1

TABLET
Tablet:Types of tablets
From Pharmpedia
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 TABLETS FOR

1.4.1.1 Standard compressed tablets
INGESTION(1-3) These tablets
are meant to be swallowed intact 1.4.1.2 Multiple compressed tablets
along with a sufficient quantity
I. Compression coated tablet
of potable water. Exception is
chewable tablet. Over 90% of II. Layered tablet
the tablets manufactured today
III. Inlay tablet
are ingested orally. This shows
that this class of formulation is 1.4.1.3 Modified Release tablet
the most popular world wide and
1.4.1.4 Delayed action tablet
the major attention of the
researcher is towards this 1.4.1.5 Targeted tablet
direction.
I. Floating tablet
II. Colon targeting tablet
1.4.1.6 Chewable tablet
1.4.1.7 Dispersible tablet
TABLETS USED IN THE ORAL
CAVITY
The tablets under this group are
aimed release API in oral cavity 1.4.2.1 Lozenges and troches
or to provide local action in this
region. The tablets under this 1.4.2.2 Sublingual tablet
1.4.2 category avoids first-pass 1.4.2.3 Buccal tablet
metabolism, decomposition in
gastric environment, nauseatic 1.4.2.4 Dental cones
sensations and gives rapid onset 1.4.2.5 Mouth dissolved tablet
of action. The tablets formulated
for this region are designed to fit
in proper region of oral cavity.
TABLETS ADMINISTERED BY
1.4.3.1 Vaginal tablet
1.4.3 OTHER ROUTES These tablets
are administered by other route 1.4.3.2 Implants
 2

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.
TABLETS USED TO PREPARE
SOLUTION The tablets under
this category are required to be
dissolved first in water or other
1.4.4.1 Effervescent tablet
solvents before administration or
1.4.4
application. This solution may be 1.4.4.2 Hypodermic tablet
for ingestion or parenteral 1.4.4.3 Soluble tablet
application or for topical use
depending upon type of
medicament used.

Key Phrases

• 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.

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

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

• 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

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

when immediate action within few minutes is desired.

• Buccal tablet is most often used when replacement hormonal therapy is to be

administered.

• Implants are inserted into subcutaneous tissue by surgical procedures where

they are very slowly absorbed over a period of a month or a year.
 3

Tablet:Formulation of tablets
From Pharmpedia
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

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)
[edit]
 4

Various excipients used in tablet formulation and their

functionalities.
(1, 4, 16)
TABLE.2. EXCIPIENT WITH THEIR FUNCTIONS IN TABLET FORMULATION

EXCIPIENT FUNCTION

Diluents or Fillers Diluents make the required bulk of the tablet when the drug dosage
itself is inadequate to produce tablets of adequate weight and size.

Binders or Granulating Binders are added to tablet formulations to add cohesiveness to

agents or Adhesives 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.
 5

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.

Key Phrases

• Tablet formulations are usually designed to satisfy following criteria-Patient

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

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

intentionally added to the formulation of a dosage form.

• Excipients play a crucial role in design of the delivery system, determining its
quality and performance.

• 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.
 6

Tablet:Formulation of tablets/Diluents

Contents
[hide]

• 1 Introduction
• 2 Classification of diluents
o 2.1 Organic diluents
o 2.2 Inorganic diluents
o 2.3 Co-processed diluents
o 2.4 Key Phrases

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.
[edit]
 7

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.

INSOLUBLE TABLET FILLERS OR SOLUBLE TABLET FILLERS OR

DILUENTS DILUENTS

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

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

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).
 8

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: Pharmatose® 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.

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.
 9

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 Parteck®M manufactured by
EMD Chemicals .Other commercial products are Pearlitol® and Mannogem®.
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 Sorbifin® and Neosorb® .

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.
 10

It is inexpensive.
It is commercially available under the trade name of Elcema®G-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 flow ability.
It exhibits binding properties.
It also possesses disintegrates activity and thus promotes fast tablet disintegration.
It is water insoluble.
) provides increased compatibility, enhancedSolidified MCC (SMCC- Prosolv flow and improved
uniformity compared to MCC (Avicel® manufactured by FMC Biopolymer)
SMCC is more suitable for cohesive poorly compressible ingredients in direct compression formulation.
Other commercial product is Emcocel® manufactured by Penwest Pharmaceutical Co.
[edit]

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 (Manufactured byDi-
Tab® (manufactured by Rhone-Poulenc) and Emcompress E.Mendell Co.).An anhydrous form of
dibasic calcium phosphate is available commercially under the trade name A-Tab® (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-Tab®.
Characteristic of Calcium Phosphates
They are directly compressible and are characterized by brittle fracture on compression during
tableting process.
 11

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.
[edit]

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 lactose which is a mixture of
Products 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 Sucrose 95-97%, invert sugar 3-4% and magnesium

Technology 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 Calcium sulfate 93% and vegetable gum 7%

Technology
 12

Cal-Carb® Ingredient Calcium carbonate 95% and maltodextrins 5%

Technology

Calcium 90® Ingredient Calcium carbonate (minimum) 90% and Starch, NF

Technology (maximum) 9%

[edit]

Key Phrases

• Diluents make the required bulk of the tablet when the drug dosage itself is
inadequate to produce tablets of adequate weight and size.

