1-3)

The tablets under this group are aimed release API in

oral cavity or to provide local action in this region. The tablets under this
category avoids first-pass metabolism, decomposition in gastric environment,
nauseatic sensations and gives rapid onset of action. The tablets formulated
for this region are designed to fit in proper region of oral cavity.

1.4.2.1 Lozenges and troches

The tablet is a flat faced at least about 18mm in

diameter and meant to suck and dissolves in the mouth. The compressed tablet is
called troches and the tablets produced by fusion or candy molding process are
called lozenges. Flavours and sweeteners are added to make tablets palatable.
The tablet generally contains sucrose or lactose and gelatin solution to impart
smooth taste. Lozenges for local action in mouth/ throat are: antiseptics,
antibiotics, demulcents, antitussive agents or astringents. To produce systemic
action: multivitamin tablet.

1.4.2.2 Sublingual tablets

They are to be placed under the tongue and produce

immediate systemic effect by enabling the drug absorbed directly through
mucosal lining of the mouth beneath the tongue.

Figure.11. Sublingual Tablets

The drug absorbed from stomach goes to mesenteric

circulation which connects to stomach via portal vein. Thus, absorption through
oral cavity avoids first-pass metabolism. The tablets are usually small and
flat, compressed lightly to keep them soft. The tablet must dissolve quickly
allowing the API to be absorbed quickly. It’s designed to dissolve in small
quantity of saliva. After the tablet is placed in the mouth below the tongue,
the patient should avoid eating, drinking, smoking and possibly talking in
order to keep the tablet in place. Swallowing of saliva should also be avoided
since the saliva may contain dissolved drug. Bland excipients are used to avoid
salivary stimulation. Due to inconvenience in administration, this dosage form
is prepared only for those API(s) for which the only satisfactory nonparenteral
method is this route. For example, Glyceryl trinitrate (vasodilator) and
Isoprinosine sulphate (bronchodilator).

1.4.2.3 Buccal tablets

Completeness of drug absorption is desired but fast drug absorption is not

intended. The tablets are designed not to disintegrate. They are flat elliptical
or capsule shaped tablets as it can be easily held between gum and cheek. It’s
placed near the opening of parotid duct to provide the medium to dissolve the
tablet.

Figure.12. Buccal Tablets

Since this tablet is to be kept for 30-60 minutes in

oral cavity, care should be taken to see that all the ingredients are finely
divided to avoid gritty or irritating sensation. This tablet is most often used
when replacement hormonal therapy is to be administered. Antifungal drugs are
preferred to be administered by this route. e.g., Miconazole – under
preclinical trial – still not in market.

1.4.2.4 Dental cones

These tables are designed to be loosely packed in the

empty socket remaining following a tooth extraction.

Figure.13. Dental Cones

Main purpose behind the use of this tablet is either

to prevent multiplication of bacteria in the socket by employing a slow
releasing antibacterial compound or to reduce bleeding by an astringent or
coagulant containing tablet. It’s formulated to dissolve or erode slowly in
presence of a small volume of serum or fluid over 20-40 minutes period.

1.4.2.5 Mouth Dissolved tablets/ Rapidly Dissolving tablets (10)

Known to the FDA as orally disintegrating tablets,
they are also called mouth-dissolving, fast-dissolving, rapid-melt, porous,
orodispersible, quick dissolving. These kinds of tablets are preferred when
fast action or relief is desired. Most commonly used drugs under this
formulation are the agents active against Migraine. The tablets are designed to
disintegrate as well as dissolve within one minute or some within 10 seconds of
oral administration in limited quantity of saliva. They liquefy on tongue and
patient swallows the liquid, without the need of water. A number of techniques
are used to prepare these tablets, including lyophilization, soft direct
compression. Matrices having an API and high porosity are also being prepared
using sublimation process. Urea, urethane, ammonium carbonate, ammonium
bicarbonate, hexamethylene, benzoic acid, naphthalene and camphor are commonly
used for sublimation processing as they they volatize rapidly. After removal by
sublimation, these inert volatile substances leave the matrices with a high
porosity. Disintegrants and sugar based excipients, such as sodium starch
glycolate, cross carmellose sodium, mannitol, xylitol, dextrose, fructose,
maltose and polydextrose have been incorporated in almost all the orally
disintegrating dosage forms (ODDFs). Loading of drug is made by preparing a
blank and drug is post loaded. Generally the drug in solution is added after
which the solvent evaporates. Taste masking poses numerous challenges since the
drug product dissolves in mouth, any taste of drug must be covered, either by
flavoring technique or by micro encapsulation or nanoencapsulation. A major
drawback of most of these systems is that the packaging system needs a higher
degree of protection due to the lower hardness and more friability of the
porous nature of tablets, except the DuraSolv technology of CIMA Labs, which
are suitable for rigors of bulk bottle packaging. Keep the orally disintegrating tablet in
the
blister pack inside the outer foil pouch until the patient is ready to take the
medicine. Make sure that operator’s hands are dry and peel open the blister to
remove the tablet. Place the tablet on tongue and let it dissolve. These dosage
forms have become a delivery system of choice for most patients as they provide
comfort for administration throughout the day. Pharmaceutical companies, on the
other hand, benefit from value addition in terms of product life-cycle
management in today’s market.

1.4.3 Tablets administered by other routes (1-3)

These tablets are administered by other route except

for the oral cavity and so the drugs are avoided from passing through gastro
intestinal tract. These tablets may be inserted into other body cavities or
directly placed below the skin to be absorbed into systemic circulation from
the site of application.

1.4.3.1 Vaginal tablets

This tablet undergoes slow dissolution and drug

release in vaginal cavity of women. The shape is kept ovoid or pear shaped to
facilitate retention in vagina. The tablet should be made compatible with
plastic tube inserters which are designed to place the tablet in the upper
region of vaginal tract. These tablets generally release antibacterial,
antiseptics or astringents to treat vaginal infections or release steroids for
systemic absorption.

1.4.3.2 Implants

These tablets are inserted into subcutaneous tissue

by surgical procedures where they are very slowly absorbed over a period of a
month or a year. A special injector with a hollow needle and plunger is used to
administer the rod shaped tablet for other shapes, surgery is required. The
tablets may be pellet, cylindrical or rosette shaped with diameter not more
than 8mm. They are sterile formulation without excipients and made hard with
large particle size to achieve gradual drug release. The tablets are produced
by a sterile single punch hand operated machine in which the die cavity is
filled with hand since the material does not normally flow well. Mainly, these
tablets are prepared to deliver growth hormones to food producing animals and
ear is the preferred site for administration of the drug.

1.4.4 Tablets used to prepare solution

The tablets under this category are required to be

dissolved first in water or other solvents before administration or
application. This solution may be for ingestion or parenteral application or
for topical use depending upon type of medicament used.

1.4.4.1 Effervescent tablets (11)

The oral dosage forms are the most popular way of

taking medication despite having some disadvantages like slow absorption and
thus onset of action is prolong. This can be overcome by administrating the
drug in liquid from but, many APIs have limited level of stability in liquid
form. So, effervescent tablets acts as an alternative dosage form. The tablet
is added into a glass of water just before administration and the drug solution
or dispersion is to be drunk immediately. The tablet is quickly broken apart by
internal liberation of CO2 in water due to interaction between
tartaric acid and citric acid with alkali metal carbonates or bicarbonates in
presence of water.

Figure.14. Effervescent Tablets

Due to liberation in CO2 gas, the

dissolution of API in water as well as taste masking effect is enhanced. The
advantages of effervescent tablets compared with other oral dosage forms
includes an opportunity for formulator to improve taste, a more gentle action
on patient’s stomach and marketing aspects. To manufacture these tablets,
either wet fusion or heat fusion is adopted. The tablets are compressed soft
enough to produce an effervescent reaction that is adequately rapid. Water
soluble lubricants are used to prevent an insoluble scum formation on water
surface. To add sweetness to the formulation, saccharin is added since sucrose
is hygroscopic and add too much of bulk to the tablet. The manufacturing shall
be done under controlled climatic condition to avoid effervescent reaction. The
packaging is done under 25% RH at 25ºC. Hands of the consumers and atmospheric
moisture after opening the container can also result in loss of product
quality. The most commonly used effervescent tablet today is aspirin
tablet.

1.4.4.2 Hypodermic tablets

These tablets contain one or more readily water

soluble ingredients and are intended to be added in water for injection of
sterile water to form a clear solution which is to be injected parenterally.
They were widely used by rural physician due to its portability. One bottle of
sterile water was carried by the doctor to prepare many types of injectables.
It can be used for medicaments whose stability in water is very poor.

1.4.4.3 Soluble tablets (12)

Tablets are pre-formed

solids of uniform shape and dimensions, usually circular, with either flat or
convex faces, the distance between faces being less than the diameter. Water
soluble tablets are intended for application after dissolution in water and
contain an active ingredient should be totally soluble in water at used
concentrations. All the excipients used to formulate these tablets are required
to be completely soluble in water including the glidants, binders, etc. So,
manufacturing of this kind of tablets are challenge for the formulator.
Companies manufacturing these tablets have patented them.

Figure.15. Soluble Tablets

Key Phrases

Ø When two or more active pharmaceutical ingredients are needed to be administered

simultaneously and they are incompatible, the best option for the formulation
pharmacist would be to formulate multilayered tablet.

Ø When we need to release the medicament slowly for long time duration after
administration of a single tablet we go for modified release formulation.

Ø When we need to release the API at a specific site in the elementary tract,
targeted drug delivery is a preferred option.

Ø Dispersible tablets disintegrate either rapidly in water, to form a

stabilized suspension, or disperse instantaneously in the mouth to be
swallowed without the aid of water

Ø Sublingual tablet is designed to dissolve in small quantity of saliva and

used when immediate action within few minutes is desired.

Ø Buccal tablet is most often used when replacement hormonal therapy is to

be administered.

Ø Implants are inserted into subcutaneous tissue by surgical procedures where

they are very slowly absorbed over a period of a month or a year.

Formulation of tablets
Submitted by on Sun, 12/06/2009 - 19:50

1.5 Formulation

Ø What will you gain?

1.5.1
Excipient and their functionalities

1.5.2
Diluents

1.5.3
Binders

1.5.4
Disintegrants

1.5.5
Antifrictional Agents

1.5.6
Miscellaneous Excipients
1.5.1 Excipient and their functionalities (13-15)

Excipient means any

component other than the active pharmaceutical ingredient(s) intentionally
added to the formulation of a dosage form. Many guidelines exist to aid in
selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS
(Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others.

While selecting excipients

for any formulation following things should be considered wherever possible:
keep the excipients to a minimum in number minimize the quantity of each
excipients and multifunctional excipients may be given preference over
unifunctional excipients.

Excipients play a crucial role in design of the

delivery system, determining its quality and performance. Excipients though
usually regarded as nontoxic there are examples of known excipient induced
toxicities which include renal failure and death from diethylene glycol,
osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from
lanolin and cardiotoxicity induced by propylene glycol.

Excipients are chosen in

tablet formulation to perform a variety of functions like

i) For providing essential manufacturing technology functions (binders, glidants,

lubricants may be added),

ii) For enhancing patient acceptance (flavors, colourants may be added),

iii) For providing aid in product identification (colourants may be added),

iv) For Optimizing or modifying drug release (disintegrants, hydrophilic polymers,

wetting agents, biodegradable polymers may be added),

v) For enhancing stability (antioxidant, UV absorbers may be added)

Various excipients used in tablet formulation and their functionalities.

(1, 4, 16)

Table.2. Excipient With Their Functions In Tablet Formulation

EXCIPIENT
Diluents or Fillers
Binders or Granulating
agents or Adhesives
FUNCTION
Diluents
make the required bulk of the tablet when the drug dosage
itself is inadequate
to produce tablets of adequate weight and size.
Binders
are added to tablet formulations to add cohesiveness to
powders, thus
 providing the necessary bonding to form granules, which
under compaction form
a cohesive mass or a compact which is referred to as a
tablet.
Disintegrants A
disintegrant is added to most tablet formulations to
facilitate a breakup or
disintegration of the tablet when placed in an aqueous
environment.
Antifrictional Agents
Lubricants Lubricants
are intended to reduce the friction during tablet formation
in a die and also
during ejection from die cavity.
Antiadherents Antiadherents
are added to reduce sticking or adhesion of any of the
tablet granulation or
powder to the faces of the punches or to the die wall.
Glidants Glidants
are intended to promote the flow of tablet granulation or
powder mixture from
hopper to the die cavity by reducing friction between the
particles.
MISCELLANEOUS
Wetting agents Wetting agents are added to tablet formulation to aid
water uptake during
disintegration and assist drug dissolution.
Dissolution retardants Dissolution
retardants as the name suggest, retards the dissolution of
active
pharmaceutical ingredient(s).
Dissolution enhancers Dissolution
enhancers as the name suggest, enhance the dissolution
rate of active
pharmaceutical ingredient(s).
Adsorbents Adsorbents
are capable of retaining large quantities of liquids without
becoming wet;
this property of absorbent allows many oils, fluid extracts
and eutectic
melts to be incorporated into tablets.
Buffers Buffers
are added to provide suitable micro environmental pH to
get improved
stability and / or bioavailability.
Antioxidants Antioxidants
are added to maintain product stability, they act by being
 preferentially
oxidized and gradually consumed over shelf life of the
product.
Chelating agents Chelating
agents are added to protect against autoxidation; they act
by forming
complexes with the heavy metal ions which are often
required to initiate oxidative
reactions.
Preservatives Preservatives
are added to tablet formulation in order to prevent the
growth of
micro-organisms.
Colours Colours
are added to tablet formulation for following purposes: to
disguise off
colour drugs, product identification and for production of
more elegant
product.
Flavours Flavours
are added to tablet formulation in order to make them
palatable enough in
case of chewable tablet by improving the taste.
Sweeteners Sweeteners
are added to tablet formulation to improve the taste of
chewable tablets.

Ø Key Phrases

Ø Tablet formulations are usually designed to satisfy following criteria-

Patient acceptability; accuracy and uniformity of drug content;
manufacturability; optimal drug dissolution and stability.

Ø Excipients are any component other than active pharmaceutical ingredient(s)

intentionally added to the formulation of a dosage form.

Ø Excipients play a crucial role in design of the delivery system, determining

its quality and performance.

Ø Various excipients used in tablet formulation are diluents, binders, disintegrants,

lubricants, antiadherents, glidants, wetting agents, dissolution retardants,
dissolution enhancers, absorbents, buffers, antioxidants, chelating agents,
preservatives, colours, flavours, sweeteners, etc.

1.5.2 Diluents (Fillers)

What will you gain?

1.5.2.1
Introduction

1.5.2.2
Classification of diluents

1.5.2.2.1 Organic diluents

1.5.2.2.2 Inorganic diluents

1.5.2.2.3 Co-processed diluents

1.5.2.1 Introduction (1, 17)

In order to facilitate tablet

handling during manufacture and to achieve targeted content uniformity, the
tablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Many
potent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in such
cases diluents provide the required bulk of the tablet when the drug dosage
itself is inadequate to produce tablets of adequate weight and size. Usually
the range of diluent may vary from 5-80%. Diluents are also synonymously known
as fillers. Diluents are often added to tablet formulations for secondary
reasons like to provide better tablet properties such as:

i)To provide improved cohesion

ii)To allow direct compression manufacturing

iii)To enhance flow

iv)To adjust weight of tablet

as per die capacity

No matter for what purpose they (diluents) are added

they must meet certain basic criteria for satisfactory performance in tablet
dosage form. They are as follows:
Diluent should not react with the drug substance and moreover it should
not have any effect on the functions of other excipients, it should not have
any physiological or pharmacological activity of its own, it should have
consistent physical and chemical characteristics, it should neither promote nor
contribute to segregation of the granulation or powder blend to which they are
added, it should be able to be milled (size reduced) if necessary in order to
match the particle size distribution of the active pharmaceutical ingredient,
it should neither support microbiological growth in the dosage form nor
contribute to any microbiological load, it should neither adversely affect the
dissolution of the product nor interfere with the bioavailability of active
pharmaceutical ingredient, it should preferably be colourless or nearly so.
1.5.2.2 Classification of diluents (16,17)

Tablet
diluents or fillers can be divided into following categories:

i)Organic materials - Carbohydrate and modified carbohydrates.

ii)Inorganic materials – Calcium phosphates and others.

iii)Co-processed Diluents.

Carbohydrate substances such as sugars, starches and celluloses may also function
as binders during wet granulation process. Whereas when used in direct compression
system, they serve as the diluent. The inorganic diluents, do not exhibit binding
properties when used in wet granulation and direct compression.

Tablet diluent or filler

may also be classified on the basis of their solubility in water as soluble and
insoluble.

Table.3. Classification Of Diluents Based On Their Solubility

INSOLUBLE TABLET FILLERS OR SOLUBLE TABLET FILLERS OR

DILUENTS DILUENTS
Starch Lactose

Powdered Sucrose
cellulose
Mannitol
Microcrystalline
cellulose Sorbitol,
etc.
Calcium
phosphates, etc.

Selection of diluent should

be done after considering properties of diluent such as: Compactibility,
flowability, solubility, disintegration qualities, hygroscopicity, lubricity
and stability.

1.5.2.2.1 Organic diluents (1,17-20)

Carbohydrates

Sugar and Sugar

alcohols

Lactose α-lactose
monohydrate, spray dried lactose and anhydrous lactose are widely used as
diluent.
Characteristics of α -Lactose
monohydrate (hydrous)
Lactose
monohydrate is not directly compressible and therefore it is suitable for use
in wet granulation.

It
has poor flow properties.

α-lactose
monohydrate is water soluble.

It
produces a hard tablet and the tablet hardness increases on storage.

Disintegrant
is usually needed in lactose containing tablets.

Drug
release rate is usually not affected.

It
is usually unreactive, except for discoloration when formulated with amines
and alkaline materials (i.e. browning or maillard reaction).

It
contains approximately 5% moisture and hence is a potential source of
instability especially with moisture sensitive drugs.

It
is inexpensive.

It
is commercially available under the trade name of: PharmatoseÒ and Respitose®
manufactured by DMV International.
Characteristics of
Lactose spray dried
It is directly
compressible diluent.

It exhibits free flowing

characteristics.

It needs high compression

pressures in order to produce hard tablets.

Its compressibility is
adversely affected if dried below 3% moisture.
It has high dilution
potential.

It is more prone to
darkening in the presence of excess moisture, amines and other compounds due
to the presence of a furaldehyde.

Usually, neutral or acid

lubricant should be used when spray dried lactose is employed.

Expensive compared to
anhydrous and hydrous lactose.

It is commercially
available as Spray Process 315® manufactured by Foremost Farms
USA.
Characteristics of
Lactose anhydrous
Lactose anhydrous is a
directly compressible diluent.

It does not exhibit free

flowing property.

It can pick up moisture at

elevated humidity as a result of which changes in tablet dimensions may occur.

It does not undergo a

maillard reaction to the extent shown by spray dried lactose, although this
may occur in some cases to a slight degree.

It is inexpensive.

It is commercially
available as Pharmatose® DCL 21 manufactured by DMV Pharma.

Starch

Characteristics of Compressible Starch

(Pregelatinized)
It
is a directly compressible diluent.

It
has better flow compared to unmodified starch.

It
also shows high compressibility as the aggregated granules undergo plastic
deformation on compression.

It
possesses good binding properties.

It
also possesses disintegrant activity.

It
requires high pressure in order to produce a hard tablet.

For
good flow, it requires a flow promoter.

It
is prone to softening when combined with large amounts of magnesium stearate.

It
is commercially available under the trade name of Starch 1500 LMÒ manufactured by
Colorcon.

Sucrose

Characteristics of Sucrose or sugar

It
requires high machine pressures, especially in cases with over wetted
granulations.

It
is water soluble.

It
possesses good binding properties.

It
is slightly hygroscopic.

It
is inexpensive.

It
produces gritty mouth feel (i.e., it is not free from grittiness).

It
is a calorie contributor and is cariogenic.

Mannitol
Characteristics of Mannitol
Mannitol
a sugar alcohol is an optical isomer of Sorbitol.

It
exhibits poor flow properties.

It
requires high lubricant content.

It
is probably the most expensive sugar used as a tablet diluent and is water
soluble.

It
is widely used in chewable tablets because of its negative heat of solution,
its slow solubility and its mild cooling sensation in mouth.

It
can be used in vitamin formulation, where moisture sensitivity may create a
problem.

It
is comparatively non hygroscopic.

It
is free from grittiness.

It
possesses low caloric value and is noncariogenic.

It
is commercially available under the brand name ParteckÒM manufactured by EMD
Chemicals .Other commercial products are PearlitolÒ and MannogemÒ.

Sorbitol

Characteristics of Sorbitol
Sorbitol is often combined
with mannitol formulations in order to reduce diluent cost.

It is highly compressible
diluent and is water soluble.

It is hygroscopic in
nature.

It has good mouth feel and

sweet cooling taste.

It is free from
grittiness.

It possesses low caloric

value and is noncariogenic.

It is commercially
available as SorbifinÒ and NeosorbÒ .

Poorly
absorbed sugar alcohols such as Sorbitol and mannitol can decrease small
intestinal transit time. Therefore absorption may be altered for the drugs that
are preferentially absorbed from this region.

Celluloses (1,17,
21)

Powdered
cellulose

Characteristics of Powdered cellulose

Powdered cellulose
products consist of finely divided amorphous and crystalline α-cellulose
particles.

Powdered cellulose may be

used alone or together with other fillers such as lactose, calcium
phosphates, dextrans and others.

It possesses poor
compressibility and exhibits poor flow properties.

It has poor binding

properties and low dilution potential.

It is water insoluble.

It possesses some degree

of inherent lubricity.

It is inexpensive.

It is commercially
available under the trade name of ElcemaÒG-250
manufactured by Degussa Corporation.
Microcrystalline
cellulose

Characteristics of Microcrystalline cellulose

Microcrystalline cellulose
(MCC) is highly compressible and is perhaps the most widely used
direct-compression tablet diluent.

Hard tablets, at low

compression pressures, are usually obtained when MCC is used as tablet
diluent.

It undergoes plastic
deformation on compression and hence it is more sensitive to lubricants.

It exhibits fair
flowability.

It exhibits binding
properties.

It also possesses
disintegrant activity and thus promotes fast tablet disintegration.

It is water insoluble.

MCC is expensive.

Silicified MCC (SMCC-

ProsolvÒ) provides increased compactibility, enhanced flow
and improved uniformity compared to MCC (AvicelÒ manufactured by FMC
Biopolymer)

SMCC is more suitable for

cohesive poorly compressible ingredients in direct compression formulation.

Other commercial product

is EmcocelÒ manufactured by Penwest Pharmaceutical Co.