• Diluents are often added to tablet formulations for secondary reasons like to
provide better tableting properties.

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

i) Organic materials
ii) Inorganic materials
iii) Co-processed diluents

• Tablet diluents or fillers may also be classified on the basis of their solubility in
water as soluble diluent and insoluble diluent.

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

compression tablet filler.

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

process.

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

better tableting properties than a single substance or the physical mixture
 13

Tablet:Formulation of tablets/Binders

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.
Contents
[hide] xc

• 1 Why to go for Granulation?

• 2 Granulation Processes
• 3 Types of Binders
o 3.1 Direct compression (DC) Binders
o 3.2 Mechanism of granule formation
o 3.3 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement
o 3.4 Factors to be considered in Granulation
▪ 3.4.1 Compatibility
▪ 3.4.2 Characteristics of drugs and other excipients
▪ 3.4.3 Spreading of Binder
▪ 3.4.4 Type and quantity of Binder
▪ 3.4.5 Temperature and Viscosity
▪ 3.4.6 Method of Addition of Binder
▪ 3.4.7 Mixing Time
▪ 3.4.8 Material of Construction of Granulator
▪ 3.4.9 Type of Granulator
▪ 3.4.10 Process Variables
▪ 3.4.11 Apparatus Variables
▪ 3.4.12 Impeller Movement
o 3.5 Evaluation tests for Binders/Granules
▪ 3.5.1 Particle Size and Particle Size Distribution
▪ 3.5.2 Surface Area
▪ 3.5.3 Density
▪ 3.5.4 % Compressibility
▪ 3.5.5 Flow Properties
▪ 3.5.6 Friability
▪ 3.5.7 Moisture Content
o 3.6 Key Phrases

[edit]
 14

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.
[edit]

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.
[edit]

Types of Binders
(18,25-28)
TABLE.5. CLASSIFICATION OF BINDERS

SUGARS NATURAL BINDERS SYNTHETIC/SEMISYNTHETIC POLYMER

Sucrose Acacia Methyl Cellulose

Liquid glucose Tragacanth Ethyl Cellulose

Gelatin Hydroxy Propyl Methyl Cellulose ( HPMC)

Starch Paste Hydroxy Propyl Cellulose

Pregelatinized Starch Sodium Carboxy Methyl Cellulose

Alginic Acid Polyvinyl Pyrrolidone (PVP)

Cellulose Polyethylene Glycol (PEG)

Polyvinyl Alcohols

Polymethacrylates
 15

TABLE.6. COMMONLY USED BINDERS

BINDER CATEGORY MANUFACTURER

Partially Pregelatinized
Starch 1500 Colorcon
Maize Starch

Hydroxy Propyl Methyl

Methocel Dow Chemicals
Cellulose

Hydroxy Propyl Methyl Wolff-Cellulosics

Walocel
Cellulose Natural Starch and Chemical Company

Luvitec Polyvinylpyrrolidone BASF Company

Luvicross Polyvinylpyrrolidone BASF Company

Luvicaprolactam Polyvinylcaprolactam BASF Company

TABLE.7. CHARACTERISTICS OF COMMONLY USED BINDER

COMMENTS
BINDER SPECIFIED
CONCENTRATION

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 starchthat have been processed chemically

Starch (PGS) and/ormechanically to rupture all or part of the granules
(Direct Compression)
in the presence of water and subsequently dried.
[Partially and Fully
5-75%w/w
PGS] - It contains 5% free amylose, 15% free amylopectin and
(Wet Granulation ) 80%unmodifiedstarch.
- 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
- Used as a binder in either wet or dry granulation
(HPMC)
processes.

Polyvinyl 0.5-5%w/w - Soluble in both water and alcohol.

Pyrrolidone (PVP)
- Used in wet granulation process.
 16

- 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 Glycol 10-15%w/w - Used as a meltable binder.

(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.

[edit]

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

Avicel (PH 101) MCCa FMC Corporation

SMCC (50) SMCCb Penwest Pharmaceutical

UNI-PURE(DW) Partially PGSc National Starch

& Chemical

UNI-PURE (LD) Low density starch National Starch & Chemica

DC Lactose DC lactose anhydrous Quest International Group

DI TAB DC-DCPDd Rhodi

a – Microcrystalline Cellulose, b – Silicified Microcrystalline Cellulose, c – Pregelatinized Starch, d –

Dibasic Calcium Phosphate Dihydrate
 17

TABLE.9. CHARACTERISTICS OF DC BINDERS

Flow Behavior DI TAB > SMCC(50) > DC Lactose , UNI PURE(DW) > Avicel (PH 101)
> UNI PURE(LD)

Compressibility UNI PURE(LD) > SMCC(50) , Avicel (PH 101) > UNI PURE(DW) , DC
Lactose > DI TAB

Crushing Strength UNI PURE(LD) > SMCC(50) > UNI PURE(DW) > Avicel(PH 101) > DC
Lactose &gt DITAB
[edit]

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.
[edit]

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.
[edit]

Factors to be considered in Granulation

(24,30,32)

[edit]
 18

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.
[edit]

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.

[edit]

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.
[edit]

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.
[edit]

Temperature and Viscosity

The temperature and viscosity of binder is also important. Fluid (less viscous) binder exhibit good
spreading behavior.

[edit]

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.
[edit]
 19

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.
[edit]

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.
[edit]

Type of Granulator
Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]

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
 20

and process variables. So it becomes essential to evaluate the granule characteristics to monitor its
suitability for tableting.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]

% 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

 21

[edit]

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 than 1.25 Good Flow

1.25 – 1.5 Moderate

More than 1.5 Poor 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 OF REPOSE TYPE OF FLOW

< 25 Excellent

25 – 30 Good

30 – 40 Passable

> 40 Very Poor

[edit]

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.
[edit]

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.
[edit]

Key Phrases
 22

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

• Wet Granulation, Dry Granulation/Slugging, Direct Compression are major

granule manufacturing methods.

• Direct Compression Binders are more efficient than conventional binders.

• Pregelatinized Starch is used as multifunctional excipient: tablet binder (wet

granulating agent as well as direct compression binder), diluent, disintegrant
and flow aid.

• Polyethylene Glycol used as meltable binder.

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

• NIR a tool for granulation end point measurement. However, it was shown to
work only for fluid-bed granulation. Torque impeller method and power
consumption are still the best methods for high-shear and planetary mixer-
granulators.

• Compatibility of binder with API and other excipients, characteristics of binder,

process variables, and apparatus variables affects the quality of granules.

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

Tablet:Formulation of tablets/Disintegrants
From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Antifrictional Agents
Previous Page: Binders

Contents
[hide]

• 1 Introduction
• 2 Mechanism of tablet disintegrants
• 3 Methods of addition of disintegrants
• 4 Types of disintegrants
o 4.1 Starch
o 4.2 Pregelatinized starch
o 4.3 Modified starch
o 4.4 Cellulose and its derivatives
 23

o 4.5 Microcrystalline cellulose (MCC)

o 4.6 Alginates
o 4.7 Ion-exchange resin
o 4.8 Miscellaneous
o 4.9 Superdisintegrants
• 5 Factors affecting disintegration
o 5.1 Effect of fillers
o 5.2 Effect of binder
o 5.3 Effect of lubricants
o 5.4 Effect of surfactants
• 6 Key Phrases

[edit]

Introduction
Boavailability 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

[edit]

Mechanism of tablet disintegrants

 24

(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

 25

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
 26

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
[edit]

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.

[edit]

Types of disintegrants
(34,40-42)

[edit]

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.
 27

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.
[edit]

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.
[edit]

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 andsubstituted carboxymethyl starches are also marketed as
Explotab 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 IN SPECIAL COMMENTS

GRANULES
(%W/W)

Starch USP 5-20 Higher amount is required,

poorly compressible

Starch 1500 5-15 -

Avicel®(PH 101, PH 102) 10-20 Lubricant properties and

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
 28

AC-Di-Sol® 1-3 Direct compression

2-4 Wet granulation

Carbon dioxide _ Created insitu in

effervescent tablet

[edit]

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.
[edit]

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.
[edit]

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.
[edit]

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

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.
Polyplasdone®XL and Polyplasdone®XL10 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.
[edit]
 29

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 MECHANISM SPECIAL

OF OF ACTION COMMENT

Crosscarmellose® Crosslinked -Swells 4-8 -Swells in two

cellulose folds in < 10 dimensions.
seconds.
-Direct
Ac-Di-Sol®
-Swelling and compression or
wicking both. granulation
Nymce ZSX®
Primellose®
Solutab®
-Starch free
Vivasol®

Crosspovidone Crosslinked -Swells very -Water insoluble

PVP little and and spongy in
Crosspovidon M®
returns to nature so get
Kollidon® original size porous tablet
after
Polyplasdone®
compression
but act by
capillary action

Sodium starch glycolate Crosslinked -Swells 7-12 -Swells in three

starch folds in <30 dimensions and
Explotab®
seconds high level serve
Primogel® as sustain
release matrix
 30

Alginic acid NF Crosslinked -Rapid swelling -Promote

alginic acid in aqueous disintegration in
Satialgine®
medium or both dry or wet
wicking action granulation

Soy polysaccharides Natural -Does not

super contain any
Emcosoy®
disintegrant starch or sugar.
Used in
nutritional
products.