1.5.2.2.2 Inorganic diluents (17,22)

Calcium phosphates

The calcium phosphates, here includes, the dihydrate

and anhydrous form of dibasic calcium phosphate and tribasic calcium phosphate.
They are granular insoluble materials.
They are widely used both as wet granulation and direct compression
diluents in tablet formulation. Bulk density of calcium phosphates is higher
than that of organic fillers. They are used extensively in vitamin and mineral
preparations. Dibasic calcium phosphate dihydrate is also commonly known as
dicalcium phosphate, calcium hydrogen phosphate dihydrate and secondary calcium
phosphate dihydrate.

Dibasic calcium phosphate is available commercially

under the trade name Di-TabÒ (manufactured by Rhone-Poulenc) and EmcompressÒ
(Manufactured by E.Mendell
Co.).An anhydrous form of dibasic calcium phosphate is available commercially
under the trade name A-TabÒ (manufactured by Rhone-Poulenc). Fujicalin®,
a novel commercially available free flowing spherically granulated dicalcium
phosphate anhydrous (SGDCPA) for direct tableting was compared with directly
compressible dicalcium phosphate dihydrate (DCPD) and it was found that SGDCPA
exhibited same good flowability and better compactibility. Whereas in contrast
to DCPD, SGDCPA exhibited significant uptake of moisture when exposed to
relative humidity exceeding 70 %.Tribasic calcium phosphate is also commonly
referred as tricalcium phosphate, tricalcium orthophosphate and hydroxyapatite.
Tribasic calcium phosphate is available under the trade name Tri-TabÒ.

Characteristic of
Calcium Phosphates
They are directly
compressible and are characterized by brittle fracture on compression during
tableting process.

Hard tablets are produced

when calcium phosphates are used as diluents.

They exhibit good flow

properties.

They are non hygroscopic.

They are inexpensive.

They are abrasive in

nature and hence can cause wear of tablet tooling.

Sometimes their alkalinity

is a major source of drug instability.

1.5.2.2.3 Co-processed diluents (17,23)

Co-processing means combining two or more materials

by an appropriate process. The products so formed are physically modified in
such a special way that they do not loose their chemical structure and
stability. Now a days direct compression technique has been one of the
well-accepted methods of tablet manufacture. An extensive range of materials from
various sources have been developed and marketed as directly compressible
diluents such as lactose, starch, cellulose derivatives, inorganic substance,
polyalcohols, and sugar-based materials. In addition to the development of
directly compressible excipients by modifying just a single substance,
co-processing of two or more components has been applied to produce composite
particles or co-processed excipients. The composite particles or co-processed
excipients are introduced in order to provide better tableting properties than
a single substance or the physical mixture.

Table.4. List Of Co-Processed Excipients Used To Achieve

Better Tableting Properties

TRADE NAME MANUFACTURER DESCRIPTION

Fast Flo lactose® Foremost Whey It is spray processed
Products lactose which is a mixture of
crystalline α-lactose monohydrate
and
amorphous lactose.
Microcellac® 75% lactose and 25% MCC
(MicroCrystalline Cellulose)

Ludipress® 93% α-lactose

monohydrate, 3.5%
polyvinylpyrrolidone, and 3.5%
crospovidone.
Nu-Tab® Ingredient Technology Sucrose 95-97%, invert
sugar 3-4% and magnesium
stearate 0.5%
Di-Pac® Amstar Corp. Sucrose 97% and modified
dextrins 3%

Sugartab® E.Mendell Co. Inc. Sucrose 90-93% and invert

sugar 7-10%.

Emdex® E.Mendell Co. Inc. Dextrose 93-99% and

maltose 1-7%
Cal-Tab® Ingredient Technology Calcium sulfate 93% and
vegetable gum 7%

Cal-Carb® Ingredient Technology Calcium carbonate 95% and

maltodextrins 5%

Calcium 90® Ingredient Technology Calcium carbonate

(minimum) 90% and Starch, NF
(maximum) 9%
Key
Phrases

Ø Diluents make the required bulk of the tablet when the drug dosage itself
is inadequate to produce tablets of adequate weight and size.
Ø Diluents are often added to tablet formulations for secondary reasons like
to provide better tableting properties.

Ø Tablet diluents or fillers can be divided into following categories:

i) Organic materials

ii) Inorganic materials

iii) Co-processed diluents

Ø Tablet diluents or fillers may also be classified on the basis of their

solubility in water as soluble diluent and insoluble diluent.

Ø Microcrystalline cellulose (MCC) is perhaps the most widely used direct-

compression
tablet filler.

Ø Co-processing means combining two or more materials by an appropriate

process.

Ø The composite particles or co-processed excipients are introduced to provide

better tableting properties than a single substance or the physical mixture.

1.5.3 Binders ( Adhesives, Granulating agent)

What
will you gain?

1.5.3.1 Why to go for Granulation?

1.5.3.2 Granulation
Processes

1.5.3.3 Types of Binders

1.5.3.4 Direct compression (DC) Binders

1.5.3.5 Mechanism
of granule formation

1.5.3.6 Near Infrared

(NIR) spectroscopy : A tool
for granulation end
point measurement

1.5.3.7 Factors to
be considered in Granulation

1.5.3.8 Evaluation
tests for Binders/Granules

Binder is one of
an important excipient
to be added
in tablet formulation.
In simpler words, binders or
adhesives are the
substances that promotes
cohesiveness. It is utilized
for converting powder
into granules through
a process known
as Granulation. Granulation
is the unit
operation by which
small powdery particles
are agglomerated into
larger entities called
granules.

1.5.3.1 Why to go for Granulation? (24)

Powders/Granules intended for compression into tablets must possess

two essential properties : flow property and compressibility.

Flow
property/Fluidity is required
to produce tablets
of a consistent
weight and uniform
strength. Compressibility is required
to form a
stable, intact compact mass
when pressure is
applied. These two objectives
are obtained by
adding binder to
tablet formulation and
then proceeding for
granulation process. Granules so
formed should possess acceptable flow property and compressibility. Some
drugs exhibit poor fluidity and
compressibility. In such
cases binders have
to be added
for improving flow
property and compressibility.

Other reasons for

Granulation process are to improve
appearance, mixing properties,
to avoid
dustiness, to densify material, to
reduce segregation, in general
to either eliminate
undesirable properties or to improve
the physical and
chemical properties of
fine powders.

1.5.3.2 Granulation Processes (24)

The standard methods frequently used today in tablet manufacturing

are granulation and direct compression. Granulation technique includes
wet granulation and dry granulation/slugging methods wherein binders
are added in solution/suspension form and in dry form respectively.
In Direct Compression, binders possessing direct compressibility characteristics
are used. Binder when used in liquid form gives better binding action
as compared to when used in dry form.

1.5.3.3 Types of Binders (18,25-28)

Table.5. Classification Of Binders

Sugars Natural Binders Synthetic/Semisynthetic Polymer

Sucrose Acacia Methyl
Cellulose
Liquid Tragacanth Ethyl
glucose Cellulose
Gelatin Hydroxy
Propyl Methyl Cellulose ( HPMC)
Starch Hydroxy
Paste Propyl Cellulose
Pregelatinized Starch Sodium
Carboxy Methyl Cellulose
Alginic Polyvinyl Pyrrolidone (PVP)
Acid
Cellulose Polyethylene Glycol (PEG)
Polyvinyl Alcohols
Polymethacrylates

Table.6. Commonly Used Binders

BINDER CATEGORY MANUFACTURER
Partially Pregelatinized
Starch 1500Ò Maize Colorcon
Starch
Hydroxy Propyl Methyl
MethocelÒ Dow Chemicals
Cellulose
Wolff-Cellulosics
Hydroxy Propyl Methyl
WalocelÒHM
Cellulose Natural Starch and
Chemical Company
LuvitecÒ Polyvinylpyrrolidone BASF Company
LuvicrossÒ Polyvinylpyrrolidone BASF Company
LuvicaprolactamÒ Polyvinylcaprolactam BASF Company

Table.7. Characteristics Of Commonly Used Binder

BINDER SPECIFIED
CONCENTRATION COMMENTS
Starch Paste 5-25%w/w - Freshly prepared starch paste is
used as a binder.

- Its method of preparation is very

crucial.
Pregelatinized 5-10%w/w - It is starch
Starch (PGS) that have been
(Direct Compression) processed chemically and/or
[Partially and Fully mechanically to rupture
PGS] 5-75%w/w all or part
of the granules
(Wet Granulation ) in the presence
of water and
subsequently dried.

-
It contains 5%
free amylose, 15% free
amylopectin and 80%
unmodified starch.

- Obtained from maize, potato or rice

starch.

- It is multifunctional excipient
used as a
tablet binder, diluent,
disintegrant and flow
aid.
 - They enhance both
flow and compressibility and
can be used
as binders in
Direct Compression as
well as Wet
Granulation.

- High purity PGS

allow simplified processing
as they swell
in cold water
and therefore reduce
time/costs compared with
traditional starch paste
preparation.
Hydroxypropyl 2-5%w/w - Comparable to Methyl Cellulose.
Methyl Cellulose
(HPMC) - Used as a
binder in either
wet or dry
granulation processes.
Polyvinyl 0.5-5%w/w - Soluble in both water and alcohol.
Pyrrolidone (PVP)
- Used in wet granulation process.

- It
is also added
to powder blends
in the dry
form and granulated
in situ by
the addition of
water, alcohol or hydroalcoholic solution.

- Valuable binder for chewable tablets.

- The drug release is not altered on

storage.
Polyethylene 10-15%w/w - Used as a meltable binder.
Glycol (PEG) 6000
- Anhydrous granulating
agent where water
or alcohol cannot
be used .

- It
may prolong disintegration time
 when concentration is
5% or higher

- It improves the plasticity of other

binders.

1.5.3.4 Direct compression (DC) Binders (29)

Due
to ease of manufacture, product stability and high efficiency, the use of
Direct Compression for tableting has increased. For Direct Compression,
directly compressible binders are required which should exhibit adequate powder
compressibility and flowability. Direct Compression binders should be selected
on the basis of compression behavior, volume reduction under applied pressure
and flow behavior in order to have optimum binding performance. The choice and
selection of binders is extremely critical for Direct Compression tablets.

Table.8. Commonly Used Dc Binders

Dc Binder Class Manufacturer

AvicelÒ (PH 101) MCC a
FMC Corporation
SMCCÒ (50) SMCCb Penwest Pharmaceutical
UNI-PUREÒ(DW) Partially PGSc National Starch

& Chemical
Ò
UNI-PURE (LD) Low density starch National Starch &
Chemica
DC LactoseÒ DC lactose anhydrous Quest International Group
DI TABÒ DC-DCPDd Rhodi

a
– Microcrystalline Cellulose, b – Silicified Microcrystalline Cellulose, c –
Pregelatinized Starch, d – Dibasic Calcium Phosphate Dihydrate

Table.9. Characteristics Of Dc Binders

Flow Behavior DI TABÒ> SMCCÒ(50) > DC LactoseÒ , UNI

PUREÒ(DW) > AvicelÒ (PH 101) > UNI PUREÒ(LD)
Compressibility UNI PUREÒ(LD) > SMCCÒ(50) , AvicelÒ(PH 101) >
UNI PUREÒ(DW) , DC LactoseÒ > DI
TABÒ
Crushing Strength UNI PUREÒ(LD) > SMCCÒ(50) > UNI PUREÒ(DW) >
AvicelÒ(PH 101) > DC
LactoseÒ > DI TABÒ
1.5.3.5 Mechanism of
granule formation (30)

Granules
are formed in three stages:

Nucleation:
Here, the particles adhere due to
liquid bridges which are the initiation step of Granulation. These adhered
particles play a role of nucleus for further enlargement of granules.

Transition: Enlargement of nucleus takes place by two possible

mechanisms. Individual particle adhere to the nucleus or two or more nuclei
combine among themselves.

Ball growth or enlargement of the

granule:
Ball growth occurs either by Coalescence or Breakage or Abrasion Transfer or
Layering. In Coalescence a larger granule is formed when two or more granules
are united. In Breakage granules break and the fragments of granule adhere to
other granules. This forms a layer of material over intact granules. In
Abrasion Transfer granule material are abraded through attrition by the
agitation of granule bed and abraded material adheres to other granules
resulting into enlarged granules. In layering particles adheres to the already
formed granules increasing their size.

1.5.3.6
Near Infrared (NIR)
spectroscopy : A tool for
granulation end point
measurement (31)

NIR Spectroscopy is applicable for

monitoring of wet granulation process when impeller torque method cannot be
applied. Watano et al determined the granulation end point using agitated
fluidized bed where in IR moisture sensor was installed. The properties of the
wet mass obtained from NIR are independent of granulator equipment variables
such as impeller design. Even the powder blending efficiency in the dry mixing
phase can be monitored inline by NIR. NIR spectroscopy could be an excellent
tool in wet granulation measurement.

1.5.3.7 Factors to be considered in Granulation (24,30,32)

Compatibility

The primary criteria is the compatibility of binder with the

API & other tablet components. This is traditionally found by
choosing appropriate stability study design. Currently Differential Scanning
Calorimetry (DSC) is used to ascertain compatibility.
Characteristics of
drugs and other excipients

The drugs characteristics like its

compressibility, particle size,
surface area, porosity,
hydrophobicity, solubility in
binder are important
while fixing a
granulation process. The
drug that exhibits
poor compressibility requires
the use of
a strong binder (liquid glucose, sucrose, etc.) while
the drugs that
exhibit good compressibility can
be successfully handled
using a weak
binder ( starch paste etc.,).
Fine and porous
particles requires higher
amount of liquid
binder as compared
to coarse particles. Hydrophilic drug/excipients exhibiting
absorption characteristics require
higher volume of
binder as compared
to hydrophobic drug/excipients. The granule
quality (size , friability) is
governed by the
solubility of the
drug in the
granulation solution.

Spreading of Binder

Spreading
of binder/granulation solution
on the powder
blend is of
paramount importance in
successful granulation. A binder
that spreads easily
on particles is
superior as compared
to that which
shows poor wetting
quality. HPMC is a
superior binder for
paracetamol as compared
to PVP.

Type and quantity of

Binder

The uniformity
of the particle
size, hardness, disintegration
and compressibility of
the granulation depends on type
and quantity of binder added to formulation. As for example hard granulations
results due to stronger binder or a highly concentrated binder solution which
require excessive compression force during tableting. On the
other hand, fragile granulations
results due to insufficient quantity
of binder which
segregates easily. Larger quantities
of granulating liquid
produce a narrower
particle size range
and coarser and
hard granules i.e.
The proportion of fine granulates particle decreases. Therefore the
optimum quantity of
liquid needed to
get a given
particle size should
be known in
order to keep
a batch to batch variations
to a minimum.

Temperature and
Viscosity

The temperature and viscosity of binder is also

important. Fluid (less viscous) binder exhibit good spreading behavior.

Method of Addition of
Binder

The
method of addition of binder is also important. PVP can
be used as
solution as a
binder or it
may be dry
blended with powders
and later activated
by adding water. Distribution of
binder is favored
if it is
dispersed instead of
pouring it.

Mixing Time

The mixing time also determines quality of

granules. If the wet
massing time is
higher (resulting into hard
granules), the tablets may
fail the dissolution
test in certain
cases since drug
release from hard
granules is altered.

Material of
Construction of Granulator

The
material of construction
of granulator determines
the volume of
binder required as
well as granule
size distribution. Any
vessel wall which
are wetted easily
by binder demands
the need of
higher volume of
binder. As for example
vessel wall made
up of Stainless Steel
require higher volume
of binder as
compared to vessel
made up of
plastics (PMMA – Polymethylmethacrylate
and PTFE –
Polytetrafluoroethylene i.e. Teflon).
In case of
PMMA and PTFE
due to high
contact angle, all
granulating liquid is
forced immediately into
the powder bed
and gives narrow
particle size distribution.
While in case
of steel, due to
less contact angle
liquid layer formed
on the wall
surface which in
turn causes inhomogeneous
distribution of liquid
over the powder
bed resulting into broader
granule size.

Type of Granulator

Fluidized
Bed Granulator produces
porous granules as
compared to High
Shear Granulators.

Process Variables

Higher
degree of densification
of the granules results due to higher impeller
speed as well
as longer wet
massing time. And also there is
tendency of agglomeration since liquid saturation increases. Consequently,
impeller speed and wet massing time affect the granule size.

Apparatus Variables

The
apparatus variables in
High Shear Mixer
have a larger
effect on granule
growth than in
Fluidized Bed Granulators
because the shear
forces are dependent
on the mixer
construction. The size and
shape of the
mixing chamber, impeller and
chopper vary in
different High Shear
Mixers.

Impeller Movement

Adhesion
of wetted mass to the vessel is less if impeller movement is helical. This
gives a narrower granule size and few lumps. In case of High Shear Mixers,
adhesion of wetted mass to the vessel is a problem which can be reduced by
proper construction of the impeller or by coating the vessel with
Polytetrafluoroethylene i.e. Teflon.

1.5.3.8 Evaluation
tests for Binders/Granules (1)

Compactness, physical and chemical stability,

rapid production capability, efficacy are some of the characteristics that make
tablet a ruling dosage form. These characteristics depend on the quality of
granules from which it is made. The characteristics of granules produced are
affected by formulation and process variables. So it becomes essential to
evaluate the granule characteristics to monitor its suitability for tableting.

Particle Size and Particle

Size Distribution

The particle size

of granules affect
the average tablet
weight, tablet weight variation, disintegration time,
granule friability,
granulation flowability and
the drying rate
kinetics of wet
granulations. Therefore the effects
of granule size
and size distribution
on the quality of tablet should
be determined by formulator. The
methods usually adopted
for measurement of
particle size and
particle size distribution
includes Microscopy, Sieving, Conductivity test.

Surface Area

Surface
area of the
drug effects upon
dissolution rate especially
in cases where
drug have limited
water solubility. The
two most common
methods for surface
area determination are Gas
Adsorption and Air
Permeability.

Density

Granule
density, True Density, Bulk Density
may influence compressibility, tablet porosity, flow property, dissolution and
other properties. Higher compression
load is required in case of dense and hard granules which in turn increases the
tablet disintegration and
drug dissolution times.
Density is usually determined by pycnometer.

% Compressibility

Compressibility is
the ability of
powder to decrease
in volume under pressure. Compressibility is a measure that is
obtained from density determinations.

% Compressibility =
(Tapped density – Bulk density/Tapped density)*100

Compressibility measures
gives idea about
flow property of
the granules as
per CARR’S Index
which is as
follows :

Table.10. Carr’s Index

% Compressibility Flow Description

5 – 15 Excellent
12 – 16 Good
18 – 21 Fair
23 – 28 Poor
28 – 35 Poor
35 – 38 Very Poor
> 40 Extremely Poor

Flow Properties

It is very
important parameter to be measured
since it affects
the mass of
uniformity of the
dose. It is
usually predicted from
Hausner Ratio and
Angle Of Repose
Measurement.

Hausner Ratio = Tapped

Density / Bulk Density

Table.11. Hausner Ratio

HAUSNER RATIO TYPE OF

FLOW
Less Good
than 1.25 Flow
1.25 – 1.5 Moderate
More Poor
than 1.5 Flow

Angle of Repose (Φ) is the

maximum angle between
the surface of
a pile of
powder and horizontal
plane. It is
usually determined by
Fixed Funnel Method
and is the
measure of the
flowability of powder/granules.

Φ = tan-1
(h / r) where, h = height of heap of pile

r = radius of base of pile

Table.12.Angle Of Repose (Φ)

ANGLE TYPE
 OF REPOSE OF FLOW
< 25 Excellent
25 – 30 Good
30 – 40 Passable
> 40 Very
Poor

Friability

Friability
is important since
it affects in
particle size distribution
of granules affecting compressibility into
tablet, tablet weight variation,
granule flowability. Friability is
determined carrying out
Tumbler Test or
using Friability Tester
( Roche Friabilator ) and
% loss is
determined.

Moisture Content

It affects the granule flowability,

compressibility as well as the stability of moisture sensitive drug and
therefore should be determined to evaluate the quality of granule.
Key Phrases

ØBinders are
added in tablet formulation to have required flow property and
compressibility of powders.

ØWet
Granulation, Dry Granulation/Slugging, Direct Compression are major granule
manufacturing methods.

ØDirect
Compression Binders are more efficient than conventional binders.

ØPregelatinized
Starch is used as multifunctional excipient: tablet binder (wet granulating
agent as well as direct compression binder), diluent, disintegrant and flow
aid.

ØPolyethylene
Glycol used as meltable binder.

ØGranules are
formed in three stages: Nucleation, Transition and Ball Growth.

ØNIR a tool for

granulation end point measurement and is better than torque impeller method.

ØCompatibility
of binder with API and other excipients, characteristics of binder, process
variables, and apparatus variables affects the quality of granules.

ØGranules have
to be evaluated in order to measure its suitability for tableting.

1.5.4
Disintegrants

What will you gain?

1.5.4.1
Introduction

1.5.4.2
Mechanism of tablet disintegrants

1.5.4.3
Methods of addition of disintegrants
1.5.4.4
Types of disintegrants

1.5.4.5
Factors affecting disintegration

1.5.4.1 Introduction

Bioavailability
of a drug depends in absorption of the drug, which is affected by solubility of
the drug in gastrointestinal fluid and permeability of the drug across
gastrointestinal membrane. The drugs solubility mainly depends on physical –
chemical characteristics of the drug. However, the rate of drug dissolution is
greatly influenced by disintegration of the tablet.

The
drug will dissolve at a slower rate from a nondisintegrating tablet due to
exposure of limited surface area to the fluid. The disintegration test is an
official test and hence a batch of tablet must meet the stated requirements of
disintegration.

Disintegrants, an important excipient of the

tablet formulation, are always added to tablet to induce breakup of tablet when
it comes in contact with aqueous fluid and this process of desegregation of
constituent particles before the drug dissolution occurs, is known as
disintegration process and excipients which induce this process are known as
disintegrants.

The objectives behind addition of

disintegrants are to increase surface area of the tablet fragments and to
overcome cohesive forces that keep particles together in a tablet.

Figure.16. Schematic Representation Of Tablet Disintegration And Subsequent

Drug Dissolution
1.5.4.2 Mechanism of tablet disintegrants (16,29,33-39)

The tablet breaks to primary particles by

one or more of the mechanisms listed below:-

I.By capillary action

II.By swelling

III.Because of
heat of wetting

IV.Due to disintegrating particle/particle repulsive forces

V.Due to
deformation

VI.Due to
release of gases

VII.By enzymatic
action

By Capillary Action

Disintegration by capillary action

is always the first step. When we
put the tablet into suitable aqueous medium, the medium penetrates into the
tablet and replaces the air adsorbed on the particles, which weakens the
intermolecular bond and breaks the tablet into fine particles. Water uptake by
tablet depends upon hydrophilicity of the drug /excipient and on tableting
conditions. For these types of
disintegrants maintenance of porous structure and low interfacial tension
towards aqueous fluid is necessary which helps in disintegration by creating a
hydrophilic network around the drug particles.