Calcium silicate -Wicking -Highly porous,

action
-light weight
-optimum
concentration is
between 20-40%
[edit]

Factors affecting disintegration

[edit]

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.
[edit]

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.
[edit]

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.
 31

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.
[edit]

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.

[edit]

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

• Disintegration by capillary action or by swelling is the major mechanism for

disintegrants.

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

• Superdisintegrants have greater efficiency at low concentration and hence, their

demand is increasing day by day.
 32

Tablet:Formulation of tablets/Antifrictional Agents

From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Miscellaneous Excipients
Previous Page: Disintegrants

Contents
[hide]

• 1 Lubricants
o 1.1 Classification of lubricants
▪ 1.1.1 Water Insoluble Lubricants
▪ 1.1.2 Water Soluble Lubricants
• 2 Antiadherents
• 3 Glidants
• 4 Key Phrases

[edit]

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.
 33

[edit]

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.
[edit]

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, Calcium Reduce tablet strength; prolong disintegration;
0.25 -1
Stearate, Sodium widely used.
stearate)

Insoluble but not hydrophobic; moderately

Talc 1 -2
effective.

Sterotex 0.25 – 1 -

Waxes 1-5 -

Stearowet 1-5 -

Glyceryl
1-5 Both lubricant and binder;
behapate(Compritol®888)

Liquid paraffin Up to 5 Dispersion problem; inferior to stearates

[edit]

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.
 34

TABLE.18. LIST OF SOLUBLE LUBRICANTS

WATER SOLUBLE CONCENTRATION RANGE

LUBRICANTS (%W/W)

Boric acid 1

Sodium benzoate 5

Sodium oleate 5

Sodium acetate 5

Sodium Lauryl sulfate

1– 5
(SLS)

Magnesium lauryl
1-2
sulfate (MLS)

[edit]

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

Talc 1– 5 Lubricant with excellent antiadherents properties

Cornstarch 3 – 10 Lubricant with excellent antiadherents properties

Does not give satisfactory results due to small surface area.

Colloidal silica 0.1 – 0.5
Cab-O-Sil® and Syloid®

DL-Leucine 3 – 10 Water soluble lubricant; excellent antiadherents properties

Sodium lauryl
<1 Antiadherents with water soluble lubricant
sulfate

Stearates <1 Antiadherents with water insoluble lubricant

[edit]
 35

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.

[edit]

Key Phrases
• Lubricants are added to reduce the friction during compression.

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

• Glidants improve the flow property of material/granules.

Tablet:Formulation of tablets/Miscellaneous Excipients

From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Ideal properties of API for formulating tablets
Previous Page: Antifrictional Agents

Contents
[hide]

• 1 Wetting Agents
• 2 Dissolution
Retardants
• 3 Dissolution
Enhancers
• 4 Adsorbents
• 5 Buffers
• 6 Antioxidants
 36

• 7 Chelating Agents
• 8 Preservatives
• 9 Colourants
• 10 Flavours
• 11 Sweeteners
• 12 Key Phrases

[edit]

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.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]
 37

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 .
[edit]

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.
[edit]

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.
[edit]

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 & C COLOUR COMMON NAME

Red 3 Erythrosine

Red 40 Allura red AC

 38

Yellow 5 Tartrazine

Yellow 6 Sunset Yellow

Blue 1 Brilliant Blue

Blue 2 Indigotine

Green 3 Fast Green

[edit]

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.
[edit]

Sweeteners
(1,4,45)
Sweeteners are added primarily to chewable tablets.
TABLE.21. SOME OF THE SWEETENERS USED IN TABLET FORMULATION

NATURAL SWEETENERS ARTIFICIAL 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 manufactured
and marketed byavailable in market under the brand Nutrasweet Nutrasweet Company.

[edit]
 39

Key Phrases
• Only FD&C and D&C approved colourants can be incorporated into tablet
formulation.

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

Tablet:Ideal properties of API for formulating tablets

From Pharmpedia
Next Page: Operations involved in tablet manufacturing
Previous Page: Formulation of tablets

Contents
[hide]

• 1 High Purity
• 2 High stability
• 3 Good compatibility with excipients
• 4 Optimum bulk powder properties
• 5 Optimum and Uniform particle size-particle size
distribution
• 6 Spherical shape
• 7 Good flowability
• 8 Optimum moisture content
• 9 Good compressibility
• 10 Absence of static charge on surface
• 11 Good organoleptic properties
• 12 Miscellaneous points
• 13 Key Phrases

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.

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.

Good compatibility with excipients

(47)
 40

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.

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.

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.

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.

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.
 41

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.

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.

Absence of static charge on surface

(55)
It is important because of the following reasons:
 42

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.

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.

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
 43

• High Purity to avoid contamination and degradation.

• High stability against photolysis, oxidation, hydrolysis, etc.

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

• Optimum bulk powder properties to prevent segregation and to have good flow.

• Optimum particle size and size distribution to have uniformity of weight,

uniformity of content, good flow and compressibility.

• Spherical shape to avoid interlocking between the particles and thus to aid flow.

• Good flow to have uniformity of weight and uniformity of drug content.

• Optimum amount of moisture to avoid problems like brittle tablet,

picking/sticking, etc.

• Good compressibility to have nicely bonded tablet.

• Absence of static charge on the surface to prevent demixing and damage to

tableting equipment by adhering to feed frame.

• Good organoleptic properties to have better patient acceptance.

• Miscellaneous: Convert liquid API to pseudosolid e.g. Valproic acid and Sodium
valproate, etc.
 44

Tablet:Manufacturing methods/Direct compression

From Pharmpedia
< Tablet:Manufacturing methods
Next Page: Granulation
Previous Page: Tablet Manufacturing methods

Contents
[hide]

• 1 Introduction
• 2 The events that motivates the industry people to use direct compression technique
• 3 Merits
• 4 Merits over wet granulation process
• 5 Demerits
• 6 Manufacturing steps for direct compression
• 7 Direct compression Excipients
o 7.1 An ideal direct compression excipient should possess the following attributes
o 7.2 Major excipients required in direct compression
▪ 7.2.1 Diluents
▪ 7.2.2 Binders
▪ 7.2.3 Disintegrants
• 8 Key Phrases

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.
 45

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.

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, , Sorbitolmicrocrystalline
cellulose, Di-Pac
II. Major advances in tablet compression machinery,
i) Improved positive die feeding
ii) Precompression of powder blend

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.

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.
 46

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.

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

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.
 47

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.

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.
 48

Disintegrants
Disintegrants are the agents

Key Phrases

• Direct compression is one of the most advanced technologies to prepare

tablets.

• It requires only blending and compression of excipients.

• It is an economical process.

• It is suitable for heat and moisture sensitive API.

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

Tablet:Manufacturing methods/Granulation
From Pharmpedia
< Tablet:Manufacturing methods
Next Page: Tablet:Operations involved in tablet manufacturing
Previous Page: Direct compression

Contents
[hide]

• 1 Introduction
• 2 Wet granulation
o 2.1 Introduction
o 2.2 Important steps involved in the wet granulation
o 2.3 Limitation of wet granulation
o 2.4 Special wet granulation techniques
▪ 2.4.1 High shear mixture granulation
▪ 2.4.2 Fluid bed granulation
▪ 2.4.3 Extrusion and Spheronization
▪ 2.4.4 Spray drying granulation
o 2.5 Lists of equipments for wet granulation
o 2.6 Current topics related to wet granulation
• 3 Dry granulation
o 3.1 Introduction
o 3.2 Advantages
o 3.3 Disadvantages
o 3.4 Steps in dry granulation
 49

o 3.5 Two main dry granulation processes

▪ 3.5.1 Slugging process
▪ 3.5.2 Roller compaction
o 3.6 Formulation for dry granulation
• 4 Advancement in Granulations
o 4.1 Steam Granulation
o 4.2 Melt Granulation / Thermoplastic Granulation
o 4.3 Moisture Activated Dry Granulation (MADG)
o 4.4 Moist Granulation Technique (MGT)
o 4.5 Thermal Adhesion Granulation Process (TAGP)
o 4.6 Foam Granulation
• 5 Key Phrases

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)

Wet granulation
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.

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.
 50

screens).iv) Coarse screening of wet mass using a suitable sieve (6-12

v) Drying of moist granules.
screen).vi) Screening of dry granules through a suitable sieve (14-20
vii) Mixing of screened granules with disintegrant, glidant, and lubricant.

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.

Special wet granulation techniques

i) High shear mixture granulation
ii) Fluid bed granulation
iii) Extrusion-spheronization
iv) Spray drying

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.

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.
 51

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.

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

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

Current topics related to wet granulation

I.Hydrate formation
 52

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 α β γ . γ is the most stable form and αis
the metastable form. The stable Glycine polymorph (γ) converts to metastable form (α) when wet
granulated with microcrystalline cellulose.

Dry granulation
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.

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

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.

Steps in dry granulation

i) Milling of drugs and excipients
 53

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

Two main dry granulation processes

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

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.

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.
 54

Examples of some tablet formulation prepared by dry granulation

Advancement in Granulations
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.

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.

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.

Moist Granulation Technique (MGT)

(59)
 55

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.

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.

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
• 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.

• 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.