By Swelling

Perhaps the most widely accepted general mechanism of

action for tablet disintegration is swelling Tablets with high porosity show
poor disintegration due to lack of adequate swelling force. On the other hand,
sufficient swelling force is exerted in the tablet with low porosity. It is
worthwhile to note that if the packing fraction is very high, fluid is unable
to penetrate in the tablet and disintegration is again slows down.
Figure.17. Disintegration Of Tablet By Wicking And Swelling

Because of heat of wetting (air expansion)

When
disintegrants with exothermic properties gets wetted, localized stress is
generated due to capillary air expansion, which helps in disintegration of
tablet. This explanation, however, is limited to only a few types of
disintegrants and can not describe the action of most modern disintegrating
agents.

Due to disintegrating particle/particle repulsive

forces

Another
mechanism of disintegration attempts to explain the swelling of tablet made
with ‘non-swellable’ disintegrants. Guyot-Hermann has proposed a particle
repulsion theory based on the observation that nonswelling particle also cause
disintegration of tablets. the
electric repulsive forces between particles are the mechanism of disintegration
and water is required for it. Researchers found that repulsion is secondary to
wicking.

Due to deformation

Hess
had proved that during tablet compression, disintegranted particles get
deformed and these deformed particles get into their normal structure when they
come in contact with aqueous media or water. Occasionally, the swelling
capacity of starch was improved when granules were extensively deformed during
compression. This increase in size of the deformed particles produces a break
up of the tablet. This may be a mechanism of starch and has only recently begun
to be studied

Figure.18. Disintegration By Deformation And Repulsion

Due to release of gases

Carbon
dioxide released within tablets on wetting due to interaction between
bicarbonate and carbonate with citric acid or tartaric acid. The tablet
disintegrates due to generation of pressure within the tablet. This
effervescent mixture is used when pharmacist needs to formulate very rapidly
dissolving tablets or fast disintegrating tablet. As these disintegrants are
highly sensitive to small changes in humidity level and temperature, strict
control of environment is required during manufacturing of the tablets. The
effervescent blend is either added immediately prior to compression or can be
added in to two separate fraction of formulation.

By enzymatic reaction

Here,
enzymes presents in the body act as disintegrants. These enzymes destroy the
binding action of binder and helps in disintegration

Table.13. Disintegrating Enzymes

ENZYMES BINDER
Amylase Starch
Protease Gelatin
Cellulase Cellulose and it’s
derivatives
Invertase Sucrose
1.5.4.3 Methods of addition of disintegrants

The method of
addition of disintegrants is also a crucial part. Disintegrating agent can be
added either prior to granulation (intragranular) or prior to compression
(after granulation i.e. extragranular) or at the both processing steps.
Extragranular fraction of disintegrant (usually, 50% of total disintegrant
requires) facilitates breakup of tablets to granules and the intragranular
addition of disintegrants produces further erosion of the granules to fine
particles.

1.5.4.4 Types of
disintegrants (34,40-42)

Starch

Starch
was the first disintegrating agent widely used in tablet manufacturing. Before
1906 potato starch and corn starch were used as disintegrants in tablet
formulation. However, native starches have certain limitations and have been
replaced by certain modified starches with specialized characteristics.

The mechanism of action of starch is wicking

and restoration of deformed starch particles on contact with aqueous fluid and
in doing so release of certain amount of stress which is responsible for
disruption of hydrogen bonding formed during compression.

Lowenthal
& Wood proved that the rupture of the surface of a tablet employing starch
as disintegrant occurs where starch agglomerates were found. The conditions
best suited for rapid tablet disintegration are sufficient number of starch
agglomerates, low compressive pressure and the presence of water.

The
concentration of starch used is also very crucial part. If it is below the
optimum concentration then there are insufficient channels for capillary action
and if it is above optimum concentration then it will be difficult to compress
the tablet.

Pregelatinized starch

Pregelatinized
starch is produced by the hydrolyzing and rupturing of the starch grain. It is
a directly compressible disintegrants and its optimum concentration is 5-10%.
The main mechanism of action of Pregelatinized starch is through swelling.

Modified starch

To
have a high swelling properties and faster disintegration, starch is modified
by carboxy methylation followed by cross linking, which is available in market
as cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even low
substituted carboxymethyl starches are also marketed as ExplotabÒ and Primojel®.

Mechanism
of action of this modified starches are rapid and extensive swelling with
minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its
limit, then it produces viscous and gelatinous mass which increases the
disintegration time by resisting the breakup of tablet. They are highly
efficient at low concentration because of their greater swelling capacity.

Table.14. List Of Disintegrants

DISINTEGRANTS CONCENTRATION SPECIAL COMMENTS

IN GRANULES (%W/W)
Starch USP 5-20 Higher amount is required,
poorly compressible
Starch 1500 5-15 -
®
Avicel (PH 101, 10-20 Lubricant properties and
PH 102) directly compressible
®
Solka floc 5-15 Purified wood cellulose
Alginic acid 1-5 Acts by swelling
Na alginate 2.5-10 Acts by swelling
®
Explotab 2-8 Sodium starch glycolate,
superdisintegrant.
®
Polyplasdone (XL) 0.5-5 Crosslinked PVP
®
Amberlite (IPR 88) 0.5-5 Ion exchange resin
Methyl cellulose, Na CMC, 5-10 -
HPMC
AC-Di-Sol® 1-3 Direct compression
2-4 Wet granulation
Carbon dioxide _ Created insitu in effervescent
tablet

Cellulose and its

derivatives

Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly

hydrophilic
structure and is soluble in water. But when it is modified by internally
crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium
which is nearly water insoluble due to cross linking. It rapidly swells to 4-8
times its original volume when it comes in contact with water.

Microcrystalline cellulose (MCC)

MCC exhibit very good disintegrating properties because MCC is insoluble and act by
wicking action. The moisture breaks the hydrogen bonding between adjacent
bundles of MCC. It also serves as an excellent binder and has a tendency to
develop static charges in the presence of excessive moisture content.
Therefore, sometimes it causes separation in granulation. This can be partially
overcome by drying the cellulose to remove the moisture.

Alginates

Alginates
are hydrophilic colloidal substances which has high sorption capacity.
Chemically, they are alginic acid and salts of alginic acid. Alginic acid is
insoluble in water, slightly acidic in reaction. Hence, it should be used in
only acidic or neutral granulation. Unlike starch and MCC, alginates do not
retard flow and can be successfully used with ascorbic acid, multivitamin
formulations and acid salts of organic bases.

Ion-exchange resin

Ion
exchange resin (AmbreliteÒ IPR-88) has highest water uptake capacity than other
disintegrating agents like starch and Sodium CMC. It has tendency to adsorb
certain drugs.

Miscellaneous

This
miscellaneous category includes disintegrants like surfactants, gas producing
disintegrants and hydrous aluminium silicate. Gas
producing disintegrating agents is used in soluble tablet, dispersible
tablet and effervescent tablet.

PolyplasdoneÒXL and PolyplasdoneÒXL10 act by wicking, swelling and possibly

some
deformation recovery. Polyplasdone®XL do not reduce tablet hardness,
provide rapid disintegration and improved dissolution. Polyplasdone®
as disintegrating agent has small particle size distribution that impart a
smooth mouth feel to dissolve quickly. Chewable tablet does not require
addition of disintegrant.

Superdisintegrants

As day’s passes, demand for faster disintegrating formulation is increased. So,

pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective
at low
concentration and have greater disintegrating efficiency and they are more
effective intragranularly. But have one drawback that it is hygroscopic
therefore not used with moisture sensitive drugs.
And this superdisintegrants act by swelling and due to swelling pressure exerted in
the outer direction or radial direction, it causes tablet to burst or the
accelerated absorption of water leading to an enormous increase in the volume
of granules to promote disintegration.

Figure.19. Mechanism of superdisintegrants by swelling

Table.15. List Of Superdisintegrants

SUPERDISINTEGRANTS EXAMPLE OF MECHANISM SPECIAL

OF ACTION COMMENT
®
Crosscarmellose Crosslinked -Swells 4-8 folds -Swells in two
cellulose in < 10 seconds. dimensions.

-Swelling and -Direct

Ac-Di-Sol® wicking both. compression or
granulation

Nymce ZSX®

Primellose®

Solutab®
-Starch free

Vivasol®
Crosspovidone Crosslinked PVP -Swells very little -Water insoluble
and returns to and spongy in
Crosspovidon M® original size after nature so get
compression but porous tablet
Kollidon® act by capillary
action
Polyplasdone®
Sodium starch glycolate Crosslinked -Swells 7-12 folds -Swells in three
starch in <30 dimensions and
Explotab® seconds high level serve as
sustain release
Primogel® matrix
Alginic acid NF Crosslinked -Rapid swelling in -Promote
 alginic acid aqueous medium disintegration in
or wicking action both dry
Satialgine® or wet granulation
Soy polysaccharides Natural super -Does not contain
disintegrant any starch or
Emcosoy® sugar. Used in
nutritional
products.
Calcium silicate -Wicking action -Highly porous,

-light weight

-optimum
concentration is
between 20-40%

1.5.4.5 Factors affecting

disintegration

Effect of fillers (43,44)

The
solubility and compression characteristics of fillers affect both rate and mechanism
of disintegration of tablet. If soluble fillers are used then it may cause
increase in viscosity of the penetrating fluid which tends to reduce
effectiveness of strongly swelling disintegrating agents and as they are water
soluble, they are likely to dissolve rather than disintegrate. Insoluble
diluents produce rapid disintegration with adequate amount of disintegrants.

Chebli
and cartilier proved that tablets made with spray dried lactose (water soluble
filler) disintegrate more slowly due to its amorphous character and has no
solid planes on which the disintegrating forces can be exerted than the tablet
made with crystalline lactose monohydrate.

Effect of binder

As
binding capacity of the binder increases, disintegrating time of tablet
increases and this counteract the rapid disintegration. Even the concentration
of the binder can also affect the disintegration time of tablet.

Effect of lubricants(16,34)

Mostly lubricants are hydrophobic and they are usually used in smaller size than any
other ingredient in the tablet formulation. When the mixture is mixed,
lubricant particles may adhere to the surface of the other particles. This
hydrophobic coating inhibits the wetting and consequently tablet
disintegration.
Lubricant
has a strong negative effect on the water uptake if tablet contains no
disintegrants or even high concentration of slightly swelling disintegrants. On
the contrary, the disintegration time is hardly affected if there is some
strongly swelling disintegrants are present in the tablet. But there is one
exception like sodium starch glycolate whose effect remains unaffected in the
presence of hydrophobic lubricant unlike other disintegrants.

Effect of surfactants

Table.16. The Effects Of Various Surfactants

Surfactant Remarks
Sodium lauryl sulfate Good-various drugs

Poor - various drugs

Polysorbate 20 Good
Polysorbate 40 & 60 Poor
Polysorbate 80 Good
Tweens Poor
Poly ethylene glycol Poor

(Good – decrease in
disintegration time, Poor – increase in disintegration time)

Sodium
lauryl sulphate increased absorption of water by starch or had a variable
effect on water penetration in tablets. Surfactants are only effective within
certain concentration ranges. Surfactants are recommended to decrease the
hydrophobicity of the drugs because the more hydrophobic the tablet the greater
the disintegration time.

Aoki
and fukuda claimed that disintegration
time of granules of water-soluble drugs did not seem to be greatly
improved by the addition of nonionic
surfactant during granulation , but the desired effect of a surfactant appeared when
granule were
made of slightly soluble drugs. The speed of water penetration was increased by
the addition of a surfactant.

Key Phrases

Ø Disintegrants
are added to tablet to induce breakup when it comes in contact with aqueous
fluid.

Ø Disintegration
by capillary action or by swelling is the major mechanism for disintegrants.

Ø Disintegrant
can be added intragranular or extragranular or at both stages.

Ø Superdisintegrants
have greater efficiency at low concentration and hence, their demand is
increasing day by day.

1.5.5
Antifrictional Agents

What
will you gain?

1.5.5.1 Lubricants

1.5.5.1.1
Classification of lubricants

1.5.5.1.1.1 Water
Insoluble Lubricants

1.5.5.1.1.2
Water Soluble Lubricants

1.5.5.2 Antiadherents

1.5.5.3 Glidants

1.5.5.1 Lubricants(4,16)

Lubricants
are the agents that act by reducing friction by interposing an intermediate
layer between the tablet constituents and the die wall during compression and
ejection. Solid lubricants, act by boundary mechanism, results from the
adherence of the polar portions of molecules with long carbon chains to the
metal surfaces to the die wall. Magnesium stearate is an example of boundary
lubricant. Other is hydrodynamic mechanism i.e. fluid lubrication where two
moving surfaces are separated by a finite and continuous layer of fluid
lubricant. Since adherence of solid lubricants to the die wall is more than
that of fluid lubricants, solid lubricants are more effective and more
frequently used.

Since
primarily lubricants are required to act at the tooling or material interface,
lubricants should be incorporated in the final mixing step, after granulation is
complete. When hydrophobic
lubricants are added to a granulation, they form a coat around the individual
particles (granules), which may cause an increase in the disintegration time
and a decrease in the drug dissolution rate. Presence of lubricants may results
in a less cohesive and mechanically weaker tablet because it may interfere with
the particle – particle bonding.

Surface
area is important parameter for deciding lubricant efficiency. Lubricants with
high surface area are more sensitive to changes in mixing time than lubricant
with low surface area. Therefore lubricant mixing time should be kept minimum.

Tooling
used to compress the tablet is important for deciding type and level of
lubricant used. Additional lubricant is often added to the tablet formulations
that are to be compressed with curved face punches.

Further,
the amount of lubricant increases as the particle size of the granulation
decreases but its concentration should not exceed to 1% for producing maximum
flow rate.

Lack
of adequate lubrication produces binding which can results in tablet machine
strain and can lead to damage of lower punch heads, lower cam track, die seats
and the tooling itself. And it may also yield tablets with scratched edges and
are often fractured at the top edges. With excessive binding the tablet may be
cracked and fragmented by ejection.

1.5.5.1.1 Classification
of lubricants

Lubricant
are classified according to their water solubility i.e. water insoluble and
water soluble. Selection of lubricant is depends partly on mode of
administration, type of tablet, desired disintegration and dissolution
properties, physicochemical properties of granules or powder and cost.

1.5.5.1.1.1 Water Insoluble Lubricants

Water
insoluble lubricants are most effective and used at reduced concentration than
water soluble lubricants. Since these
lubricants function by coating ,
their effectiveness is related with their surface area, extent of particle size
reduction, time, procedure of addition
and length of mixing.

Table.17. List Of Insoluble Lubricants

INSOLUBLE CONCENTRATION COMMENTS

 LUBRICANTS
Stearates(Magnesium Stearate,
Reduce tablet strength; prolong
Calcium Stearate, Sodium 0.25 -1
disintegration; widely used.
stearate)
Insoluble but not hydrophobic;
Talc 1 -2
moderately effective.
Sterotex 0.25 – 1 -
Waxes 1-5 -
Stearowet 1-5 -
Glyceryl
1-5 Both lubricant and binder;
behapate(Compritol®888)
Dispersion problem; inferior to
Liquid paraffin Up to 5
stearates
1.5.5.1.1.2 Water Soluble Lubricants

Water
Soluble Lubricants are used when a tablet is completely soluble or when unique
disintegration and dissolution characteristics are required. Tablet containing
soluble lubricant shows higher dissolution rate than tablet with insoluble
lubricants. Physical mixture of this lubricant i.e. SLS or MLS with stearates
can lead to the best compromise in terms of lubricity, tablet strength and
disintegration.

Table.18. List Of Soluble Lubricants

WATER SOLUBLE LUBRICANTS CONCENTRATION RANGE (%W/W)

Boric acid 1
Sodium benzoate 5
Sodium oleate 5
Sodium acetate 5
Sodium Lauryl sulfate
1–5
(SLS)
Magnesium lauryl sulfate
1-2
(MLS)

1.5.5.2 Antiadherents (4, 16)

Some
material have strong adhesive properties towards the metal of punches and dies
or the tablet formulation containing excessive moisture which has tendency to
result in picking and sticking problem. Therefore antiadherents are added,
which prevent sticking to punches and die walls.

Talc,
magnesium stearate and corn starch have excellent antiadherent properties.
Vegan had suggested that silicon oil can be used as antiadherent.
Table.19. List Of Antiadherents

ANTIADHERENT RANGE(%W/W) COMMENT

Lubricant with
Talc 1–5
excellent antiadherents properties
Lubricant with
Cornstarch 3 – 10
excellent antiadherents properties
Does not give
satisfactory results due to small surface
Colloidal silica 0.1 – 0.5
area. Cab-O-Sil® and
Syloid®
Water soluble
DL-Leucine 3 – 10 lubricant; excellent antiadherents
properties
Sodium lauryl Antiadherents with
<1
sulfate water soluble lubricant
Antiadherents with
Stearates <1
water insoluble lubricant

1.5.5.3 Glidants (4, 16)

GLIDANTS
are added to the formulation to improve the flow properties of the material
which is to be fed into the die cavity and aid in particle rearrangement within
the die during the early stages of compression. If the flow properties are
extremely poor then glidants are ineffective and consideration of force free
mechanisms may be necessary. Starch is a popular glidant because it has
additional value of disintegrant. Concentration of starch is common up to 10%,
but should be limited otherwise it will worsen the flow of material. Talc is a
glidant which is superior to starch; its concentration should be limited
because it has retardant effect on dissolution-disintegration profile.

Silaceous
material like colloidal silica i.e. syloid, pyrogenic silica (0.25%), hydrated
sodium silioaluminate (0.75%) are also successfully used to induce flow.

Glidants
act by interposing their particles between those of material and lower the
overall interparticulate friction of the system by virtue of their reduced
adhesive tendencies. Similar to lubricants, they are required at the surface of
feed particles and they should be in fine state of division and appropriately
incorporated in the mixture.

Key
Phrases

Ø
Lubricants are
added to reduce the friction during compression.

Ø
Antiadherents
avoid sticking to die walls and picking by punches.

Ø
Glidants
improve the flow property of material/granules.

1.5.6 Miscellaneous Excipients

What
will you gain?

1.5.6.1 Wetting Agents

1.5.6.2 Dissolution Retardants

1.5.6.3 Dissolution Enhancers

1.5.6.4 Adsorbents

1.5.6.5 Buffers

1.5.6.6 Antioxidants

1.5.6.7 Chelating Agents

1.5.6.8 Preservatives

1.5.6.9 Colourants

1.5.6.10 Flavours

1.5.6.11 Sweeteners

1.5.6.1 Wetting Agents

Wetting Agents in tablet formulation

aid water uptake and thereby enhancing disintegration and assisting in drug
dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate
(SLS) is known to enhance the dissolution.It has been established that SLS
improves permeation of drug through biological membrane since it destroys the
path through which drug has to pass and thus minimizing the path length for the
drug to travel. Wetting agents are mainly added when hydrophobic drug is to be
formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as
wetting agent in tablet formulation.
1.5.6.2 Dissolution
Retardants

Dissolution Retardants are incorporated into tablet

formulation only when controlled release of drug is required. Waxy materials
like stearic acid and their esters can be used as dissolution retardants.

1.5.6.3 Dissolution Enhancers

They are the agents that alter the

molecular forces between ingredients to enhance the dissolution of solute in
the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.

1.5.6.4 Adsorbents (4)

Adsorbents are the agents that can

retain large quantities of liquids. Therefore liquids like Vitamin E can be
incorporated into tablets by addition of adsorbents .Most commonly used
adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch,
magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and
silicon dioxide. Generally the liquid to be adsorbed is first mixed with the
adsorbent prior to incorporation into the formulation. Silicon dioxide when
added can play as both glidant and an adsorbent role in the formula.

1.5.6.5 Buffers

Buffers are added to maintain a required pH since a

change in pH may cause significant alteration in stability. Most commonly used
buffering agent in tablet formulation includes sodium bicarbonate, calcium
carbonate, and sodium citrate.

1.5.6.6 Antioxidants

Antioxidants are added in tablet formulation to

protect drug from undergoing oxidation. Antioxidants undergo oxidation in place
of drug or they block the oxidation reaction or they act as synergists to other
antioxidants. Chelators may also act as antioxidant. Most commonly used
antioxidants include ascorbic acid and
their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium
metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated
Hydroxy Anisole (BHA) , citric acid , and tartaric acid .

1.5.6.7 Chelating Agents

Chelating agents tend to form complexes with trace

amount of heavy metal ions inactivating their catalytic activity in the
oxidation of medicaments. Ethylenediamine tetracetic acid and its salts,
Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used
chelators.
1.5.6.8
Preservatives

Preservatives may be a part of tablet formulation in

order to prevent the growth of microorganisms in tablet formulation. Parabens
like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as
preservatives.

1.5.6.9 Colourants(1, 4,16)

Colourants neither contribute to therapeutic activity

nor do they improve product bioavailability or stability but are incorporated
into tablets for purposes like to facilitate identification of similar looking
products with in a product line to avoid mix ups, to facilitate identification
of products of similar appearance that exist in the lines of different manufacturers, to
overcome colour change on
aging, disguising of off-colour drugs, for brand image in the market, to
enhance the aesthetic appearance of the product to have better patient
acceptance. Most widely used colourants are dyes and lakes which are FD & C
and D & C approved. Dyes are generally applied as solution especially in
the granulating agent. Lakes are usually employed as dry powders for colouring.
In general, direct compression tablets are coloured with lakes because no
granulation step is used. Natural colourants can be used and generally they do
not require the FDA certification before use in drug products. One of the
important advantage in using lakes is reduced risk of interaction between the
drug and other ingredients as well as colour development is rapid which reduces
processing time .While employing wet granulation , care should be taken to
prevent colour migration during drying . In any coloured tablet, the
formulation should be checked for resistance to colour changes on exposure to
light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements
and Microreflectance Photometer used to measure the colour uniformity and gloss
on a tablet surface.

Table.20. Some Commonly Used Pharmaceutical Colourants (Synthetic)

FD & COMMON
C COLOUR NAME
Red 3 Erythrosine
Red 40 Allura red AC
Yellow 5 Tartrazine
Yellow 6 Sunset Yellow
Blue 1 Brilliant Blue
Blue 2 Indigotine
Green 3 Fast Green

1.5.6.10 Flavours(1,4)

Flavors are commonly used to improve

the taste of chewable tablets as well as mouth dissolved tablets. Flavors are
incorporated either as solids (spray dried flavors) or oils or aqueous (water
soluble) flavors. Solids that is dry flavors are easier to handle and generally
more stable than oils. Oil is usually added at the lubrication step because of
its sensitivity to moisture and their tendency to volatilize when heated during
drying. It may also be adsorbed onto an excipient and added during the
lubrication process. The maximum amount of oil that can be added to granulation
without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous
flavors are less used because of its instability on aging.

1.5.6.11 Sweeteners(1,4,45)

Sweeteners are added primarily to chewable

tablets.

Table.21. Some Of The Sweeteners Used In Tablet Formulation

NATURAL ARTIFICIAL
SWEETENERS SWEETENERS
Mannitol
Saccharin
Lactose
Cyclamate
Sucrose
Aspartame
Dextrose

Saccharin
is 500 times sweeter than sucrose. Its major disadvantages are that it has a
bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic
.Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of
aspartame is its lack of stability in the presence of moisture. When aspartame
is used with hygroscopic components, it will be necessary to determine its
stability under conditions in which the product can adsorb atmospheric
moisture. Aspartame is available in market under the brand NutrasweetÒ
manufactured and marketed by Nutrasweet Company.

Key Phrases

ØOnly FD&C
and D&C approved colourants can be incorporated into tablet formulation.

ØFlavours and
Sweeteners are one of the important ingredients of chewable and mouth
dissolving tablet formulation.

Ideal properties of API for formulating

tablets
Submitted by on Sun, 12/06/2009 - 19:52

1.6
Ideal Properties of API for formulating tablets (46)

What will you gain?

The desirable properties of API for formulating

tablets :

1.6.1 High
purity

1.6.2 High
stability

1.6.3 Good
compatibility with excipients

1.6.4
Optimum bulk powder properties

1.6.5 Optimum
and uniform particle size – particle size distribution

1.6.6
Spherical shape

1.6.7 Good
flowability

1.6.8
Optimum moisture content

1.6.9 Good
compressibility

1.6.10 Absence of static charge on surface

1.6.11 Good organoleptic properties

1.6.12 Miscellaneous

1.6.1 High Purity

API
has to be in pure form otherwise impurities can catalyze series of chemical
reactions, e.g. in case of hydrocortisone impurity of cupric ion causes
oxidation of ketone functional group.
API should meet specifications given in the respective
Pharmacopoeia.

1.6.2 High stability

The
API should be stable against photolysis, oxidation, hydrolysis, etc. to keep
the formulation a simple one. Sensitive
particles require careful handling during manufacturing.

1.6.3 Good compatibility with

excipients (47)

In order to formulate a tablet one

need to add excipient along with API.
There should not be any kind of interaction between excipient and
API. Excipients have to be inert in nature. However there are some reported examples
of
API-excipient interactions like Lisinopril reacts with lactose and undergoes
browning reaction leading to darkening on storage. So, avoid the use of lactose and
use other
fillers for API containing primary amine.
To ascertain drug and excipient interaction, 1:1 mixture is prepared and
stored under accelerated/ICH conditions.
The amount of drug degraded shall be determined to select the most
suitable excipient.

1.6.4 Optimum bulk powder properties

Bulk
powder properties have to be optimum to:

i) Prevent
segregation.

ii) Have optimum size tablet particularly for low

potency-low density API.

iii) Have good flow.

1.6.5 Optimum and Uniform particle size-particle size distribution

API
should have uniform particle size and close particle size distribution because
it has pronounce effect on uniformity of content, uniformity of weight,
disintegration time, granule friability, drying rate kinetics of wet
granulation, flowability, compressibility, stability, dissolution,
bioavailability, etc. The flow and
compression characteristics are important from the viewpoint of industrial
pharmacist. Strong tablets are obtained if fine particles are used due to
increase in surface area and surface energy.

1.6.6 Spherical shape

The shape of particles decides flowability. Spherical

shaped particles exhibit good flow as compared to needle shaped particles. Particles
with irregular shape may exhibit
hindered flow due to interlocking between particles. This point is very important since
it is
directly related with weight of tablet and uniformity.

1.6.7 Good flowability (48-50)

Flow is important for having uniformity of weight and uniformity of drug

content. It can be measured using angle
of repose, Carr’s index and Hausner ratio.

The methods used to improve flow are summarized

below

i)Addition of glidants

ii) Addition of fines:

Addition of fines up to certain extent improves flow. This is because of
filling of void space and decrease in surface roughness.

iii) By wet granulation: Wet granulation gives regular

sphere shaped granules and removes static charge if present on particle
surface. Thus, flow property improved.

iv) By densification with help of slugging.

1.6.8 Optimum moisture content (51-53)

Moisture content has to be optimum

because of the following reasons:

i)Total lack of moisture results into brittle tablet.

ii) Moisture affects flow, which in turn affects

uniformity of content.

iii)High amount of moisture gives stickiness, which will

affect compaction.

iv)Picking/sticking may be observed.

Moisture content can be controlled by:

i)Use of anhydrous salts.

ii)Use of non-aqueous solvent.

iii) Optimum drying time.

iv) Addition of finely powdered adsorbent like magnesium

oxide.

1.6.9 Good compressibility (1,2,4,5,54)

API should exhibit good compressibility.

However this depends upon its intrinsic nature like:

(A) Elasticity:

The particles deform under the effect of pressure in

a die but they revert back to original state on removal of applied pressure
i.e. on ejection. Such tablets may
exhibit capping and or lamination. The
intrinsic nature of particle can be changed by:

i)Wet massing

ii)Pre-compression

iii)Plastic tabulating matrix (micro crystalline

cellulose)

Elastic material is less suitable for

direct compression.

(B)Plasticity:

Plastic material gets bonded after viscoelastic

deformation. Viscoelastic deformation is
time dependent. Hence, the crushing
strength is dependent on the time that tablet spends in a die. Changing the turret speed
can change dwell
time. Plastic materials may exhibit
viscoelastic deformaiton.

(C) Brittle fracture:

A particle fractures into small particles on

application of pressure in a die.
Brittle fracture also promotes tableting. Brittle materials are less lubricant
sensitive as compared to plastic materials.
A blend of lactose and MCC is widely used in industry to get advantages
of brittle materials and plastic materials.
1.6.10 Absence of static charge on
surface (55)

It is important because of the following reasons:

i)Affects uniformity of dose and weight variation (flow worsen if attractive forces
generated).

ii) During mixing it may cause segregation and lead to

non-uniformity of content if API and excipients are charged.

iii) Charged API may adhere to feed frame and result into
serious damage to tablet equipment.

In order to remove charge certain treatments can be given

like granulation, addition of diluents or lubricant, surface coating with help
of colloidal silica, etc.

1.6.11 Good organoleptic properties

Many API are unpalatable and unattractive in their natural form. In such cases, tablet
formulation require certain
care. API has to be checked for colour
and taste.

I. Colour

Ideally API should be colourless. For coloured

API, the following steps shall be considered:

i)Select appropriate excipient to avoid mottling.

ii)Incorporate API in smallest particle size.

iii)Incorporate colour in dry form along with binder and

activate mixture by addition of water or other activator.

iv)Coating can be applied to conceal non-uniform colour

(sugar coated multivitamin tablet).

II. Taste

It is very important for tablets because they come in contact with taste
buds. Ideally API should have no
taste. But sometimes it might have
unpleasant taste like bitter e.g. Chloramphenicol, Clindamycin, etc. The following
taste masking options can be
tried:
i)Use of prodrug
to decrease API solubility in saliva or to reduce affinity for taste receptor e.g.
Chloramphenicol Palmitate.

ii)Sugar coating or film coating.

iii)Addition of sweeteners like mannitol in cause of fast

dissolving tablet or chewable tablet.

iv) Use of drug-ion exchange adsorbent in formulation.

v)Drug β-cyclodextrin complex may exhibit good

taste profile and good compressibility as well.

1.6.12 Miscellaneous points

i)API should not

exhibit sublime characteristics

ii)Liquid APIs are

less suitable for tablet formulation.
One of the options is conversion of liquid in pseudosolid (mix liquid
API with adsorbents). A combination of
Valproic acid and Sodium Valproate is a typical example of converting a liquid
into pseudosolid.

iii)BCS class IV drugs are difficult to formulate if

dissolution and bioavailability requirements are to meet as per regulatory
agencies.

Key Phrases

ØHigh Purity to
avoid contamination and degradation.

ØHigh stability
against photolysis, oxidation, hydrolysis, etc.

ØGood compatibility with excipients. For example, avoid use of lactose with drugs
with primary amine functional group.

ØOptimum bulk powder properties to prevent segregation and to have good flow.

ØOptimum particle size and size distribution to have uniformity of weight, uniformity
of content,
good flow and compressibility.

ØSpherical shape
to avoid interlocking between the particles and thus to aid flow.
ØGood flow to
have uniformity of weight and uniformity of drug content

ØOptimum amount
of moisture to avoid problems like brittle tablet, picking/sticking, etc.

ØGood compressibility to have nicely bonded tablet.

ØAbsence of static charge on the surface to prevent demixing and damage to tableting
equipment by adhering to feed frame.

ØGood organoleptic properties to have better patient acceptance.

ØMiscellaneous: Convert liquid API to pseudosolid e.g.

Valproic acid and Sodium valproate, etc.

Operations involved in tablet

manufacturing
Submitted by on Sun, 12/06/2009 - 19:52

1.7 Operations involved in tablet manufacturing(1-3)

What will you gain?

1.7.1 Introduction

1.7.2 Dispensing (weighing and measuring)

1.7.3 Sizing

1.7.4 Powder blending

1.7.5 Granulation

1.7.6 Drying

1.7.7 Tablet compression

1.7.8 Auxillary equipments

1.7.9 Packaging

1.7.1 Introduction

The manufacture of oral solid dosage

forms such as tablets is a complex multi-stage process under which the starting
materials change their physical characteristics a number of times before the
final dosage form is produced.

Traditionally, tablets have been made by granulation, a

process that imparts two primary requisites to formulate: compactibility and
fluidity. Both wet granulation and dry granulation (slugging and roll
compaction) are used. Regardless of weather tablets are made by direct
compression or granulation, the first step, milling and mixing, is the same;
subsequent step differ.

Numerous unit processes are involved in making tablets, including

particle size reduction and sizing, blending, granulation, drying, compaction,
and (frequently) coating. Various factors associated with these processes can
seriously affect content uniformity, bioavailability, or stability.

Figure.20. Various Unit Operation Sequences In Tablet Manufacturing

Figure.21. Typical Manufacturing Process Of Tablet

Table.22. Typical Unit Operation Involved In Wet Granulation, Dry

Granulation And Direct Compression(13)

WET GRANULATION DRY GRANULATION DIRECT

COMPRESSION
1. 1. 1. Milling and mixing
Milling Milling of drugs and excipients
and mixing of drugs and and mixing of drugs and
excipients excipients
2. 2. 2.
Preparation Compression Compression of tablet
of binder solution into slugs or roll compaction
3. 3.
Wet Milling
massing by addition of binder and screening of slugs and
solution compacted powder
or granulating solvent
4. 4.
Screening Mixing
of wet mass with lubricant and disintegrant
5. 5.
Drying Compression
of the wet granules of tablet
6.
Screening
of dry granules
7.
Blending
with lubricant and disintegrant to
produce “running powder”
8.
Compression
of tablet

1.7.2 Dispensing (weighing and measuring)

Dispensing is the first step in any

pharmaceutical manufacturing process. Dispensing is one of the most critical
steps in pharmaceutical manufacturing; as during this step, the weight of each
ingredient in the mixture is determined according to dose.

Dispensing may be done by purely manual

by hand scooping from primary containers and weighing each ingredient by hand
on a weigh scale, manual weighing with material lifting assistance like Vacuum
transfer and Bag lifters, manual or assisted transfer with automated weighing
on weigh table, manual or assisted filling of loss-in weight dispensing system,
automated dispensaries with mechanical devices such as vacuum loading system
and screw feed system.

Issues like
weighing accuracy, dust control (laminar air flow booths, glove boxes), during
manual handling, lot control of each ingredient, material movement into and out
of dispensary should be considered during dispensing.

1.7.3 Sizing

The sizing (size reduction, milling, crushing, grinding,

pulverization) is an impotent step (unit operation) involved in the tablet
manufacturing.

In manufacturing of compressed tablet, the mixing or blending of several solid

ingredients of pharmaceuticals is easier and more uniform if the ingredients
are approximately of same size. This provides a greater uniformity of dose. A
fine particle size is essential in case of lubricant mixing with granules for
its proper function.

Advantages associated with size reduction in tablet

manufacture are as follows:

i) It increases surface area, which may enhance an active ingredient’s dissolution

rate and hence bioavailability.
ii)Improved the tablet-to-tablet content uniformity by virtue of the increased number
of
particles per unit weight.

iii)Controlled particle size distribution of dry granulation or mix to promote better

flow of
mixture in tablet machine.

iv)Improved flow properties of raw materials.

v)Improved colour and/or active ingredient dispersion in tablet excipients.

vi)Uniformly sized wet granulation to promote uniform drying.

There are also certain disadvantages associated with this unit operation if not
controlled properly. They are as follows:

i)A possible change in polymorphic form of the active ingredient, rendering it less
or totally inactive, or unstable.

ii) A decrease in bulk density of active compound and/or excipients, which may cause
flow problem and segregation in the mix.

iii)An increase in surface area from size reduction may promote the adsorption of air,
which may
inhibit wettability of the drug to the extent that it becomes the limiting
factor in dissolution rate.

A number of different types of machine

may be used for the dry sizing or milling process depending on whether gentle
screening
or particle milling is needed. The
ranges of equipment employed for this process includes Fluid energy mill,
Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical
mill, etc.

1.7.4 Powder blending

The successful mixing of powder is acknowledged to be more

difficult unit operation because, unlike the situation with liquid, perfect
homogeneity is practically unattainable.

In practice, problems also arise because of the inherent cohesiveness and

resistance to movement between the individual particles. The process is further
complicated in many system, by the presence of substantial segregation
influencing the powder mix. They arise because of difference in size, shape,
and density of the component particles.

The powder/granules blending

are involved at stage of pre granulation and/or post granulation stage of
tablet manufacturing. Each process of mixing has optimum mixing time and so
prolonged mixing may result in an undesired product. So, the optimum mixing
time and mixing speed are to be evaluated. Blending step prior to compression
is normally achieved in a simple tumble blender. The Blender may be a fixed
blender into which the powders are charged, blended and discharged. It is now
common to use a bin blender which blends.

In special cases of mixing a lubricant, over mixing should

be particularly monitered.

The various blenders used include “V”

blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder
blender, etc.

But now a days to

optimize the manufacturing process particularly in wet granulation the various
improved equipments which combines several of processing steps (mixing,
granulation and/or drying) are used. They are “Mixer granulator” or “High shear
mixing machine”.

1.7.5 Granulation

Following particle size reduction and

blending, the formulation may be granulated, which provides homogeneity of drug
distribution in blend.

1.7.6 Drying

Drying is a most important step in the formulation and

development of pharmaceutical product. It is important to keep the residual
moisture low enough to prevent product deterioration and ensure free flowing
properties.

The commonly used dryer includes Fluidized – bed dryer,

Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray
dryer, Pan dryer, etc.

1.7.7 Tablet compression

After the preparation of granules (in case of wet

granulation) or sized slugs (in case of dry granulation) or mixing of
ingredients (in case of direct compression), they are compressed to get final
product. The compression is done either by single punch machine (stamping
press) or by multi station machine (rotary press).

The tablet press

is a high-speed mechanical device. It 'squeezes' the ingredients into the
required tablet shape with extreme precision. It can make the tablet in many
shapes, although they are usually round or oval. Also, it can press the name of
the manufacturer or the product into the top of the tablet.
Each tablet is made by
pressing the granules inside a die, made up of hardened steel. The die is a
disc shape with a hole cut through its centre. The powder is compressed in the
centre of the die by two hardened steel punches that fit into the top and
bottom of the die.

The punches and dies are fixed to a turret that spins round.
As it spins, the punches are driven together by two fixed cams - an upper cam
and lower cam. The top of the upper punch (the punch head) sits on the upper
cam edge .The bottom of the lower punch sits on the lower cam edge.

The shapes of the two cams

determine the sequence of movements of the two punches. This sequence is
repeated over and over because the turret is spinning round.

The force exerted on the ingredients in the dies is very

carefully controlled. This ensures that each tablet is perfectly formed. Because
of the high speeds, they need very sophisticated lubrication systems. The
lubricating oil is recycled and filtered to ensure a continuous supply.

Common stages occurring during compression

Stage 1: Top punch is withdrawn from the die

by the upper cam

Bottom punch is low in the die so powder falls in through the hole and fills the die

Stage 2: Bottom punch moves up to adjust the powder

weight-it raises and expels some powder

Stage 3: Top punch is driven into the die by upper cam

Bottom punch is raised by lower cam

Both punch heads pass between heavy rollers to compress the powder

Stage 4: Top punch is withdraw by the upper cam

Lower punch is pushed up and expels the tablet

Tablet is removed from the die surface by surface plate

Stage 5: Return to stage 1

Figure.22. Stage Occurring During Compression

1.7.8 Auxiliary Equipments (1)

I. Granulation Feeding Device:

In many cases, speed of die table is such that the time of

die under feed frame is too short to allow adequate or consistent gravity
filling of die with granules, resulting in weight variation and content
uniformity. These also seen with poorly flowing granules. To avoid these
problems, mechanized feeder can employ to force granules into die cavity.

II.Tablet weight monitoring devices:-

High rate of tablet output with

modern press requires continuous tablet weight monitoring with electronic
monitoring devices like Thomas Tablet Sentinel,
Pharmakontroll and Killan control System-MC. They monitors force at each
compression station by starin gage technology which is then correlated with
tablet weight.

III. Tablet Deduster : -

In almost all cases, tablets coming out of a tablet machine

bear excess powder on its surface and are run through the tablet deduster to
remove that excess powder.
IV. Fette machine

Fette machine is device that chills the compression

components to allow the compression of low melting point substance such as
waxes and thereby making it possible to compress product with low meting
points.

1.7.9 Packaging

Pharmaceutical
manufacturers have to pack their medicines before they can be sent out for
distribution. The type of packaging will depend on the formulation of the
medicine.

'Blister packs' are a common

form of packaging used for a wide variety of products. They are safe and easy
to use and they allow the consumer to see the contents without opening the
pack. Many pharmaceutical companies use a standard size of blister pack. This
saves the cost of different tools and to change the production machinery
between products. Sometimes the pack may be perforated so that individual tablets
can be detached. This means that the expiry date and the name of the product
have to be printed on each part of the package. The blister pack itself must
remain absolutely flat as it travels through the packaging processes,
especially when it is inserted into a carton. This poses interesting problems
for the designers. Extra ribs are added to the blister pack to improve its
stiffness.

Key Phrases

The manufacturing of tablet involves numerous unit

processes including

ØParticle size reduction and sizing

ØBlending

ØGranulation

ØDrying,compaction

ØCoating.

Manufacturing methods of tablets

Submitted by on Sun, 12/06/2009 - 19:53

1.8 Manufacturing methods

1.8.1 Direct compression(1-3,5,17)

What
will you gain?

1.8.1.1 Introduction.

1.8.1.2 The events that

motivates the industry people to use direct compression technique.

1.8.1.3 Merits

1.8.1.4 Merits over wet granulation process

1.8.1.5 Demerits

1.8.1.6 Manufacturing steps for direct compression

1.8.1.7 Direct compression Excipients

1.8.1.7.1 An ideal direct

compression excipient should possess
the following attributes.

1.8.1.7.2 Major excipients required in direct

compression.

1.8.1.1 Introduction

In early days, most of the tablets require granulation of the powdered Active
Pharmaceutical Ingredient (API) and Excipients. At the availability of new
excipients or modified form of old excipients and the invention of new tablet
machinery or modification of old tablet machinery provides an ease in
manufacturing of tablets by simple procedure of direct compression.

Amongst the techniques used to prepare tablets, direct

compression is the most advanced technology. It involves only blending and
compression. Thus offering advantage particularly in terms of speedy
production. Because it requires fewer unit operations, less machinery, reduced
number of personnel and considerably less processing time along with increased
product stability.

Definition:

The term “direct compression” is defined as the process

by which tablets are compressed directly from powder mixture of API and
suitable excipients. No pretreatment of the powder blend by wet or dry
granulation procedure is required.

1.8.1.2 The events that motivates the industry people to use direct compression technique
I.Commercial availability of the directly compressible excipients possessing both
good
compressibility and good flowability.

For example,
Spray dried lactose, Anhydrous lactose, Starch-1500, microcrystalline
cellulose, Di-PacÒ, Sorbitol

II.Major advances
in tablet compression machinery:

i)Improved positive die feeding,

ii)Precompression of powder blend.

1.8.1.3 Merits

i)Direct compression is more efficient and economical process as compared to other

processes, because it involves only dry blending and compaction of API and
necessary excipients.

ii)The most important advantage of direct compression is

economical process.

Reduced
processing time, reduced labor costs, fewer manufacturing steps, and less
number of equipments are required, less process validation, reduced consumption
of power.

iii)Elimination of heat and moisture, thus increasing not

only the stability but also the suitability of the process for thermolabile and
moisture sensitive API’s.

iv)Particle size uniformity.

v)Prime particle dissolution.

In case of directly compressed tablets after

disintegration, each primary drug particle is liberated. While in the case of
tablets prepared by compression of granules, small drug particles with a larger
surface area adhere together into larger agglomerates; thus decreasing the
surface area available for dissolution.

vi)The chances of batch-to-batch variation are negligible,

because the unit operations required for manufacturing processes is fewer.

vii)Chemical stability problems for API and excipient would be avoided.

viii)Provides
stability against the effect of aging which affects the dissolution rates.
1.8.1.4 Merits over wet granulation process

The variables faced in the processing of the granules

can lead to significant tableting problems. Properties of granules formed can
be affected by viscosity of granulating solution, the rate of addition of
granulating solution, type of mixer used and duration of mixing, method and
rate of dry and wet blending. The above variables can change the density and
the particle size of the resulting granules and may have a major influence on
fill weight and compaction qualities. Drying can lead to unblending as soluble
API migrates to the surface of the drying granules.

1.8.1.5 Demerits

Excipient Related

i)Problems in the
uniform distribution of low dose drugs.

ii)High dose drugs having high bulk volume, poor

compressibility and poor flowability are not suitable for direct compression.

For example, Aluminium Hydroxide, Magnesium Hydroxide

iii) The choice of excipients for direct compression is

extremely critical. Direct compression diluents and binders must possess both
good compressibility and good flowability.

iv) Many active ingredients are not compressible either

in crystalline or amorphous forms.

v) Direct compression blends may lead to unblending

because of difference in particle size or density of drug and excipients.
Similarly the lack of moisture may give rise to static charges, which may lead
to unblending.

vi) Non-uniform distribution of colour, especially in

tablets of deep colours.

Process Related

i)Capping, lamination, splitting, or layering of tablets is sometimes related to air

entrapment during direct compression. When air is trapped, the resulting
tablets expand when the pressure of tablet is released, resulting in splits or
layers in the tablet.

ii)In some cases require greater sophistication in

blending and compression equipments.

iii) Direct compression equipments are expensive.

1.8.1.6 Manufacturing steps for direct compression

Direct compression involves

comparatively few steps:

i)Milling of drug and excipients.

ii) Mixing of drug and excipients.

iii) Tablet compression.

Figure.23. Manufacturing Steps For Direct Compression

1.8.1.7 Direct compression Excipients

Direct compression excipients mainly include

diluents, binders and disintegrants. Generally these are common materials that
have been modified during the chemical manufacturing process, in such a way to
improve compressibility and flowability of the material.