• 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:Operations involved in tablet manufacturing

From Pharmpedia
 56

Next Page: Tablet Manufacturing methods

Previous Page: Ideal properties of API for formulating tablets

Contents
[hide]

• 1 Introduction
• 2 Dispensing
• 3 Sizing
• 4 Powder blending
• 5 Granulation
• 6 Drying
• 7 Tablet compression
• 8 Auxiliary Equipments
o 8.1 Granulation Feeding Device
o 8.2 Tablet weight monitoring devices
o 8.3 Tablet Deduster
o 8.4 Fette machine
• 9 Packaging
o 9.1 Key Phrases

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

57
 58

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. Milling and mixing of drugs 1. Milling and mixing of

1. Milling and mixing of drugs and excipients
and excipients drugs and excipients

2. Preparation of binder 2. Compression into slugs

2. Compression of tablet
solution or roll compaction

3. Wet massing by addition of 3. Milling and screening of

binder solution or granulating slugs and compacted
solvent powder

4. Mixing with lubricant

4. Screening of wet mass
and disintegrant

5. Drying of the wet granules 5. Compression of tablet

6. Screening of dry granules

7. Blending with lubricant and

disintegrant to produce
“ running powder”

8. Compression of tablet

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.

Sizing
 59

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.

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.
 60

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” .

Granulation
Following particle size reduction and blending, the formulation may be granulated, which provides
homogeneity of drug distribution in blend.

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.

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

 61

FIGURE.22. STAGE OCCURRING DURING COMPRESSION

Stage 1: Top punch is withdrawn from the die by the upper camBottom 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

Auxiliary Equipments
(1)

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.

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.

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.

Fette machine
 62

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.

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

• Particle size reduction and sizing

• Blending

• Granulation

• Drying, compaction

• Coating.

Tablet:Tablet coating
From Pharmpedia
Next Page: Problems in tablet manufacturing
Previous Page: Tablet Manufacturing methods

Contents
[hide]

• 1 Introduction
• 2 Aspects of tablet coating
• 3 Basic principle of tablet coating
• 4 Type of tablet coating process
o 4.1 Sugar coating
▪ 4.1.1 Sealing/Water proofing
▪ 4.1.2 Subcoating
▪ 4.1.3 Grossing/ smoothing
 63

▪ 4.1.4 Colour coating

▪ 4.1.5 Polishing
o 4.2 Film Coating
▪ 4.2.1 Process description
▪ 4.2.2 Process details
▪ 4.2.3 Basic process requirements for film coating
▪ 4.2.4 Coating formula optimization
▪ 4.2.5 Materials used in film coating
o 4.3 Enteric coating
▪ 4.3.1 = Enteric sugar coating
▪ 4.3.2 Enteric film coating
▪ 4.3.3 Controlled release coating
o 4.4 Specialized coating
▪ 4.4.1 Compressed coating
▪ 4.4.2 Electrostatic coating
▪ 4.4.3 Dip coating
▪ 4.4.4 Vacuum film coating
• 5 Equipments
• 6 Process parameters
o 6.1 Air capacity
o 6.2 Coating composition
o 6.3 Tablet surface area
o 6.4 Equipment efficiency
• 7 Key Phrases

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.

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
 64

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

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.

Type of tablet coating process

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.
 65

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.

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 100 to 100

TABLE.24. TYPICAL DUSTING POWDER FORMULATION FOR SUBCOATING(1)

%W/W %W/W

Calcium carbonate 40.0 -

Titanium dioxide 5.0 1.0

Talc, asbestos free 25.0 61.0

Sucrose( powdered ) 28.0 38.6

Gum acacia (powdered) 2.0 -

 66

TABLE.25. TYPICAL SUSPENSION SUBCOATING FORMULATION(1)

%W/W

Sucrose 40.0

Calcium carbonate 20.0

Talc, asbestos free 12.0

Gum acacia(powdered) 2.0

Titanium dioxide 1.0

Distilled water 25.0

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.

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.

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.

Film Coating
Film coating is more favored over sugar coating.
TABLE.26. COMPARISON BETWEEN FILM COATING AND SUGAR COATING(1)
 67

FEATURES FILM COATING SUGAR COATING

Tablet:
Appearance Retain contour of original Rounded with high degree
core. Usually not as shiny of polish
as sugar coat type

Weight increase because

2-3%
of coating material 30-50%

Logo or ‘ break lines’

Possible
Not possible

Process
Operator training required Process tends itself to Considerable
automation and easy
training of operator

Adaptability to GMP
High
Difficulty may arise
Process stages
Usually single stage
Multistage process
Functional coatings
Easily adaptable for
controlled release Not usually possible apart
from enteric coating

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
 68

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 factorial
study.

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)
 69

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.
 70

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
E is cationic. EudragitIt is marketed under the name of Eudragit E is freely soluble in gastric fluid up
to pH 5 andco-polymer. Only Eudragit expandable and permeable above pH 5. This material is
available as organic solution (12.5% in isopropanol/acetone), solid material or 30% aqueous
RLdispersion. Eudragit & 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)
 71

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 (opaque colour
concentrate for film coating) andintestinal track. Opasray (complete film coating concentrate) are
promoted as achieving lessOpadry 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.

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
 72

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.

= 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.

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.

Controlled release coating

(2)
Polymers like modified acrylates, water insoluble cellulose (ethyl cellulose), etc. used for control
release coating.
 73

Specialized coating
(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.

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.

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.

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.