The physicochemical properties of the ingredients

such as particle size, flowability and moisture are critical in direct
compression tableting. The success of direct compression formulation is highly
dependent on functional behavior of excipients.

1.8.1.7.1 An ideal direct compression excipient should possess the following attributes

i)It should have

good compressibility.

ii)It should possess good hardness after compression,

that is material should not possess any deformational properties;
otherwise this may lead to capping and
lamination of tablets.

iii) It should have good flowability.

iv) It should be physiologically inert.

v) It should be compatible with wide range of API.

vi) It should be stable to various environmental
conditions (air, moisture, heat, etc.).

vii) It should not show any physical or chemical change in

its properties on aging.

viii) It should have high dilution potential. i.e. Able to incorporate high amount of
API.

ix) It should be colourless, odorless and tasteless.

x) It should accept colourants uniformity.

xi) It should possess suitable organoleptic properties

according to formulation type, that is in case of chewable tablet diluent
should have suitable taste and flavor. For example mannitol produces cooling
sensation in mouth and also sweet test.

xii) It should not interfere with bioavailability and

biological activity of active ingredients.

xiii)It should be
easily available and economical in cost.

1.8.1.7.2 Major excipients required in direct

compression

I.Diluents

II.Binders

III.Disintegrants

Diluents

Selection
of direct compression diluent is extremely critical, because the success or
failure of direct compression formulation completely depends on characteristics
of diluents. There are number of factors playing key role in selection of
optimum diluent. Factors like- Primary properties of API (particle size and
shape, bulk density, solubility), the characteristics needed for processing
(flowability, compressibity), and factors affecting stability (moisture, light,
and other environmental factors), economical approach and availability of material.

After
all, one can say that raw material specifications should be framed in such a
way that they provide an ease in manufacturing procedures and reduce chances of
batch to batch variation. This becomes possible only when the raw material
specifications reflect most of properties of diluents as mentioned in section
1.5.
Binders (56)

Binders are the agents used to impart cohesive qualities

to the powdered material. The quality of binder used has considerable influence
on the characteristic of the direct compression tablets. The direct compression
method for preparing tablets requires materials which are not only free flowing
but also sufficiently cohesive to act as binder.

Key Phrases

Ø Direct
compression is one of the most advanced technologies to prepare tablets.

Ø It requires
only blending and compression of excipients.

Ø It is an
economical process.

Ø It is suitable
for heat and moisture sensitive API.

It is not
suitable for very low and very high dose drugs.

1.8.2 Granulation (1,4,5,57)

What will you gain?

1.8.2.1
Introduction

1.8.2.2
Wet granulation

1.8.2.2.1 Introduction

1.8.2.2.2 Important steps involved in the wet

granulation

1.8.2.2.3 Limitation of wet granulation

1.8.2.2.4 Special wet granulation techniques

1.8.2.2.4.1 High shear mixture granulation

1.8.2.2.4.2 Fluid bed granulation

1.8.2.2.4.3 Extrusion and Spheronization

1.8.2.2.4.4 Spray drying granulation

1.8.2.2.5 Lists of equipments for wet granulation

1.8.2.2.6 Current topics related to wet

granulation

1.8.2.3
Dry granulation

1.8.2.3.1 Introduction

1.8.2.3.2 Advantages

1.8.2.3.3 Disadvantages

1.8.2.3.4 Steps in dry granulation

1.8.2.3.5 Two main dry granulation processes

1.8.2.3.5.1Slugging process

1.8.2.3.5.2 Roller compaction

1.8.2.3.6 Formulation for dry granulation

1.8.2.3 Advancement in Granulations

1.8.2.3.1 Steam Granulation

1.8.2.3.2 Melt Granulation/Thermoplastic

Granulation

1.8.2.3.3 Moisture
Activated Dry Granulation

1.8.2.3.4 Moist
Granulation Technique (MGT)

1.8.2.3.5 Thermal Adhesion Granulation Process

(TAGP)

1.8.2.3.6 Foam Granulation

1.8.2.1 Introduction
Granulation may be defined as a size enlargement process
which converts small particles into physically stronger & larger
agglomerates.

Granulation method can be broadly classified into two

types:

Wet granulation and Dry granulation

Ideal characteristics of granules

The ideal characteristics of granules include spherical

shape, smaller particle size distribution with sufficient fines to fill void
spaces between granules, adequate moisture (between 1-2%), good flow, good
compressibility and sufficient hardness.

The effectiveness of granulation depends on the

following properties

i) Particle size of
the drug and excipients

ii) Type of binder (strong or weak)

iii) Volume of binder (less or more)

iv) Wet massing time ( less or more)

v) Amount of shear applied

vi) Drying rate ( Hydrate formation and polymorphism)

1.8.2.2 Wet granulation

1.8.2.2.1 Introduction

The most widely used process of agglomeration

in pharmaceutical industry is wet granulation. Wet granulation process simply
involves wet massing of the powder blend with a granulating liquid, wet sizing
and drying.

1.8.2.2.2 Important steps involved in the wet

granulation

i) Mixing of the
drug(s) and excipients

ii) Preparation of binder solution

iii) Mixing of binder solution with powder mixture to form
wet mass.

iv) Coarse screening of wet mass using a suitable sieve

(6-12 # screens).

v) Drying of moist granules.

vi) Screening of dry granules through a suitable sieve

(14-20 # screen).

vii) Mixing of screened granules with disintegrant,

glidant, and lubricant.

1.8.2.2.3 Limitation of wet granulation

i) The greatest
disadvantage of wet granulation is its cost. It is an expensive process because
of labor, time, equipment, energy and space requirements.

ii) Loss of material during various stages of processing

iii) Stability may be major concern for moisture sensitive

or thermo labile drugs

iv) Multiple processing steps add complexity and make

validation and control difficult

v) An inherent limitation of wet granulation is that any

incompatibility between formulation components is aggravated.

1.8.2.2.4 Special wet granulation techniques

i) High shear
mixture granulation

ii) Fluid bed granulation

iii) Extrusion-spheronization

iv)Spray drying

1.8.2.2.4.1 High shear mixture granulation

High shear mixture has been widely used in Pharmaceutical

industries for blending and granulation. Blending and wet massing is
accompanied by high mechanical agitation by an impeller and a chopper. Mixing,
densification and agglomeration are achieved through shear and compaction force
exerted by the impeller.
Advantages:

i) Short processing
time

ii) Less amount of liquid binders required compared with

fluid bed.

iii) Highly cohesive material can be granulated.

1.8.2.2.4.2 Fluid bed granulation

Fluidization is the operation by which fine solids are

transformed into a fluid like state through contact with a gas. At certain gas
velocity the fluid will support the particles giving them free mobility without
entrapment.

Fluid bed granulation is a process by which granules are

produced in a single equipment by
spraying a binder solution onto a fluidized powder bed. The material processed
by fluid bed granulation are finer, free flowing and homogeneous.

1.8.2.2.4.3 Extrusion and Spheronization

It
is a multiple step process capable of making uniform sized spherical particles.
It is primarily used as a method to produce multi-particulates for controlled
release application.

Advantages:

i) Ability to
incorporate higher levels of active components without producing excessively
larger particles.

ii) Applicable to both immediate and controlled release

dosage form.

1.8.2.2.4.4 Spray drying granulation

It is a unique granulation technique that directly

converts liquids into dry powder in a single step. This method removes moisture
instantly and converts pumpable liquids into a dry powder.

Advantages:

i) Rapid process

ii) Ability to be operated continuously

iii) Suitable for heat sensitive product

1.8.2.2.5 Lists of equipments for wet granulation

High Shear granulation:

i)Little ford Lodgie granulator

ii)Little ford MGT granulator

iii)Diosna granulator

iv)Gral mixer

Granulator with drying facility:

i)Fluidized bed granulator

ii) Day nauta mixer processor

iii)Double cone or twin shell processor

iv)Topo granulator

Special granulator:

i)Roto granulator

ii)Marumerizer

1.8.2.2.6 Current topics related to wet granulation

I. Hydrate formation

For example, theophylline anhydrous during

high shear wet granulation transfers to theophylline monohydrate. The midpoint
conversion occurs in three minutes after the binder solution is added.

For online monitoring of the transformation from one form to another, Raman
spectroscopy is most widely used.

II. Polymorphic transformation

The
drying phase of wet granulation plays a vital role for conversion of one form
to another.

For
example, glycine which exist in three polymorphs that is a, β, g . g
is the most stable form and a
is the metastable form. The stable Glycine polymorph (g) converts to metastable form
(a) when wet granulated with microcrystalline
cellulose.

1.8.2.3 Dry granulation

1.8.2.3.1 Introduction

In dry granulation process the powder mixture is

compressed without the use of heat and solvent. It is the least desirable of
all methods of granulation. The two basic procedures are to form a compact of
material by compression and then to mill the compact to obtain a granules. Two
methods are used for dry granulation. The more widely used method is slugging,
where the powder is precompressed and the resulting tablet or slug are milled
to yield the granules. The other method is to precompress the powder with
pressure rolls using a machine such as Chilosonator.

1.8.2.3.2 Advantages

The main advantages of dry granulation or slugging are

that it uses less equipments and space. It eliminates the need for binder
solution, heavy mixing equipment and the costly and time consuming drying step
required for wet granulation. Slugging can be used for advantages in the
following situations:

i) For moisture
sensitive material

ii) For heat sensitive material

iii) For improved disintegration since powder particles

are not bonded together by a binder

1.8.2.3.3 Disadvantages

i) It requires a
specialized heavy duty tablet press to form slug

ii) It does not permit uniform colour distribution as can

be

iii) Achieved with wet granulation where the dye can be

incorporated into binder liquid.

iv) The process tends to create more dust than wet

granulation, increasing the potential contamination.

1.8.2.3.4 Steps in dry granulation

i) Milling of drugs
and excipients
ii) Mixing of milled powders

iii) Compression into large, hard tablets to make slug

iv) Screening of slugs

v) Mixing with lubricant and disintegrating agent

vi) Tablet compression

1.8.2.3.5 Two main dry granulation processes

1.8.2.3.5.1 Slugging process

Granulation by slugging is the process of compressing dry

powder of tablet formulation with tablet press having die cavity large enough
in diameter to fill quickly. The accuracy or condition of slug is not too
important. Only sufficient pressure to compact the powder into uniform slugs
should be used. Once slugs are produced they are reduced to appropriate granule
size for final compression by screening and milling.

Factors which determine how well a material may slug

i) Compressibility
or cohesiveness of the mater

ii) Compression ratio of powder

iii) Density of the powder

iv) Machine type

v) Punch and die size

vi) Slug thickness

vii) Speed of compression

viii) Pressure used to

produce slug

1.8.2.3.5.2 Roller compaction

The compaction of
powder by means of pressure roll can also be accomplished by a machine called
chilsonator. Unlike tablet machine, the
chilsonator turns out a compacted mass in a steady continuous flow. The powder
is fed down between the rollers from the hopper which contains a spiral auger
to feed the powder into the compaction zone. Like slugs, the aggregates are
screened or milled for production into granules.
1.8.2.3.6 Formulation for dry granulation

The excipients used for dry granulation are basically

same as that of wet granulation or that of direct compression. With dry
granulation it is often possible to compact the active ingredient with a minor
addition of lubricant and disintegrating agent. Fillers that are used in dry
granulation include the following examples: Lactose, dextrose, sucrose, MCC,
calcium sulphate, Sta-Rx® etc .

Examples of some tablet

formulation prepared by dry granulation:

Aspirin tablet Aspirin effervescent

tablet

Rx Rx

Starch Sodium
bicarbonate

Cab-o-sil
®
Citric
acid

Aspirin Fumaric
acid

Aspirin

Antacid tablet

Rx

Aluminum
hydroxide

Magnesium
hydroxide

Magnesium
carbonate

Sucrose

PEG

1.8.2.3 Advancement in Granulations

1.8.2.3.1 Steam
Granulation
It is modification of wet granulation. Here steam is used as a binder instead
of water. Its several
benefits includes higher
distribution uniformity, higher diffusion
rate into powders, more
favourable thermal balance
during drying step, steam
granules are more spherical, have large surface
area hence increased
dissolution rate of
the drug from
granules, processing time is
shorter therefore more
number of tablets are
produced per batch, compared to
the use of
organic solvent water vapour
is environmentally friendly,
no health hazards
to operators, no restriction
by ICH on
traces left in
the granules, freshly distilled
steam is sterile
and therefore the
total count can
be kept under
control, lowers dissolution rate
so can be
used for preparation
of taste masked
granules without modifying
availability of the
drug. But the limitation is that it is unsuitable for thermolabile
drugs. Moreover special equipments
are required and
are unsuitable for
binders that cannot
be later activated
by contact with
water vapour.

1.8.2.3.2 Melt Granulation / Thermoplastic Granulation (24)

Here granulation is achieved by the addition of meltable binder. That is

binder is in solid state at room temperature but melts
in the temperature range of 50 – 80˚C. Melted binder then acts like a binding
liquid. There is no need of drying phase since dried granules
are obtained by cooling it to room temperature. Moreover, amount of liquid
binder can be controlled precisely and the production and
equipment costs are reduced. It is useful for granulating water
sensitive material and producing SR granulation or solid dispersion. But this
method is not suitable for thermolabile
substances. When water soluble
binders are needed, Polyethylene Glycol (PEG) is used
as melting binders. When water
insoluble binders are
needed, Stearic acid, cetyl or stearyl
alcohol, various waxes and
mono-, di-, & triglycerides are used
as melting binders.

1.8.2.3.3 Moisture
Activated Dry Granulation (MADG) (58)

It involves moisture distribution and

agglomeration. Tablets prepared using MADG method has better content
uniformity. This method utilizes very little granulating fluid. It decreases
drying time and produces granules with excellent flowability.

1.8.2.3.4 Moist Granulation Technique (MGT) (59)

A small amount granulating fluid is added

to activate dry binder and to facilitate agglomeration. Then
a moisture absorbing material like Microcrystalline Cellulose (MCC) is
added to absorb any excess moisture. By adding MCC
in this way drying step is
not necessary. It is applicable for developing a controlled release formulation.

1.8.2.3.5 Thermal
Adhesion Granulation Process (TAGP) (60)

It is applicable for preparing direct tableting formulations. TAGP is

performed under low
moisture content or low content
of pharmaceutically acceptable
solvent by subjecting
a mixture containing
excipients to heating
at a temperature
in the range
from about 30ºC
to about 130ºC
in a closed
system under mixing
by tumble rotation
until the formation
of granules. This
method utilizes less
water or solvent
than traditional wet
granulation method. It
provides granules with
good flow properties
and binding capacity
to form tablets
of low friability, adequate hardness
and have a
high uptake capacity
for active substances
whose tableting is
poor.

1.8.2.3.6 Foam
Granulation (61)

Here liquid binders are added as aqueous foam. It

has several benefits
over spray(wet) granulation
such as it
requires less binder
than Spray Granulation, requires less
water to wet
granulate, rate of
addition of foam
is greater than
rate of addition
of sprayed liquids, no
detrimental effects on
granulate, tablet, or invitro
drug dissolution properties, no plugging
problems since use
of spray nozzles
is eliminated, no overwetting, useful for
granulating water sensitive
formulations, reduces drying time, uniform
distribution of binder
throughout the powder
bed, reduce manufacturing time, less
binder required for
Immediate Release (IR) and
Controlled Release (CR)
formulations.

Key Phrases

Ø In wet granulation process a granulating liquid is

used to facilitate the agglomeration process. Wet granulation has been and
continues to be the most widely used agglomeration process. Typically wet
massing of pharmaceutical powder is carried out in the high shear mixture
before wet screening and dried in fluidized bed equipment.

Ø In the dry granulation process granulation takes

place without utilizing liquid. In this process dry powder particles may be
brought together mechanically by compression into slug or by rolled
compaction.

Ø
Steam Granulation, Melt Granulation, MADG, MGT,
TAGP, Foam Granulation are some of
the new advancements in
granulation and show
better quality granule
formation as compared
to conventional granulation
methods.

Tablet coating
Submitted by on Sun, 12/06/2009 - 19:54

1.9 Tablet coating

What will you gain?

1.9.1
Introduction

1.9.2
Aspects of tablet coating

1.9.3
Basic principle of tablet coating

1.9.4
Type of tablet coating process

1.9.4.1 Sugar coating

1.9.4.2 Film coating

1.9.4.3 Enteric coating

1.9.4.3.1 Enteric sugar coating

1.9.4.3.2 Enteric film coating

1.9.4.3.3
Controlled release coating

1.9.4.4 Specialized coating

1.9.4.4.1 Compressed coating

1.9.4.4.2 Electrostatic coating

1.9.4.4.3 Dip coating

1.9.4.4.4 Vacuum film coating

1.9.5
Equipments

1.9.6
Processing parameters

1.9.1 Introduction (1-3,5)

Coated
tablets are defined as “tablets covered with one or more layers of mixture of
various substances such as natural or synthetic resins ,gums ,inactive and
insoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes
,authorized colouring material
and some times flavoring material .

Coating
may also contain active ingredient. Substances used for coating are usually
applied as solution or suspension under conditions where vehicle evaporates.

1.9.2 Aspects of
tablet coating

I. Therapy

i) Avoid irritation of oesophagus and stomach

ii) Avoid bad taste

iii) Avoid inactivation of drug in the stomach

iv) Improve drug effectiveness

v) Prolong dosing interval

vi) Improve dosing interval

vii) Improve patient compliance

II. Technology

i) Reduce influence
of moisture

ii) Avoid dust formation

iii) Reduce influence of atmosphere

iv) Improve drug stability

v) Prolong shelve life

III. Marketing

i) Avoid bad taste

ii) Improve product identity

iii) Improve appearance and acceptability

1.9.3 Basic principle of tablet

coating

The principle of tablet coating is relatively

simple. Tablet coating is the
application of coating composition to moving bed of tablets with concurrent use
of heated air to facilitate evaporation of solvent.

Basic
principles involve

i) Insulation which
influences the release pattern as little as possible and does not markedly
change the appearance.

ii) Modified release with specific requirement and

release mechanism adapted to body function in the digestive tract

iii) Colour coating which provides insulation or is

combined with modified release coating.

1.9.4 Type of tablet coating process

1.9.4.1 Sugar coating (1,3,5)

Compressed
tablets may be coated with coloured or uncoloured sugar layer. The coating is
water soluble and quickly dissolves after swallowing. The sugarcoat protects
the enclosed drug from the environment and provides a barrier to objectionable
taste or order. The sugar coat also enhances the appearance of the compressed
tablet and permit imprinting manufacturing’s information. Sugar coating
provides a combination of insulation, taste masking, smoothing the tablet core,
colouring and modified release. The disadvantages of sugar coating are the time
and expertise required in the coating process and thus increases size, weight
and shipping costs.

Sugar coating process involves five separate

operations:

I. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface.

II. Subcoating:
causes a rapid buildup to round off the tablet edges.

III. Grossing/Smoothing:
smoothes out the subcoated surface and increases the tablet size to
predetermine dimension.

IV. Colouring: gives

the tablet its colour and finished size.

V. Polishing:
produces the characteristics gloss.

I. Sealing/Water
proofing

Prior
to applying any sugar/water syrup, the tablet cores must be sealed, thoroughly
dried and free of all residual solvents.

The seal coat provides a moisture barrier and hardness

the surface of the tablet in order to minimize attritional effects. Core
tablets having very rapid disintegration rates conceivably could start the
disintegration process during the initial phase of sugar coating. The sealants
are generally water-insoluble polymers/film formers applied from an organic
solvent solution. The quantities of material applied as a sealing coat will
depend primarily on the tablet porosity, since highly porous tablets will tend
to soak up the first application of solution, thus preventing it from spreading
uniformly across the surface of every tablet in the batch. Hence, one or more
further application of resin solution may be required to ensure that the tablet
cores are sealed effectively.
Common materials used as a sealant include Shellac, Zine,
Cellulose acetate phthalate (CAP), Polyvinylacetate phthalate,
Hyroxylpropylcellulose, Hyroxypropylmethylcellulose etc.

II. Subcoating

Subcoating is the actual start of the sugar coating

process and provides the rapid buildup necessary to round up the tablet edge.
It also acts as the foundation for the smoothing and colour coats.

Generally two methods are used for subcoating:

i) The application
of gum based solution followed by dusting with powder and then drying. This
routine is repeated until the desired shape is achieved.

ii) The application of a suspension of dry powder in

gum/sucrose solution followed by drying.

Thus subcoating is a sandwich of alternate layer of gum

and powder. It is necessary to remove the bulk o the water after each
application of coating syrup.

Table.23. Typical Binder Solution Formulation For Subcoating(1)

%W/W %W/W
Gelatin 6 3.3
Gum acacia (powdered) 8 8.7
Sucrose (powdered) 45 55.3
Distilled water to to
100 100

Table.24. Typical Dusting Powder Formulation For Subcoating(1)

%W/W %W/W
Calcium 40.0 -
carbonate
Titanium 5.0 1.0
dioxide
Talc, 25.0 61.0
asbestos free
Sucrose( 28.0 38.6
powdered )
Gum 2.0 -
acacia (powdered)

Table.25. Typical Suspension Subcoating Formulation(1)

 %W/W
Sucrose 40.0
Calcium 20.0
carbonate
Talc, 12.0
asbestos free
Gum 2.0
acacia(powdered)
Titanium 1.0
dioxide
Distilled 25.0
water

III. Grossing/ smoothing

The grossing/smoothing process is specifically for smoothing and filing the

irregularity on the surface generated during subcoating. It also increases the
tablet size to a predetermined dimension.

If the subcoating is rough with high

amount of irregularities then the use of grossing syrup containing suspended
solids will provide more rapid buildup and better filling qualities. Smoothing
usually can be accomplished by the application of a simple syrup solution
(approximately 60-70 % sugar solid). This syrup generally contains pigments,
starch, gelatin, acacia or opacifier if required.

Small quantities of colour

suspension can be applied to impart a tint of the desired colour when there are
irregularities in coating.

IV.Colour coating

This stage is often critical in the successful

completion of a sugar coating process and involves the multiple application of
syrup solution (60-70 % sugar solid) containing the requisite colouring matter.
Mainly soluble dyes were used in the sugar coating to achieve the desired
colour, since the soluble dye will migrate to the surface during drying. But
now a days the insoluble certified lakes have virtually replaced the soluble
dyes in pharmaceutical tablet coating. The most efficient process for colour
coating involves the use of a predispersed opacified lake suspension.

V. Polishing

Sugar-coated tablets needs to be polished to achieve

a final elegance. Polishing is achieved by applying the mixture of waxes like
beeswax, carnubawax, candelila wax or hard paraffin wax to tablets in polishing
pan.
1.9.4.2 Film Coating

Film coating is more favored over sugar coating.

Table.26. Comparison Between Film Coating And Sugar Coating(1)

FEATURES FILM COATING SUGAR COATING

Tablet:

Appearance Retain contour of original Rounded with high degree of

core. polish
Usually not as shiny as sugar
coat type

Weight
increase because of coating 2-3% 30-50%
material

Logo
or ‘break lines’ Possible Not possible
Process

Operator Process tends itself to Considerable

training required automation and easy training
of operator

High
Adaptability
to GMP Difficulty may arise

Usually single stage

Process Multistage process

stages
Easily adaptable for
controlled release
Not usually possible apart
Functional from enteric coating
coatings

Process description (1)

Film coating is deposition of a thin film of polymer surrounding the
tablet core. Conventional pan equipments
may be used but now a day’s more sophisticated equipments are employed to have
a high degree of automation and coating time.
The polymer is solubilized into solvent.
Other additives like plasticizers and pigments are added. Resulting solution is sprayed
onto a rotated
tablet bed. The drying conditions cause
removal of the solvent, giving thin deposition of coating material around each
tablet core.

Process details (1)

Usually spray process is employed in preparation of film

coated tablets. Accela cota is the
prototype of perforated cylindrical drum providing high drying air
capacity. Fluidized bed equipment has
made considerable impact where tablets are moving in a stream of air passing
through the perforated bottom of a cylindrical column. With a smaller cylindrical
insert, the stream
of cores is rising in the center of the device together with a spray mist
applied in the middle of the bottom. For
fluidized bed coating, very hard tablets (hardness > 20 N) have to be used.

Basic process requirements for film coating (2)

The fundamental requirements are independent of the

actual type of equipments being used and include adequate means of atomizing
the spray liquid for application to the tablet core, adequate mixing and
agitation of tablet bed, sufficient heat input in the form of drying air to
provide the latent heat of evaporation of the solvent. This is particularly
important with aqueous-based spraying and good exhaust facilities to remove
dust and solvent laden air.

Development of film coating formulations (1)

If the following questions are answered concomitantly

then one can go for film coating:

i) Is it necessary
to mask objectionable taste, colour and odor?

ii) Is it necessary
to control drug release?

iii) What tablets size, shape, or colour constrains must

be placed on the developmental work?

Colour, shape and size of final coated tablet are

important for marketing and these properties have a significant influence on
the marketing strategies. An experienced
formulator usually takes the pragmatic approach and develops a coating
formulations modification of one that has performed well in the past. Spraying or
casting films can preliminarily
screen film formulations. Cast films cab
is prepared by spreading the coating composition on teflon, glass or aluminum
foil surface using a spreading bar to get a uniform film thickness. Sprayed films can
be obtained by mounting a
plastic-coated surface in a spray hood or coating pan.

Coating formula optimization (1)

Basic formula is obtained from past experience or from various sources

in the literature. Modifications are
required to improve adhesion of the coating to the core, to decrease bridging
of installations, to increase coating hardness, etc. Usually concentration of colorant
and
opaquant are fixed to get predetermined shade.
Common modification is to alter polymer-to-plasticizer ratio or addition
of different plasticizer/ polymer.
Experimentation of this type can be best achieved by fractional

Materials used in film coating (1,13)

I. Film formers, which may be enteric or nonenteric

II. Solvents

III. Plasticizers

IV. Colourants

V. Opaquant-Extenders

VI. Miscellaneous coating solution components

I. Film
formers (1)

Ideal requirements of film coating materials are

summarized below:

i) Solubility in
solvent of choice for coating preparation

ii) Solubility requirement for the intended use e.g. free

water-solubility, slow water-solubility or pH -dependent solubility

iii) Capacity to produce an elegant looking product

iv) High stability against heat, light, moisture, air and
the substrate being coated

v) No inherent colour, taste or odor

vi) High compatibility with other coating solution

additives

vii) Nontoxic with no pharmacological activity

viii) High resistance

to cracking

ix) Film former should not give bridging or filling of

the debossed tablet

x) Compatible to printing procedure

Commonly used film formers

are as follow

i. Hydroxy
Propyl Methyl Cellulose (HPMC)

It
is available in different viscosity grades. It is a polymer of choice for air
suspension and pan spray coating systems because of solubility characteristic
in gastric fluid, organic and aqueous solvent system.

Advantages
include: it does not affect tablet disintegration and drug availability, it is
cheap, flexible, highly resistant to heat, light and moisture, it has no taste
and odor, colour and other additives can be easily incorporated.

Disadvantage
includes: when it is used alone, the
polymer has tendency to bridge or fill the debossed tablet surfaces. So mixture of
HPMC and other polymers/
plasticizers is used.

ii. Methyl
Hydroxy Ethyl Cellulose (MHEC)

It is available in wide variety of viscosity grades. It is not frequently used as HPMC

because
soluble in fewer organic solvents.

iii. Ethyl
Cellulose (EC)
Depending on the degree of ethoxy substitution, different
viscosity grades are available. It is completely insoluble in water and gastric
fluids. Hence it is used in combination
with water-soluble additives like HPMC and not alone. Unplasticized ethyl cellulose
films are
brittle and require film modifiers to obtain an acceptable film
formulation. Aqua coat is aqueous
polymeric dispersion utilizing ethyl cellulose.
These pseudolatex systems contain high solids, low viscosity
compositions that have coating properties quite different from regular ethyl
cellulose solution.

iv. Hydroxy
Propyl Cellulose (HPC)

It is soluble in water below 40oc (insoluble

above 45 oC), gastric fluid and many polar organic solvents. HPC is extremely tacky
as it dries from
solution system. It is used for sub coat
and not for colour or glass coat. It
gives very flexible film.

v. Povidone

Degree of
polymerization decides molecular weight of material. It is available in four viscosity
grades i.e.
K-15, K-30, K-60 and K-90. Average
molecular weight of these grades is 10000, 40000, 160000 and 360000
respectively. K-30 is widely used as
tablet binder and in tablet coating. It
has excellent solubility in wide variety of organic solvents, water, gastric
and intestinal fluids. Povidone can be
cross-linked with other materials to produce films with enteric
properties. It is used to improve
dispersion of colourants in coating solution.

vi. Sodium carboxy methyl

cellulose

It is available in medium, high and

extra high viscosity grades. It is
easily dispersed in water to form colloidal solutions but it is insoluble in
most organic solvents and hence not a material of choice for coating solution
based on organic solvents. Films
prepared by it are brittle but adhere well to tablets. Partially dried films of are tacky.
So coating compositions must be modified with
additives.
viii. Polyethylene
glycols (PEG)

Lower molecular weights

PEG (200-600) are liquid at room temperature and are used as plasticizers. High
molecular weights PEG (900-8000series)
are white, waxy solids at room temperature.
Combination of PEG waxes with CAP gives films that are soluble in
gastric fluids.

ix. Acrylate polymers

It is marketed under
the name of EudragitÒ. EudragitÒE is cationic co-polymer. Only
EudragitÒE is freely soluble in gastric fluid up to pH 5 and
expandable and permeable above pH 5.
This material is available as organic solution (12.5% in
isopropanol/acetone), solid material or 30% aqueous dispersion. EudragitÒRL & RS
are co-polymers with low content of
quaternary ammonium groups. These are
available only as organic solutions and solid materials. They produce films for
delayed action (pH
dependent).

II. Solvents(1)

Solvents are used to dissolve or

disperse the polymers and other additives and convey them to substrate
surface.

Ideal
requirement are summarized below:

i) Should be either
dissolve/disperse polymer system

ii) Should easily

disperse other additives into solvent system

iii) Small concentration of polymers (2-10%) should not in

an extremely viscous solution system
creating processing problems

iv) Should be colourless, tasteless, odorless, inexpensive,

inert, nontoxic and nonflammable

v) Rapid drying
rate

vi) No environmental pollution

Mostly solvents are used either alone or in
combination with water, ethanol, methanol, isopropanol, chloroform, acetone,
methylene chloride, etc. Water is more
used because no environmental and economic considerations. For drugs that readily
hydrolyze in presence
of water, non aqueous solvents are used.

III. Plasticizers(1)

As solvent is removed, most polymeric materials tend to

pack together in 3-D honey comb arrangement.
“Internal” or “External” plasticizing technique is used to modify
quality of film. Combination of
plasticizer may be used to get desired effect.
Concentration of plasticizer is expressed in relation to the polymer
being plasticized. Recommended levels of
plasticizers range from 1-50 % by weight of the film former. Commonly used
plasticizers are castor oil,
PG, glycerin, lower molecular weight (200-400 series), PEG, surfactants,
etc. For aqueous coating PEG and PG are
more used while castor oil and spans are primarily used for organic-solvent
based coating solution. External
plasticizer should be soluble in the solvent system used for dissolving the
film former and plasticizer. The
plasticizer and the film former must be at least partially soluble or miscible
in each other.

IV. Colourants(1)

Colourants can be used in solution form or in suspension

form. To achieve proper distribution of
suspended colourants in the coating solution requires the use of the powdered
colourants (<10 microns). Most common
colourants in use are certified FD & C or D & C colourants. These are synthetic dyes
or lakes. Lakes are choice for sugar or film coating as
they give reproducible results.
Concentration of colourants in the coating solutions depends on the
colour shade desired, the type of dye, and the concentration of
opaquant-extenders. If very light shade
is desired, concentration of less than 0.01 % may be adequate on the other
hand, if a dark colour is desired a concentration of more than 2.0 % may be
required. The inorganic materials (e.g.
iron oxide) and the natural colouring materials (e.g. anthrocyanins,
carotenoids, etc) are also used to prepare coating solution. Magenta red dye is non
absorbable in biologic
system and resistant to degradation in the gastro intestinal track. OpasrayÒ (opaque
colour concentrate for film coating) and
OpadryÒ (complete film coating concentrate) are promoted as
achieving less lot-to-lot colour variation.
V. Opaquant-Extenders(1)

These are very fine inorganic powder used to provide more

pastel colours and increase film coverage.
These inorganic materials provide white coat or mask colour of the
tablet core. Colourants are very
expensive and higher concentration is required.
These inorganic materials are cheap.
In presence of these inorganic materials, amount of colourants required
decreases. Most commonly used materials
are titanium dioxide, silicate (talc &aluminum silicates), carbonates
(magnesium carbonates), oxides (magnesium oxide) & hydroxides (aluminum
hydroxides). Pigments were investigated in the production of opaque films and
it was found that they have good hiding power and film-coated tablets have
highlighted intagliations.

VI. Miscellaneous coating solution component (1)

Flavors, sweeteners, surfactants, antioxidants,

antimicrobials, etc. may be incorporated into the coating solution.

1.9.4.3 Enteric coating (1, 2, 13)

This
type of coating is used to protect tablet core from disintegration in the acid
environment of the stomach for one or more of the following reasons:

i) To prevent
degradation of acid sensitive API

ii) To prevent
irritation of stomach by certain drugs like sodium salicylate

iii) Delivery of API into intestine

iv) To provide a delayed release component for repeat

action tablet

Several kinds of enteric layer systems are now

available

One
layer system - The coating formulation is applied in one homogeneous layer,
which can be whites-opaque or coloured.
Benefit is only one application needed.

Two
layer system - To prepare enteric tablets of high quality and pleasing
appearance the enteric formulation is applied first, followed by coloured
film. Both layers can be of enteric
polymer or only the basic layer contains enteric polymer while top layer is fast
disintegrating & water-soluble polymer

Ideal properties of enteric

coating material are summarized as below

i) Resistance to
gastric fluids

ii) Susceptible/permeable
to intestinal fluid

iii) Compatibility with most coating solution components

and the drug substrate

iv) Formation of continuous film

v) Nontoxic, cheap
and ease of application

vi) Ability to be readily printed

Polymers used for enteric

coating are as follow

i. Cellulose
acetate phthalate (CAP)

It is widely used in industry. Aquateric is reconstituted colloidal

dispersion of latex particles. It is composed
of solid or semisolid polymer spheres of CAP ranging in size from 0.05 - 3
microns. Cellulose acetate trimellitate
(CAT) developed as an ammoniated aqueous formulation showed faster dissolution
than a similar formulation of CAP.

Disadvantages
include: It dissolves above pH 6 only, delays absorption of drugs, it is
hygroscopic and permeable to moisture in comparison with other enteric polymer,
it is susceptible to hydrolytic removal of phthalic and acetic acid changing
film properties. CAP films are brittle and usually used with other
hydrophobic film forming materials.

ii. Acrylate polymers

Eudragit®L & Eudragit®S

are two forms of commercially available enteric acrylic resins. Both of them produce
films resistant to
gastric fluid. Eudragit®L
& S are soluble in intestinal fluid at pH 6 & 7 respectively. Eudragit®L is available as
an
organic solution (Isopropanol), solid or aqueous dispersion. Eudragit®S is available
only as an
organic solution (Isopropanol) and solid.

iii Hydroxy propyl methyl cellulose phthalate

HPMCP
50, 55 & 55-s (also called HP-50, HP-55 & HP-55-s) is widely used. HP-55 is
recommended for general enteric
preparation while HP-50 & HP-55-s for special cases. These polymers dissolve at a
pH 5-5.5.

iii. Polyvinyl
acetate phthalate

It
is similar to HP-55 in stability and pH dependent solubility.

1.9.4.3.1 Enteric sugar coating (2)

Here the sealing coat is tailored to include one of the enteric polymers
in sufficient quantity to pass the enteric test for disintegration. The sub coating and
subsequent coating steps
are then as for conventional sugar coating.

1.9.4.3.2
Enteric film coating (2)

Enteric polymers are capable of forming a direct film in

a film coating process. Sufficient
weight of enteric polymer has to be used to ensure an efficient enteric
effect. Enteric coating can be combined
with polysaccharides, which are enzyme degraded in colon e.g. Cyclodextrin
& galactomannan.

1.9.4.3.3
Controlled release coating (2)

Polymers like modified acrylates, water insoluble

cellulose (ethyl cellulose), etc. used for control release coating.

1.9.4.4 Specialized coating (1)

1.9.4.4.1 Compressed coating

This type of coating requires a specialization tablet

machine. Compression coating is not widely used but it has advantages in some
cases in which the tablet core cannot tolerate organic solvent or water and yet
needs to be coated for taste masking or to provide delayed or enteric
properties to the finished product and also to avoid incompatibility by
separating incompatible ingredients.
1.9.4.4.2
Electrostatic coating

Electrostatic coating is an efficient method of

applying coating to conductive substrates. A strong electrostatic charge is
applied to the substrate. The coating material containing conductive ionic species
of opposite charge is sprayed onto the charged substrate. Complete and uniform
coating of corners and adaptability of this method to such relatively
nonconductive substrate as pharmaceutical is limited.

1.9.4.4.3 Dip coating

Coating is applied to the tablet cores by dipping

them into the coating liquid. The wet tablets are dried in a conventional
manner in coating pan. Alternative dipping and drying steps may be repeated
several times to obtain the desired coating. This process lacks the speed,
versatility, and reliability of spray-coating techniques. Specialized equipment
has been developed to dip-coat tablets, but no commercial pharmaceutical
application has been obtained.

1.9.4.4.4 Vacuum film coating

Vacuum film coating is a new coating procedure that

employs a specially designed baffled pan.
The pan is hot water jacketed, and it can be sealed to achieve a vacuum
system. The tablets are placed in the sealed pan, and the air in the pan is
displaced by nitrogen before the desired vacuum level is obtained. The coating
solution is then applied with airless spray system. The evaporation is caused
by the heated pan, and the vapour is removed by the vacuum system. Because
there is no high-velocity heated air, the energy requirement is low and coating
efficiency is high. Organic solvent can be effectively used with this coating
system with minimum environmental or safety concerns.

1.9.5 Equipments

Three general types of equipments are available

1. Standard coating pan

e.g., Pellegrin pan system

Immersion sword system

Immersion tube system

2. Perforated pan system

e.g., Accela cota system

Hicoater system
Glattcoater system

Driacoated system

3. Fluidized bed coater

1.9.6 Process parameters

Air capacity:
This value represents the quantity of water or solvent that can be removed
during the coating process which depends on the quantity of air flowing through
the tablet bed, temperature of the air and quantity of water that the inlet air
contains.

Coating composition: The coating contains the ingredients that are to be applied on
the
tablet surface and solvents which act as carrier for the ingredients.

Tablet surface area: It plays an important role for uniform coating. The total surface
area
for unit weight decreases significantly from smaller to larger tablets.
Application of a film with the same thickness requires less coating
composition. In the coating process only a portion of the total surface is
coated. Continuous partial coating and recycling eventually results in fully
coated tablets.

Equipment efficiency: Tablet coaters use the expression “coating efficiency” a value
obtained
by dividing the net increase in coated tablet weight by the total nonvolatile
coating weight applied to the tablet. Ideally 90-95 % of the applied film
coating should be on the tablet surface. Coating efficiency for conventional
sugar coating is much less and 60% would be acceptable. The significant
difference in coating efficiency between film and sugar coating relates to the
quantity of coating material that collects on the wall.

Key Phrases

Ø The sugar coating involves several steps like,

sealing, subcoating, colour coating and printing.

Ø Sugar coating
process yields elegant and highly glossed tablet.

Ø Newer
techniques utilize spraying systems and varying degree of automation to
improve coating efficiency and product uniformity.

Ø Film coating
is deposition of a thin film of polymer surrounding the tablet core.
Ø Film coating
is more favored than sugar coating because weight increase is 2-3%, single
stage process, easily adaptable to controlled release, it retains colour of
original core, high adaptability to GMP, automation is possible, etc.

Ø Accela cota
and fluidized bed equipments are
widely used for film coating

Ø Basic formula
is obtained from past experience or from literature and modifications are
made accordingly. Common modifications
are to alter polymer-to-plasticizer ratio or addition of different
plasticizer/polymer. Experimentation
of this type can be best achieved by fractional factorial study.

Ø Materials used
in film coating include film formers, solvents, plasticizers, colourants,
opaquant-extenders, surfactant, anti oxidant, etc.

Ø Widely used
film formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl Hydroxy Ethyl
Cellulose (MHEC), Ethyl Cellulose (EC), Hydroxy Propyl Cellulose (HPC),
PovidoneÒ (four grades available i.e. K-15, K-30, K-60and
K-90), Sodium carboxy methyl cellulose, Polyethylene glycols (PEG) and
Acrylate polymers (EudragitÒ, EudragitÒRL, EudragitÒRS, EudragitÒE) are used for
film coating. Eudragit®L & S are
used for enteric coating.
Eudragit®RL, Eudragit®RS, Eudragit®S
are available as organic solution and solid while Eudragit®L and
Eudragit®E are available as organic, solid or aqueous dispersion.

Ø Quality of film
can be modified by plasticizer.
Commonly used plasticizers include PG, glycerin, low molecular weight
PEG, castor oils, etc. Castor oil and
spans are more used for organic-solvent based coating solution while PE and
PEG are used for aqueous coating.

Ø
FD & C or
D & C certified colourants are used.
Lakes are choice for film coating as they give reproducible
results. Opaspray® (opaque colour concentrate for film
coating) and Opadry® (complete film coating concentrate) are
promoted as achieving less lot-to-lot variation.

Ø Colourants are
expensive and higher concentration is required. So materials like titanium dioxides,
silicates, and carbonates are used to provide more pastel colours and
increase film coverage.

Enteric
Coating:

Ø Enteric
coating is used to protect tablet core from disintegration in the acid
environment of stomach to prevent degradation of acid sensitive API, prevent
irritation to stomach by certain drugs, delivery of API into intestine, to
provide a delayed release components for repeat action, etc.

Ø Several kinds
of enteric layer systems are available like one layer system and two-layer
system. Polymers used for enteric
coating are cellulose Acetate Phthalate (CAP), Acrylates (Eudragit®L
and Eudragit®S, Hydroxy Propyl Methyl Cellulose Phthalate
(HPMCP50, HPMCP55 & HPMCP 55s) and polyvinyl acetate phthalate

Enteric sugar coating:

Ø Here sealing
coat is modified to comprise one of the enteric polymers in sufficient
quantity to pass the enteric test for disintegration. The sub coating and subsequent
coating
steps are then as for conventional sugar coating.

Ø Enteric
polymers are capable of forming a direct film in a film coating process. Sufficient
weight of enteric polymer has to
be used to ensure an efficient enteric effect.

Ø Enteric coating
can be combined with polysaccharides, which are enzymatically degraded in
colon. For example, Cyclodextrin &
Galactomannan.

Controlled
release coating:

Ø Polymers like
modified acrylates, ethyl cellulose, etc are used for the same.

Problems in tablet manufacture and

related remedies
Submitted by Mukesh C Gohel on Sun, 12/06/2009 - 19:54

1.10 Problems In Tablet Manufacture

And Related Remedies
What
will you gain?

1.10.1 Introduction

1.10.1.1
Capping

1.10.1.2 Lamination / Laminating

1.10.1.3 Chipping

1.10.1.4 Cracking

1.10.1.5 Sticking / Filming

1.10.1.6 Picking

1.10.1.7 Binding

1.10.1.8 Mottling

1.10.1.9 Double impression

1.10.2 Problems and

Remedies for tablet coating

1.10.2.1 Blistering

1.10.2.2 Chipping

1.10.2.3 Cratering

1.10.2.4 Picking

1.10.2.5 Pitting

1.10.2.6 Blooming
1.10.2.7 Blushing

1.10.2.8 Colour variation

1.10.2.9
Infilling

1.10.2.10
Orange peel/Roughness

1.10.2.11
Cracking/Splitting

1.10.1
Introduction (62,63)

An
ideal tablet should be free from any visual defect or functional defect. The
advancements and innovations in tablet manufacture have not decreased the
problems, often encountered in the production, instead have increased the
problems, mainly because of the complexities of tablet presses; and/or the
greater demands of quality.

An
industrial pharmacist usually encounters number of problems during
manufacturing. Majority of visual defects are due to inadequate fines or
inadequate moisture in the granules ready for compression or due to faulty
machine setting. Functional defects are due to faulty formulation. Solving many
of the manufacturing problems requires an in–depth knowledge of granulation
processing and tablet presses, and is acquired only through an exhaustive study
and a rich experience.

Here,
we will discuss the imperfections found in tablets along–with their causes and
related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are
either related to imperfections in any one or more of the following factors:

I. Tableting Process

II. Excipient

III. Machine

The
defects related to Tableting Process are as follows:
i)
CAPPING: It is
due air-entrapment in the granular material.

ii) LAMINATION: It is due air-entrapment in the granular

material.

iii) CRACKING: It is due to rapid expansion of tablets

when deep concave punches are used.

The defects related to Excipient are as follows:

iv) CHIPPING: It is due to very dry granules

v) STICKING

vi) PICKING

vii) BINDING

These problems (v, vi, vii) are due to

more amount of binder in the granules or wet granules.

The
defect related to more than one factor:

viii) MOTTLING: It
is either due to any one or more of these factors:

Due
to a coloured drug, which has different colour than the rest of the granular
material? (Excipient- related); improper mixing of granular material
(Process-related); dirt in the granular material or on punch faces; oil spots
by using oily lubricant.

The
defect related to Machine

ix) DOUBLE IMPRESSION: It is due to free rotation of the

punches, which have some engraving on the punch faces.

Further,
in this section, each problem is described along-with its causes and remedies
which may be related to either of formulation (granulation) or of machine
(dies, punches and entire tablet press).