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
 74

Driacoated system
3.Fluidized bed coater

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

• The sugar coating involves several steps like, sealing, subcoating, colour
coating and printing.

• Sugar coating process yields elegant and highly glossed tablet.

• Newer techniques utilize spraying systems and varying degree of automation to

improve coating efficiency and product uniformity.

• Film coating is deposition of a thin film of polymer surrounding the tablet core.
 75

• 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.

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

• 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.

• Materials used in film coating include film formers, solvents, plasticizers,

colourants, opaquant-extenders, surfactant, anti oxidant, etc.

• Widely used film formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl
Hydroxy Ethyl Cellulose (MHEC), Ethyl Cellulose (EC), Hydroxy Propyl Cellulose
(four grades available i.e. K-15, K-30, K-60and K-90), Sodium(HPC),
Povidone carboxy methyl cellulose, Polyethylene glycols (PEG) and Acrylate
polymers (Eudragit®, Eudragit®RL, Eudragit®RS, Eudragit®E) 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.

• 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.

• 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.

• 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:

• 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.
 76

• 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:

• 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.

• 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 enzymatically

degraded in colon. For example, Cyclodextrin & Galactomannan.

Controlled release coating:

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

Problems and remedies

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:
 77

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).

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 TESTS TO BE

TABLET PERFORMED
Content of active
ingredients
For all
tablets Disintegration
Uniformity of content
Labeling
BRITISH Uncoated Disintegration test
PHARMACOPOEIA tablet Uniformity of weight
Effervescent Disintegration test
tablet Uniformity of weight
Coated
Disintegration test
tablet
Uniformity of weight
 78

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

Uncoated Content of active

tablet ingredient
Uniformity of weight
Uniformity of content
Disintegration test
Enteric
INDIAN coated
Disintegration test
PHARMACOPOEIA tablet

Dispersible Uniformity of dispersion

tablet Disintegration
Soluble
Disintegration test
tablet
Disintegration/
Effervescent
Dissolution / Dispersion
tablet
test
Bulk density /Tapped
density of powder
Powder fineness
Loss on drying
Physical Disintegration test
tests Tablet friability
UNITED STATES Dissolution test
applicable
PHARMACOPOEIA Drug release testing
to tablet
formulation Uniformity of dosage
form
Container permeation
test
Labeling of inactive
ingredients
 79

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.

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.

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.

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.
 80

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 mesh
1.
granulation screen

Too dry or very low moisture content

Moisten the granules suitably. Add hygroscopic
2. (leading to loss of proper binding
substance e.g.: sorbitol, methyl- cellulose or PEG-4000.
action).

3. Not thoroughly dried granules. Dry the granules properly.

Increasing the mount of binder OR

Insufficient amount of binder or Adding dry binder such as pre-gelatinized starch, gum
4.
improper binder. acacia, powdered sorbitol, PVP, hydrophilic silica or
powdered sugar.

Increase the amount of lubricant or change the type of

5. Insufficient or improper lubricant.
lubricant.

Granular mass too cold to compress

6. Compress at room temperature.
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 steels or

1. Poorly finished dies
other materials.

Deep concave punches or beveled-edge faces

2. Use flat punches.
of punches.

Lower punch remains below the face of die Make proper setting of lower punch during
3.
during ejection. ejection.

Adjust sweep-off blade correctly to facilitate

4. Incorrect adjustment of sweep-off blade.
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.
 81

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)
REMEDIES
Sr. CAUSES
No.

Modify mixing process. Add adsorbent or

1. Oily or waxy materials in granules
absorbent.

Too much of hydrophobic lubricant e.g.: Use a less amount of lubricant or change
2.
Magnesium-stearate. the type of lubricant.

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 regions of Use tapered dies, i.e. upper part of the die bore
1.
a tablet, on ejection from a die. has an outward taper of 3° to 5°.

Use pre-compression step. Reduce turret speed

2. Rapid decompression
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.

1. Sticking on punch faces Dry the granules properly or increase lubrication.

Moisten the granules to plasticize. Add hygroscopic

2. Too dry granules.
substances.

Too much binding causes chipping at

3. Optimize binding, or use dry binders.
bottom.
 82

TABLE.32. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND
TABLET PRESS)

Sr. CAUSES REMEDIES

No.

1. Groove of die worn at compression point. Polish to open end, reverse or replace the die.

Barreled die (center of the die wider than

2. Polish the die to make it cylindrical
ends)

3. Edge of punch face turned inside/inward. Polish the punch edges

Reduce concavity of punch faces. Use flat

4. Concavity too deep to compress properly.
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)

REMEDIES
Sr. No. CAUSES

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
 83

(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.

Dry the granules properly. Make moisture analysis to determine

1. Granules not dried properly.
limits.

Too little or improper

2. Increase or change lubricant.
lubrication.

3. Too much binder Reduce the amount of binder or use a different type of binder.

Hygroscopic granular
4. Modify granulation and compress under controlled humidity.
material.