1.10.1.1 Capping (1,5)

Definition:
‘Capping’ is the term used, when the upper or lower segment of the tablet
separates horizontally, either partially or completely from the main body of a
tablet and comes off as a cap, during ejection from the tablet press, or during
subsequent handling.

Reason:
Capping is usually due to the air–entrapment in a compact during compression,
and subsequent expansion of tablet on ejection of a tablet from a die.

Table.27. The Causes And Remedies Of Capping Related To ‘Formulation’

(Granulation)

Sr. No. CAUSES REMEDIES

1. Large amount of fines in Remove some or all fines
the granulation through 100 to 200 mesh screen
2. Too dry or very low Moisten the granules
moisture content (leading to loss of suitably. Add hygroscopic substance e.g.:
proper binding action). sorbitol, methyl- cellulose or
PEG-4000.
3. Not thoroughly dried Dry the granules properly.
granules.
4. Insufficient amount of Increasing the mount of
binder or improper binder. binder OR

Adding dry binder such as

pre-gelatinized starch, gum acacia,
powdered sorbitol, PVP, hydrophilic
silica or powdered sugar.
5. Insufficient or improper Increase the amount of
lubricant. lubricant or change the type of lubricant.
6. Granular mass too cold to Compress at room
compress firm. temperature.

Table.28. The Causes And Remedies Of Capping Related To ‘Machine’ (Dies,

Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Poorly finished dies Polish dies properly.
Investigate other steels or other
materials.
2. Deep concave punches or Use flat punches.
beveled-edge faces of punches.
3. Lower punch remains below Make proper setting of
the face of die during ejection. lower punch during ejection.
4. Incorrect adjustment of Adjust sweep-off blade
sweep-off blade. correctly to facilitate proper
ejection.
5. High turret speed. Reduce speed of turret
 (Increase dwell time).

1.10.1.2 Lamination /
Laminating (1,5)

Definition:
‘Lamination’ is the separation of a tablet into two or more distinct horizontal
layers.

Reason:
Air–entrapment during compression and subsequent release on ejection.

The
condition is exaggerated by higher speed of turret.

Table.29. The Causes And Remedies Of Lamination Related To Formulation

(Granulation)

Sr. No. CAUSES REMEDIES

1. Oily or waxy materials in Modify mixing process. Add
granules adsorbent or absorbent.
2. Too much of hydrophobic Use a less amount of
lubricant e.g.: Magnesium- lubricant or change the type of lubricant.
stearate.

Table.30. The Causes And Remedies Of Lamination Related To Machine (Dies,

Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Rapid relaxation of the
peripheral regions of a tablet, on
ejection from a die.
2. Rapid decompression
Use tapered dies, i.e.
upper part of the die bore has an outward
taper of 3° to 5°.
Use pre-compression step.
Reduce turret speed and reduce the final
compression pressure.

1.10.1.3 Chipping (1)

Definition: ‘Chipping’ is defined as the breaking of tablet edges, while

the tablet leaves the press or during subsequent handling and coating
operations.

Reason:
Incorrect machine settings, specially mis-set ejection take-off.

Table.31. The Causes And Remedies Of Chipping Related To Formulation

(Granulation) Are As Follows
Sr. No. CAUSES REMEDIES
1. Sticking on punch faces Dry the granules properly
or increase lubrication.
2. Too dry granules. Moisten the granules to
plasticize. Add hygroscopic substances.
3. Too much binding causes Optimize binding, or use
chipping dry binders.
at bottom.

Table.32. The Causes And Remedies Of Chipping Related To Machine (Dies,

Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Groove of die worn at
compression point.
2. Barreled die (center of
the die wider than ends)
3. Edge of punch face turned
inside/inward.
4. Concavity too deep to
compress properly.
Polish to open end,
reverse or replace the die.
Polish the die to make it
cylindrical
Polish the punch edges
Reduce concavity of punch
faces. Use flat punches.

1.10.1.4 Cracking (1)

Definition: Small, fine cracks observed on the upper

and lower central surface of tablets, or very rarely on the sidewall are
referred to as ‘Cracks’.

Reason: It is observed as a result of

rapid expansion of tablets, especially when deep concave punches are used.

Table.33. The Causes And Remedies Of Cracking Related To Formulation

(Granulation)

Sr. No. CAUSES REMEDIES

1. Large size of granules. Reduce granule size. Add
fines.
2. Too dry granules. Moisten the granules
properly and add proper amount of binder.
3. Tablets expand. Improve granulation. Add
dry binders.
4. Granulation too cold. Compress at room
temperature.

Table.33. The Causes And Remedies Of Cracking Related To Formulation

(Granulation)
Sr. No. CAUSES REMEDIES
1. Tablet expands on ejection Use tapered die.
due to air entrapment.
2. Deep concavities cause Use special take-off.
cracking while

removing tablets

1.10.1.5 Sticking / Filming (1)

Definition: ‘Sticking’ refers to the tablet material

adhering to the die wall.

Filming is a slow form of sticking and is largely due to excess moisture

in the granulation.

Reason: Improperly dried or improperly lubricated

granules.

Table.35. The Causes And Remedies Of Sticking Related To Formulation

(Granulation)

Sr. No. CAUSES REMEDIES

1. Granules not dried Dry the granules properly.
properly. Make moisture analysis to determine
limits.
2. Too little or improper Increase or change
lubrication. lubricant.
3. Too much binder Reduce the amount of
binder or use a different type of binder.
4. Hygroscopic granular Modify granulation and
material. compress under controlled humidity.
5. Oily or way materials Modify mixing process. Add
an absorbent.
6. Too soft or weak granules. Optimize the amount of
binder and granulation technique.

Table.36. The Causes And Remedies Of Sticking Related To Machine (Dies,

Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Concavity too deep for Reduce concavity to
granulation. optimum.
2. Too little pressure. Increase pressure.
3. Compressing too fast. Reduce speed.

1.10.1.6 Picking (1)

Definition:
‘Picking’ is the term used when a small amount of material from a tablet is
sticking to and being removed off from the tablet-surface by a punch face.

The
problem is more prevalent on the upper punch faces than on the lower ones. The
problem worsens, if tablets are repeatedly manufactured in this station of
tooling because of the more and more material getting added to the already
stuck material on the punch face.

Reason: Picking is of
particular concern when punch tips have engraving or embossing letters, as well
as the granular material is improperly dried.

Table.37. The Causes And Remedies Of Picking Related To Formulation

(Granulation)

Sr. No. CAUSES REMEDIES

1. Excessive moisture in Dry properly the granules,
granules. determine optimum limit.
2. Too little or improper Increase lubrication; use
lubrication. colloidal silica as a ‘polishing agent’, so
that material does not cling to
punch faces.
3. Low melting point Add high melting-point
substances, may soften from the materials. Use high meting point
heat of compression and lead to lubricants.
picking.
4. Low melting point Refrigerate granules and
medicament in high concentration. the entire tablet press.
5. Too warm granules when Compress at room
compressing. temperature. Cool sufficiently before
compression.
6. Too much amount of binder. Reduce the amount of
binder, change the type or use dry binders.

Table.38. The Causes And Remedies Of Picking Related To Machine (Dies,

Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Rough or scratched punch
faces.
2. Embossing or engraving
letters on punch faces such as
B, A, O, R, P, Q, G.
Polish faces to high
luster.
Design lettering as large
as possible.
Plate the punch faces with
chromium to produce a smooth and non-
adherent face.
3. Bevels or dividing lines Reduce depths and
too deep. sharpness.
4. Pressure applied is not Increase pressure to
enough; too soft tablets. optimum.

1.10.1.7 Binding (1)

Definition:
‘Binding’ in the die, is the term used when the tablets adhere, seize or tear
in the die.

A
film is formed in the die and ejection of tablet is hindered. With excessive
binding, the tablet sides are cracked and it may crumble apart.

Reason:
Binding is usually due to excessive amount of moisture in granules, lack of
lubrication and/or use of worn dies.

Table.39. The Causes And Remedies Of Binding Related To Formulation

(Granulation)

Sr. No. CAUSES REMEDIES

1. Too moist granules and
extrudes around lower punch.
2. Insufficient or improper
lubricant.
3. Too coarse granules.
4. Too hard granules for the
lubricant to be effective.
5. Granular material very
abrasive and cutting into dies.
Dry the granules properly.
Increase the amount of
lubricant or use a more effective lubricant.
Reduce granular size, add
more fines, and increase the quantity of
lubricant.
Modify granulation. Reduce
granular size.
If coarse granules, reduce
its size.

Use wear-resistant dies.

6. Granular material too Reduce temperature.
warm, sticks to the die.
Increase clearance if it
is extruding.

Table.40. The Causes And Remedies Of Binding Related To Machine (Dies,

Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Poorly finished dies. Polish the dies properly.
2. Rough dies due to Investigate other steels
 abrasion, corrosion.
3. Undersized dies. Too
little clearance.
4. Too much pressure in the
tablet press.
or other materials or modify granulation.
Rework to proper size.
Increase clearance.
Reduce pressure. OR
Modify granulation.

1.10.1.8 Mottling (1)

Definition: ‘Mottling’ is the term used to describe

an unequal distribution of colour on a tablet, with light or dark spots
standing out in an otherwise uniform surface.

Reason: One cause of mottling may be a

coloured drug, whose colour differs from the colour of excipients used for
granulation of a tablet.

Table.41. The Causes And Remedies Of Mottling

Sr. No. CAUSES REMEDIES

1. A coloured drug used along
with colourless or white-
coloured excipients.
2. A dye migrates to the
surface of granulation while
drying.
Use appropriate
colourants.
Change the solvent system,
Change the binder,

Reduce drying temperature

and

Use a smaller particle

3. Improperly mixed dye,
especially during ‘Direct
Compression’.
4. Improper mixing of a
coloured binder solution.
size.
Mix properly and reduce
size if it is of a larger size to prevent
segregation.
Incorporate dry colour
additive during powder blending step, then
add fine powdered adhesives such
as acacia and tragacanth and mix well and
finally add granulating liquid.

1.10.1.9 Double
impression (1)

Definition: ‘Double Impression’ involves only those

punches, which have a monogram or other engraving on them.
Reason: At the moment of compression,
the tablet receives the imprint of the punch. Now, on some machines, the lower
punch freely drops and travels uncontrolled for a short distance before riding
up the ejection cam to push the tablet out of the die, now during this free
travel, the punch rotates and at this point, the punch may make a new
impression on the bottom of the tablet, resulting in ‘Double Impression’.

If the upper punch is uncontrolled, it can rotate

during the short travel to the final compression stage and create a double
impression.

Table.42. The Causes And Remedies Of Double Impression

Sr. No. CAUSE REMEDIES

1. Free rotation of either -Use keying in tooling, i.e. inset
upper punch or lower punch a key alongside of the punch, so
during ejection of a tablet. that it fits the punch and prevents punch rotation.

-Newer presses have anti-turning devices, which

prevent punch rotation.

1.10.2 Problems and remedies for

tablet coating

1.10.2.1 Blistering (1,64)

Definition:
It is local detachment of film from the substrate forming blister.

Reason:
Entrapment of gases in or underneath the film due to overheating either during
spraying or at the end of the coating run.

Table.43. The Cause And Remedy Of Blistering

Sr. No. CAUSE REMEDY

1. Effect of temperature on Use mild drying condition.
the strength, elasticity and adhesion
of the film.

1.10.2.2 Chipping (1,64)

Definition:
It is defect where the film becomes chipped and dented, usually at the edges of
the tablet.

Reason:
Decrease in fluidizing air or speed of rotation of the drum in pan coating.
Table.44. The Cause And Remedy Of Chipping

Sr. No. CAUSE REMEDY

1. High degree of attrition Increase hardness of the
associated with the coating film by increasing the molecular weight
process. grade of polymer.

1.10.2.3 Cratering (1,64)

Definition:
It is defect of film coating whereby volcanic-like craters appears exposing the
tablet surface.

Reason:
The coating solution penetrates the surface of the tablet, often at the crown
where the surface is more porous, causing localized disintegration of the core
and disruption of the coating.

Table.45. The Causes And Remedies Of Cratering

Sr. No. CAUSES REMEDIES

1. Inefficient drying. Use efficient and optimum
drying conditions.

2. Higher rate of application Increase viscosity of

of coating solution. coating solution to decrease spray
application rate.

1.10.2.4 Picking (1,64)

Definition:
It is defect where isolated areas of film are pulled away from the surface when
the tablet sticks together and then part.

Reason: Conditions similar to cratering that produces

an overly wet tablet bed where adjacent tablets can stick together and then
break apart.

Table.46. The Causes And Remedies Of Picking

Sr. CAUSE REMEDY

No.
1. Inefficient drying. Use optimum and efficient
drying conditions or increase the inlet air
temperature.
2. Higher rate of application Decrease the rater of
of coating solution application of coating solution by increasing
viscosity of coating solution.

1.10.2.5 Pitting (1,64)

Definition:
It is defect whereby pits occur in the surface of a tablet core without any
visible disruption of the film coating.

Reason:
Temperature of the tablet core is greater than the melting point of the
materials used in the tablet formulation.

Table.47. The Cause And Remedy Of Pitting

Sr. No. CAUSE REMEDY

1. Inappropriate drying
(inlet air ) temperature
Dispensing with preheating
procedures at the initiation of coating and
modifying the drying (inlet air)
temperature such that the temperature of
the tablet core is not greater than
the melting point of the batch of additives
used.

1.10.2.6 Blooming (1,64)

Definition:
It is defect where coating becomes dull immediately or after prolonged storage
at high temperatures.

Reason:
It is due to collection on the surface of low molecular weight ingredients
included in the coating formulation. In
most circumstances the ingredient will be plasticizer.

Table.48. The Cause And Remedy Of Blooming

Sr. No. CAUSE REMEDY

1. High concentration and low Decrease plasticizer
molecular weight of plasticizer. concentration and increase molecular
weight of plasticizer.

1.10.2.7 Blushing (1,64)

Definition:
It is defect best described as whitish specks or haziness in the film.
Reason:
It is thought to be due to precipitated polymer exacerbated by the use of high
coating temperature at or above the thermal gelation temperature of the
polymers.

Table.49. The Causes And Remedies Of Blushing

Sr. No. CAUSES REMEDIES

1. High coating temperature
2. Use of sorbitol in
formulation which causes largest
fall in the thermal gelation
temperature of
the Hydroxy Propyl Cellulose,
Hydroxy Propyl Methyl Cellulose,
Methyl
Cellulose and Cellulose ethers.
Decrease the drying air
temperature
Avoid use of sorbitol with
Hydroxy Propyl Cellulose, Hydroxy
Propyl Methyl Cellulose, Methyl Cellulose
and Cellulose ethers.

1.10.2.8 Colour variation (1,64)

Definition:
A defect which involves variation in colour of the film.

Reason:
Alteration of the frequency and duration of appearance of tablets in the spray
zone or the size/shape of the spray zone.

Table.50. The Cause And Remedy Of Colour Variation

Sr. No. CAUSE REMEDY

1. Improper mixing, uneven
spray pattern, insufficient coating,
migration of soluble dyes-
plasticizers
and other additives during drying.
Go for geometric mixing,
reformulation with different plasticizers
and additives or use mild drying
conditions.

1.10.2.9 Infilling (1,64)

Definition:
It is defect that renders the intagliations indistinctness.

Reason: Inability of foam, formed by air

spraying of a polymer solution, to break.
The foam droplets on the surface of the tablet breakdown readily due to
attrition but the intagliations form a protected area allowing the foam to
accumulate and “set”. Once the foam has
accumulated to a level approaching the outer contour of the tablet surface, normal
attrition can occur allowing the structure to be covered with a continuous
film.

Table.51. The Cause And Remedy Of Infilling

Sr. No. CAUSE REMEDY

1. Bubble or foam formation Add alcohol or use spray nozzle
because of air spraying of a capable of finer atomization.
polymer solution

1.10.2.10 Orange peel/Roughness (1,64)

Definition:
It is surface defect resulting in the film being rough and nonglossy. Appearance is
similar to that of an orange.

Reason: Inadequate spreading of the coating

solution before drying.

Table.52. The Causes And Remedies Of Orange Peel/Roughness

Sr. No. CAUSES REMEDIES

1. Rapid Drying Use mild drying conditions
2. High solution viscosity Use additional solvents to
decrease viscosity of solution.

1.10.2.11 Cracking/Splitting (1,64)

Definition:
It is defect in which the film either cracks across the crown of the tablet
(cracking) or splits around the edges of the tablet (Splitting)

Reason: Internal stress in the film exceeds

tensile strength of the film.

Table.53. The Cause And Remedy Of Cracking/Splitting

Sr. No. CAUSE REMEDY

1. Use of higher molecular Use lower molecular weight
weight polymers or polymeric polymers or polymeric blends. Also
blends. adjust plasticizer type and concentration.

Key
Phrases

Ø During tablet
manufacture, an industrial pharmacist
usually encounters many problems.
Solving these problems requires an in-
depth knowledge of tablet-formulation
as well as machine-operating processes.

Ø Capping and
Lamination are the defects arising as a
result of air-entrapment in the
granular material.

Ø Chipping is a
defect related arising due to very dry
granules.

Ø Cracking is
due to rapid expansion of tablets, when
deep concave punches are used.

Ø Sticking,
Picking and Binding are the imperfections
related to more amount of binder in
granules.

Ø Mottling is an
imperfection arising due to more than one
factor: a coloured drug, dirt in
granules or the use of an oily lubricant.

Ø Double-Impression
is related to a machine defect: it is caused
by the free rotation of punches
that have some engraving on the punch-
faces.

Coating defects:

Ø Blistering is
related to entrapment of gases in or
underneath the film due to overheating
either during spraying or at the end of the
coating run. Use of mild drying conditions
can solve this
problem.

Ø Chipping is
related to higher degree of attrition
associated with the coating
process. Increase in hardness of the
film by increasing the molecular weight
grade of polymer can solve this
problem.

Ø Cratering is
related to penetration of the coating
solution into the surface of the
tablet, often at the crown where the surface
is more porous, causing
localized disintegration of the core and
disruption of the coating. Decrease in spray
application rate and use
of optimum and efficient drying conditions
can solve this problem.

Ø Pitting is
defect in which temperature of the tablet
core is greater than the melting
point of the materials used in tablet
formulation. Dispensing with preheating
procedures at
the initiation of coating and modifying the
drying (inlet air) temperature
can solve this problem.

Ø Blooming or
dull film is generally because of higher
concentration and lower molecular
weight of plasticizer. So use lower
concentration and higher molecular grade
of plasticizer.

Ø Blushing/Whitish
specks/Haziness of the film is related to
precipitation of polymer
exacerbated by the use of high coating
temperature at or above the thermal
gelation temperature of the polymers.

Ø Colour
variation is because of improper mixing,
uneven spray pattern, insufficient coating
or migration of soluble dyes during drying.
Geometric mixing, mild drying conditions
and reformulation with
different plasticizers can solve this
problem.

Ø Infilling is
because of bubble/foam formation during
air spraying of a polymer
 solution. Addition of alcohol or use
of spray nozzle capable of finer
atomization can solve this problem.

Ø Orange
peel/Roughness is related to inadequate
spreading of the coating solution
before drying. So decrease in
viscosity of coating solution can counter
this defect.

Ø Cracking is
seen when internal stresses in the film
exceeds tensile strength of the
film. This is common with higher
molecular weight polymers or polymeric
blends. So use lower molecular weight
polymers or
polymeric blends.

Quality Control tests for tablets

Submitted by Mukesh C Gohel on Sun, 12/06/2009 - 19:55

1.11
Quality Control Tests for Tablets
What
will you gain?

1.11.1 Official Standards

as per I.P. / B.P. / U.S.P.

1.11.2 Non – compendial

standards

1.11.3 In – Process Quality Control

1.11.1 Official Standards

as per I.P. / B.P. / U.S.P. (65-67)
Table: 54. Comparison Of Different Pharmacopoeial Quality Control Tests

PHARMACOPOEIAS TYPE OF TABLET TESTS TO BE PERFORMED

BRITISH For all tablets Content of active
PHARMACOPOEIA ingredients

Disintegration

Uniformity of content

Labeling
Uncoated tablet Disintegration test

Uniformity of weight
Effervescent tablet Disintegration test

Uniformity of weight
Coated tablet Disintegration test

Uniformity of weight
Gastro resistant tablet Disintegration test
Modified release tablet Uniformity of weight
Tablet for use in mouth Uniformity of weight
Soluble tablet Disintegration test

Uniformity of weight
Dispersible tablet Disintegration test

Uniformity of dispersion

Uniformity of weight
INDIAN Uncoated tablet Uniformity of container
PHARMACOPOEIA content

Content of active
ingredient

Uniformity of weight

Uniformity of content

Disintegration test
Enteric coated tablet Disintegration test
Dispersible tablet Uniformity of dispersion

Disintegration
Soluble tablet Disintegration
 Effervescent tablet Disintegration/
Dissolution / Dispersion

test
UNITED STATES Physical tests Bulk density /Tapped
PHARMACOPOEIA applicable density of powder
to tablet formulation
Powder fineness

Loss on drying

Disintegration test

Tablet friability

Dissolution test

Drug release testing

Uniformity of dosage form

Container permeation test

Labeling of inactive
ingredients

1.11.2 Non – compendial

standards (2,13)

Measurement
of mechanical properties is not covered pharmacopoeial monograph. There are
also a number of tests frequently applied to tablets for which there are no
pharmacopoeial requirement but will form a part of a manufacturer’s own product
specification.

I.Hardness
tests/ Crushing strength

The test measures crushing strength property defined

as the compressional force applied diametrically to a tablet which just
fractures it. Among a large number of measuring devices, the most favored ones
are Monsanto tester, Pfizer tester, and Strong cobb hardness tester. All are
manually used. So, strain rate depends on the operator. Heberlein Schleuniger,
Erweka, Casburt hardness testers are motor driven.

II.Friability
(Official in USP)
The tablet may well be subjected to a tumbling
motion. For example, Coating, packaging, transport, which are not severe enough
to break the tablet, but may abrade the small particle from tablet surface. To
examine this, tablets are subjected to a uniform tumbling motion for specified
time and weight loss is measured. Roche friabilator is most frequently used for
this purpose.

Tests for coated tablets

I. Water vapor permeability

II. Film tensile

strength

III.Coated tablet
evaluations:

i)Adhesion test
with tensile-strength tester: Measures
force required toe peel the film from
the tablet surface

ii)Diametral crushing strength of coated tablet: Tablet hardness testers are used. This
test gives information on the relative
increase in crushing strength provided by the film and the contribution made by
changes in the film composition

iii)Temperature and humidity may cause film defects. Hence studies are to be carried
out

iv)Quantification of film surface roughness, hardness,

& colour uniformity. Visual inspection or instruments are used. Resistance
of coated tablet on a white sheet of paper.
Resisilient films remain intact, & no colour is transferred to the
paper; very soft coating are readily “erased” from the tablet surface to the
paper

1.11.3 In – Process Quality Control (13)

The control of the tableting process in production is

concerned with the following :

I. Weight
of tablet – Single pan electric balance.

II. Crushing
strength – Controls friability and disintegration time.

III. Tablet
thickness – Very thick tablet affect packaging particularly into blisters.
IV.
Disintegration time.

V. Friability

As
a part of Current Good Manufacturing Practice (cGMP), the production run is
monitored under control chart. At regular interval (10 – 15minutes) the
operator must sample specified number of tablets, weigh them individually,
check thickness, crushing strength and all the properties as mentioned above.
The process can be automated and interfaced with printer. Such data promotes
process improvement.

Key Phrases

ØUSP mentions
some of the quality control tests to be performed before the powder is
compressed. e.g., powder fineness, density. etc.

ØFriability is
official test as per USP.

ØAt regular
interval (10 – 15minutes) during the course of manufacturing the operator
must sample specified number of tablets for testing.

Tablet:Problems in tablet
manufacturing
From Pharmpedia

Next Page: Quality control tests for tablets

Previous Page: Tablet coating
Contents
[hide]

• 1 Introduction
o 1.1 Capping
o 1.2 Lamination / Laminating
o 1.3 Chipping
o 1.4 Cracking
o 1.5 Sticking / Filming
o 1.6 Picking
o 1.7 Binding
o 1.8 Mottling
o 1.9 Double impression
• 2 Problems and remedies for tablet coating
o 2.1 Blistering
o 2.2 Chipping
o 2.3 Cratering
o 2.4 Picking
o 2.5 Pitting
o 2.6 Blooming
o 2.7 Blushing
o 2.8 Colour variation
o 2.9 Infilling
o 2.10 Orange peel/Roughness
o 2.11 Cracking/Splitting

• 3 Key Phrases

Introduction

(62,63)

An ideal tablet should be free from any visual defect or functional defect. The
advancements and innovations in tablet manufacture have not decreased the problems,
often encountered in the production, instead have increased the problems, mainly
because of the complexities of tablet presses; and/or the greater demands of quality.

An industrial pharmacist usually encounters number of problems during

manufacturing. Majority of visual defects are due to inadequate fines or inadequate
moisture in the granules ready for compression or due to faulty machine setting.
Functional defects are due to faulty formulation. Solving many of the manufacturing
problems requires an in–depth knowledge of granulation processing and tablet
presses, and is acquired only through an exhaustive study and a rich experience.

Here, we will discuss the imperfections found in tablets along–with their causes and
related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are
either related to imperfections in any one or more of the following factors:
I. Tableting Process

II. Excipient

III. Machine

The defects related to Tableting Process are as follows:

i) CAPPING: It is partial or complete separation of the top or bottom of tablet due air-
entrapment in the granular material.

ii) LAMINATION: It is separation of tablet into two or more layers due to air-
entrapment in the granular material.

iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches
are used.

The defects related to Excipient are as follows:

iv) CHIPPING: It is due to very dry granules.

v) STICKING: It is the adhesion of granulation material to the die wall

vi) PICKING: It is the removal of material from the surface of tablet and its
adherance to the face of punch.

vii) BINDING

These problems (v, vi, vii) are due to more amount of binder in the granules or wet
granules.

The defect related to more than one factor:

viii) MOTTLING: It is either due to any one or more of these factors: Due to a
coloured drug, which has different colour than the rest of the granular material?
(Excipient- related); improper mixing of granular material (Process-related); dirt in
the granular material or on punch faces; oil spots by using oily lubricant.

The defect related to Machine

ix)DOUBLE IMPRESSION: It is due to free rotation of the punches, which have

some engraving on the punch faces.

Further, in this section, each problem is described along-with its causes and remedies
which may be related to either of formulation (granulation) or of machine (dies,
punches and entire tablet press).
Capping

(1,5)

‘Capping’ is the term used, when the upper or lower segment of the tablet separates
horizontally, either partially or completely from the main body of a tablet and comes
off as a cap, during ejection from the tablet press, or during subsequent handling.

Reason: Capping is usually due to the air–entrapment in a compact during

compression, and subsequent expansion of tablet on ejection of a tablet from a die.

TABLE.27. THE CAUSES AND REMEDIES OF CAPPING RELATED TO

‘FORMULATION’ (GRANULATION)

Sr.
CAUSES REMEDIES
No.
Large amount of fines in the Remove some or all fines through 100 to 200
1.
granulation mesh screen
Too dry or very low moisture Moisten the granules suitably. Add hygroscopic
2. content (leading to loss of substance e.g.: sorbitol, methyl- cellulose or
proper binding action). PEG-4000.
3. Not thoroughly dried granules. Dry the granules properly.
Increasing the mount of binder OR
Insufficient amount of binder or
4. Adding dry binder such as pre-gelatinized
improper binder.
starch, gum acacia, powdered sorbitol, PVP,
hydrophilic silica or powdered sugar.
Insufficient or improper Increase the amount of lubricant or change the
5.
lubricant. type of lubricant.
Granular mass too cold to
6. Compress at room temperature.
compress firm.

TABLE.28. THE CAUSES AND REMEDIES OF CAPPING RELATED TO

‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS)

Sr.
CAUSES REMEDIES
No.
Polish dies properly. Investigate other
1. Poorly finished dies
steels or other materials.
Deep concave punches or beveled-
2. Use flat punches.
edge faces of punches.
Lower punch remains below the face Make proper setting of lower punch
3.
of die during ejection. during ejection.
Incorrect adjustment of sweep-off Adjust sweep-off blade correctly to
4.
blade. facilitate proper ejection.
5. High turret speed. Reduce speed of turret (Increase dwell
 time).

Lamination / Laminating

(1,5)

Definition: ‘Lamination’ is the separation of a tablet into two or more distinct

horizontal layers.

Reason: Air–entrapment during compression and subsequent release on ejection.

The condition is exaggerated by higher speed of turret.

TABLE.29. THE CAUSES AND REMEDIES OF LAMINATION RELATED TO

FORMULATION (GRANULATION)

Sr. REMEDIES
CAUSES
No.
Modify mixing process. Add adsorbent or
1. Oily or waxy materials in granules
absorbent.
Too much of hydrophobic Use a less amount of lubricant or change the
2. lubricant e.g.: Magnesium- type of lubricant.
stearate.

TABLE.30. The Causes and Remedies of Lamination related to MACHINE (Dies,

Punches and Tablet Press)

Sr.
CAUSES REMEDIES</ b>
No.
Rapid relaxation of the peripheral
Use tapered dies, i.e. upper part of the die
1. regions of a tablet, on ejection from a
bore has an outward taper of 3° to 5°.
die.
Use pre-compression step. Reduce turret
2. Rapid decompression speed and reduce the final compression
pressure.

Chipping

(1)

Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet
leaves the press or during subsequent handling and coating operations.
Reason: Incorrect machine settings, specially mis-set ejection take-off.

TABLE.31. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO

FORMULATION (GRANULATION) ARE AS FOLLOWS

Sr.
CAUSES REMEDIES
No.
Dry the granules properly or increase
1. Sticking on punch faces
lubrication.
Moisten the granules to plasticize. Add
2. Too dry granules.
hygroscopic substances.
Too much binding causes
3. Optimize binding, or use dry binders.
chipping at bottom.

TABLE.32. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO

MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr.
CAUSES REMEDIES
No.
Groove of die worn at compression Polish to open end, reverse or replace the
1.
point. die.
Barreled die (center of the die wider
2. Polish the die to make it cylindrical
than ends)
Edge of punch face turned
3. Polish the punch edges
inside/inward.
Concavity too deep to compress Reduce concavity of punch faces. Use
4.
properly. flat punches.

Cracking

(1)

Definition: Small, fine cracks observed on the upper and lower central surface of
tablets, or very rarely on the sidewall are referred to as ‘Cracks’.

Reason: It is observed as a result of rapid expansion of tablets, especially when deep

concave punches are used.
TABLE.33. THE CAUSES AND REMEDIES OF CRACKING RELATED TO
FORMULATION (GRANULATION)

Sr. No. CAUSES REMEDIES

1. Large size of granules. Reduce granule size. Add fines.
Moisten the granules properly and add proper
2. Too dry granules.
amount of binder.
3. Tablets expand. Improve granulation. Add dry binders.
4. Granulation too cold. Compress at room temperature.

TABLE.34. THE CAUSES AND REMEDIES OF CRACKING RELATED TO

MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Tablet expands on ejection due to air entrapment. Use tapered die.
Deep concavities cause cracking while
2. Use special take-off.
removing tablets

Sticking / Filming

(1)

Definition: ‘Sticking’ refers to the tablet material adhering to the die wall.

Filming is a slow form of sticking and is largely due to excess moisture in the
granulation.

Reason: Improperly dried or improperly lubricated granules.

TABLE.35. THE CAUSES AND REMEDIES OF STICKING RELATED TO

FORMULATION (GRANULATION)

Sr.
CAUSES REMEDIES
No.
Granules not dried Dry the granules properly. Make moisture analysis
1.
properly. to determine limits.
Too little or improper
2. Increase or change lubricant.
lubrication.
Reduce the amount of binder or use a different type
3. Too much binder
of binder.
 Hygroscopic granular Modify granulation and compress under controlled
4.
material. humidity.
5. Oily or way materials Modify mixing process. Add an absorbent.
Optimize the amount of binder and granulation
6. Too soft or weak granules.
technique.

TABLE.36. THE CAUSES AND REMEDIES OF STICKING RELATED TO

MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Concavity too deep for granulation. Reduce concavity to optimum.
2. Too little pressure. Increase pressure.
3. Compressing too fast. Reduce speed.

Picking

(1)

Definition: ‘Picking’ is the term used when a small amount of material from a tablet
is sticking to and being removed off from the tablet-surface by a punch face.

The problem is more prevalent on the upper punch faces than on the lower ones. The
problem worsens, if tablets are repeatedly manufactured in this station of tooling
because of the more and more material getting added to the already stuck material on
the punch face.

Reason: Picking is of particular concern when punch tips have engraving or

embossing letters, as well as the granular material is improperly dried.

TABLE.37. THE CAUSES AND REMEDIES OF PICKING RELATED TO

FORMULATION (GRANULATION)

Sr.
CAUSES REMEDIES
No.
Dry properly the granules, determine
1. Excessive moisture in granules.
optimum limit.
Increase lubrication; use colloidal silica as
2. Too little or improper lubrication. a ‘polishing agent’, so that material does
not cling to punch faces.
Low melting point substances, may
Add high melting-point materials. Use
3. soften from the heat of compression
high meting point lubricants.
and lead to picking.
4. Low melting point medicament in Refrigerate granules and the entire tablet
 high concentration. press.
Too warm granules when Compress at room temperature. Cool
5.
compressing. sufficiently before compression.
Reduce the amount of binder, change the
6. Too much amount of binder.
type or use dry binders.

TABLE.38. THE CAUSES AND REMEDIES OF PICKING RELATED TO

MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr.
CAUSES REMEDIES
No.
1. Rough or scratched punch faces. Polish faces to high luster.
Design lettering as large as possible.
Embossing or engraving letters on
2. punch faces such as B, A, O, R, P, Q,
Plate the punch faces with chromium to
G.
produce a smooth and non-adherent face.
3. Bevels or dividing lines too deep. Reduce depths and sharpness.
Pressure applied is not enough; too
4. Increase pressure to optimum.
soft tablets.

Binding

(1)

Definition: ‘Binding’ in the die, is the term used when the tablets adhere, seize or tear
in the die. A film is formed in the die and ejection of tablet is hindered. With
excessive binding, the tablet sides are cracked and it may crumble apart.

Reason: Binding is usually due to excessive amount of moisture in granules, lack of

lubrication and/or use of worn dies.

TABLE.39. THE CAUSES AND REMEDIES OF BINDING RELATED TO

FORMULATION (GRANULATION)

Sr.
CAUSES REMEDIES
No.
Too moist granules and extrudes
1. Dry the granules properly.
around lower punch.
Insufficient or improper Increase the amount of lubricant or use a more
2.
lubricant. effective lubricant.
Reduce granular size, add more fines, and
3. Too coarse granules.
increase the quantity of lubricant.
4. Too hard granules for the Modify granulation. Reduce granular size.
 lubricant to be effective.
If coarse granules, reduce its size.
Granular material very abrasive
5.
and cutting into dies.
Use wear-resistant dies.
Reduce temperature.
Granular material too warm,
6.
sticks to the die.
Increase clearance if it is extruding.

TABLE.40. THE CAUSES AND REMEDIES OF BINDING RELATED TO

MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr.
CAUSES REMEDIES
No.
1. Poorly finished dies. Polish the dies properly.
Rough dies due to abrasion, Investigate other steels or other materials or
2.
corrosion. modify granulation.
Rework to proper size.
Undersized dies. Too little
3.
clearance.
Increase clearance.
Reduce pressure. OR
Too much pressure in the
4.
tablet press.
Modify granulation.

Mottling

(1)

Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour

on a tablet, with light or dark spots standing out in an otherwise uniform surface.

Reason: One cause of mottling may be a coloured drug, whose colour differs from the
colour of excipients used for granulation of a tablet.

TABLE.41. THE CAUSES AND REMEDIES OF MOTTLING

Sr.
CAUSES REMEDIES
No.
A coloured drug used along
1. with colourless or white- Use appropriate colourants.
coloured excipients.
2. A dye migrates to the Change the solvent system,
surface of granulation while
drying.
 Change the binder,

Reduce drying temperature and

Use a smaller particle size.

Improperly mixed dye,
3. especially during ‘Direct
Compression’.
Improper mixing of a
4.
coloured binder solution.
Mix properly and reduce size if it is of a larger size
to prevent segregation.
Incorporate dry colour additive during powder
blending step, then add fine powdered adhesives
such as acacia and tragacanth and mix well and
finally add granulating liquid.

Double impression

(1)

Definition: ‘Double Impression’ involves only those punches, which have a

monogram or other engraving on them.

Reason: At the moment of compression, the tablet receives the imprint of the punch.
Now, on some machines, the lower punch freely drops and travels uncontrolled for a
short distance before riding up the ejection cam to push the tablet out of the die, now
during this free travel, the punch rotates and at this point, the punch may make a new
impression on the bottom of the tablet, resulting in ‘Double Impression’.

If the upper punch is uncontrolled, it can rotate during the short travel to the final
compression stage and create a double impression.

TABLE.42. THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION

Sr.
CAUSE REMEDIES
No.
-Use keying in tooling, i.e. inset a key alongside
of the punch, so that it fits the punch and
Free rotation of either upper
prevents punch rotation.
1. punch or lower punch during
ejection of a tablet.
-Newer presses have anti-turning devices, which
prevent punch rotation.

Problems and remedies for tablet coating

Blistering

(1,64)

Definition: It is local detachment of film from the substrate forming blister.

Reason: Entrapment of gases in or underneath the film due to overheating either
during spraying or at the end of the coating run.

TABLE.43. THE CAUSE AND REMEDY OF BLISTERING

Sr.
CAUSE REMEDY
No.
Effect of temperature on the strength, elasticity and Use mild drying
1.
adhesion of the film. condition.

Chipping

(1,64)

Definition: It is defect where the film becomes chipped and dented, usually at the
edges of the tablet.

Reason: Decrease in fluidizing air or speed of rotation of the drum in pan coating.

TABLE.44. THE CAUSE AND REMEDY OF CHIPPING

Sr.
CAUSE REMEDY
No.
High degree of attrition associated
with the coating process. Increase hardness of the film by increasing the
1.
molecular weight grade of polymer.

Cratering

(1,64)

Definition: It is defect of film coating whereby volcanic-like craters appears exposing

the tablet surface.

Reason: The coating solution penetrates the surface of the tablet, often at the crown
where the surface is more porous, causing localized disintegration of the core and
disruption of the coating.

TABLE.45. THE CAUSES AND REMEDIES OF CRATERING

Sr. CAUSES REMEDIES

No.
Inefficient drying.
1. Use efficient and optimum drying conditions.

Higher rate of application of Increase viscosity of coating solution to

2.
coating solution. decrease spray application rate.

Picking

(1,64)

Definition: It is defect where isolated areas of film are pulled away from the surface
when the tablet sticks together and then part.

Reason: Conditions similar to cratering that produces an overly wet tablet bed where
adjacent tablets can stick together and then break apart.

TABLE.46. THE CAUSES AND REMEDIES OF PICKING

Sr.
CAUSE REMEDY
No.
Use optimum and efficient drying conditions or
1. Inefficient drying.
increase the inlet air temperature.
Higher rate of application Decrease the rater of application of coating solution
2.
of coating solution by increasing viscosity of coating solution.

Pitting

(1,64)

Definition: It is defect whereby pits occur in the surface of a tablet core without any
visible disruption of the film coating.

Reason: Temperature of the tablet core is greater than the melting point of the
materials used in the tablet formulation.

TABLE.47. THE CAUSE AND REMEDY OF PITTING

Sr.
CAUSE REMEDY
No.
 Dispensing with preheating procedures at the initiation of
Inappropriate drying
coating and modifying the drying (inlet air) temperature
1. (inlet air )
such that the temperature of the tablet core is not greater
temperature
than the melting point of the batch of additives used.

Blooming

(1,64)

Definition: It is defect where coating becomes dull immediately or after prolonged

storage at high temperatures.

Reason: It is due to collection on the surface of low molecular weight ingredients

included in the coating formulation. In most circumstances the ingredient will be
plasticizer.

TABLE.48. THE CAUSE AND REMEDY OF BLOOMING

Sr.
CAUSE REMEDY
No.
High concentration and low
molecular weight of plasticizer. Decrease plasticizer concentration and
1.
increase molecular weight of plasticizer.

Blushing

(1,64)

Definition: It is defect best described as whitish specks or haziness in the film.

Reason: It is thought to be due to precipitated polymer exacerbated by the use of high

coating temperature at or above the thermal gelation temperature of the polymers.

TABLE.49. THE CAUSES AND REMEDIES OF BLUSHING

Sr.
CAUSES REMEDIES
No.
Decrease the drying air
1. High coating temperature
temperature
2. Use of sorbitol in formulation which causes Avoid use of sorbitol with
largest fall in the thermal gelation temperature Hydroxy Propyl Cellulose,
of the Hydroxy Propyl Cellulose, Hydroxy Hydroxy Propyl Methyl Cellulose,
Propyl Methyl Cellulose, Methyl Cellulose Methyl Cellulose and Cellulose
 and Cellulose ethers. ethers.

Colour variation

(1,64)

Definition: A defect which involves variation in colour of the film.

Reason: Alteration of the frequency and duration of appearance of tablets in the spray
zone or the size/shape of the spray zone.

TABLE.50. THE CAUSE AND REMEDY OF COLOUR VARIATION

Sr.
CAUSE REMEDY
No.
Improper mixing, uneven spray pattern, Go for geometric mixing,
insufficient coating, migration of soluble reformulation with different
1.
dyes-plasticizers and other additives plasticizers and additives or use mild
during drying. drying conditions.

Infilling

(1,64)

Definition: It is defect that renders the intagliations indistinctness.

Reason: Inability of foam, formed by air spraying of a polymer solution, to break. The
foam droplets on the surface of the tablet breakdown readily due to attrition but the
intagliations form a protected area allowing the foam to accumulate and “set”. Once
the foam has accumulated to a level approaching the outer contour of the tablet
surface, normal attrition can occur allowing the structure to be covered with a
continuous film.

TABLE.51. THE CAUSE AND REMEDY OF INFILLING

Sr.
CAUSE REMEDY
No.
Bubble or foam formation because of air Add alcohol or use spray nozzle
1.
spraying of a polymer solution capable of finer atomization.

Orange peel/Roughness
(1,64)

Definition: It is surface defect resulting in the film being rough and nonglossy.
Appearance is similar to that of an orange.

Reason: Inadequate spreading of the coating solution before drying.

TABLE.52. THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS

Sr. No. CAUSES REMEDIES

1. Rapid Drying Use mild drying conditions
Use additional solvents to decrease viscosity of
2. High solution viscosity
solution.

Cracking/Splitting

(1,64)

Definition: It is defect in which the film either cracks across the crown of the tablet
(cracking) or splits around the edges of the tablet (Splitting)

Reason: Internal stress in the film exceeds tensile strength of the film.

TABLE.53. THE CAUSE AND REMEDY OF CRACKING/SPLITTING

Sr.
CAUSE REMEDY
No.
Use of higher molecular Use lower molecular weight polymers or
1. weight polymers or polymeric polymeric blends. Also adjust plasticizer type and
blends. concentration.

Key Phrases

• During tablet manufacture, an industrial pharmacist usually

encounters many problems. Solving these problems requires
an in-depth knowledge of tablet-formulation as well as
machine-operating processes.

• Capping and Lamination are the defects arising as a result of

air-entrapment in the granular material.

• Chipping is a defect related arising due to very dry granules.

• Cracking is due to rapid expansion of tablets, when deep

concave punches are used.
 • Sticking, Picking and Binding are the imperfections related to
more amount of binder in granules.

• Mottling is an imperfection arising due to more than one

factor: a coloured drug, dirt in granules or the use of an oily
lubricant.

• Double-Impression is related to a machine defect: it is caused

by the free rotation of punches that have some engraving on
the punch-faces.

Coating defects:

• Blistering is related to entrapment of gases in or underneath

the film due to overheating either during spraying or at the
end of the coating run. Use of mild drying conditions can solve
this problem.

• Chipping is related to higher degree of attrition associated

with the coating process. Increase in hardness of the film by
increasing the molecular weight grade of polymer can solve
this problem.

• Cratering is related to penetration of the coating solution into

the surface of the tablet, often at the crown where the surface
is more porous, causing localized disintegration of the core
and disruption of the coating. Decrease in spray application
rate and use of optimum and efficient drying conditions can
solve this problem.

• Pitting is defect in which temperature of the tablet core is

greater than the melting point of the materials used in tablet
formulation. Dispensing with preheating procedures at the
initiation of coating and modifying the drying (inlet air)
temperature can solve this problem.

• Blooming or dull film is generally because of higher

concentration and lower molecular weight of plasticizer. So
use lower concentration and higher molecular grade of
plasticizer.

• Blushing/Whitish specks/Haziness of the film is related to

precipitation of polymer exacerbated by the use of high
coating temperature at or above the thermal gelation
temperature of the polymers.

• Colour variation is because of improper mixing, uneven spray

pattern, insufficient coating or migration of soluble dyes
 during drying. Geometric mixing, mild drying conditions and
reformulation with different plasticizers can solve this
problem.

• Infilling is because of bubble/foam formation during air

spraying of a polymer solution. Addition of alcohol or use of
spray nozzle capable of finer atomization can solve this
problem.

• Orange peel/Roughness is related to inadequate spreading of

the coating solution before drying. So decrease in viscosity of
coating solution can counter this defect.

• Cracking is seen when internal stresses in the film exceeds

tensile strength of the film. This is common with higher
molecular weight polymers or polymeric blends. So use lower
molecular weight polymers or polymeric blends