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 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)
 84

Sr. CAUSES REMEDIES

No.

Dry properly the granules, determine optimum

1. Excessive moisture in granules.
limit.

Increase lubrication; use colloidal silica as a

2. Too little or improper lubrication. ‘ polishing agent’ , so that material does not cling
to punch faces.

Low melting point substances, may soften

Add high melting-point materials. Use high meting
3. from the heat of compression and lead to
point lubricants.
picking.

Low melting point medicament in high

4. Refrigerate granules and the entire tablet press.
concentration.

Compress at room temperature. Cool sufficiently

5. Too warm granules when compressing.
before compression.

Reduce the amount of binder, change the type or

6. Too much amount of binder.
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 punch
2. Plate the punch faces with chromium to produce
faces such as B, A, O, R, P, Q, G.
a smooth and non-adherent face.

3. Bevels or dividing lines too deep. Reduce depths and sharpness.

Pressure applied is not enough; too soft

4. Increase pressure to optimum.
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)
 85

Sr. CAUSES REMEDIES

No.

Too moist granules and extrudes

1. Dry the granules properly.
around lower punch.

Increase the amount of lubricant or use a more

2. Insufficient or improper lubricant.
effective lubricant.

Reduce granular size, add more fines, and increase the

3. Too coarse granules.
quantity of lubricant.

Too hard granules for the lubricant to

4. Modify granulation. Reduce granular size.
be effective.

Granular material very abrasive and If coarse granules, reduce its size.
5.
cutting into dies. Use wear-resistant dies.

Granular material too warm, sticks to Reduce temperature.

6.
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 modify
2.
corrosion. granulation.

Undersized dies. Too little Rework to proper size.

3.
clearance. Increase clearance.

Too much pressure in the tablet Reduce pressure. OR

4.
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

 86

Sr. CAUSES REMEDIES

No.

A coloured drug used along with

1. colourless or white-coloured Use appropriate colourants.
excipients.

Change the solvent system,

A dye migrates to the surface of Change the binder,

2.
granulation while drying. Reduce drying temperature and
Use a smaller particle size.

Improperly mixed dye, especially Mix properly and reduce size if it is of a larger size to prevent
3.
during ‘ Direct Compression’ . segregation.

Incorporate dry colour additive during powder blending step,

Improper mixing of a coloured
4. then add fine powdered adhesives such as acacia and
binder solution.
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

Free rotation of either upper punch or punch, so that it fits the punch and prevents punch
1. lower punch during ejection of a rotation.
tablet. -Newer presses have anti-turning devices, which prevent
punch rotation.

Problems and remedies for tablet coating

Blistering
(1,64)
 87

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 adhesion of the Use mild drying
1.
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 coating Increase viscosity of coating solution to decrease spray
2.
solution. application rate.
 88

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 increase the inlet

1. Inefficient drying.
air temperature.

Higher rate of application of Decrease the rater of application of coating solution by increasing
2.
coating solution 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 coating and

Inappropriate drying
modifying the drying (inlet air) temperature such that the temperature of
1. (inlet air )
the tablet core is not greater than the melting point of the batch of
temperature
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

 89

No.

High concentration and low molecular

weight of plasticizer. Decrease plasticizer concentration and increase
1.
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.

1. High coating temperature Decrease the drying air temperature

Use of sorbitol in formulation which causes largest fall in
the thermal gelation temperature of the Hydroxy Propyl
2.
Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl
Cellulose and Cellulose ethers.
Avoid use of sorbitol with Hydroxy
Propyl Cellulose, Hydroxy Propyl Methyl
Cellulose, Methyl Cellulose and
Cellulose 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, reformulation with
1. insufficient coating, migration of soluble dyes- different plasticizers and additives or use
plasticizers and other additives during drying. mild drying conditions.

Infilling
(1,64)
Definition: It is defect that renders the intagliations indistinctness.
 90

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 spraying Add alcohol or use spray nozzle capable of
1.
of a polymer solution 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

2. High solution viscosity Use additional solvents to decrease viscosity of 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 weight Use lower molecular weight polymers or polymeric blends.
1.
polymers or polymeric blends. Also adjust plasticizer type and concentration.
 91

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.
 92

• 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

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 TESTS TO BE

TABLET PERFORMED
Content of active
ingredients
BRITISH For all
PHARMACOPOEIA tablets Disintegration
Uniformity of content
 93

Labeling
Uncoated Disintegration test
tablet Uniformity of weight
Effervescent Disintegration test
tablet Uniformity of weight
Coated Disintegration test
tablet Uniformity of weight

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

Dispersible Uniformity of
tablet dispersion

Uniformity of weight
Uniformity of
container content

Content of active
Uncoated
ingredient
tablet
Uniformity of weight
Uniformity of content

INDIAN Disintegration test

PHARMACOPOEIA Enteric
coated Disintegration test
tablet

Uniformity of
Dispersible
dispersion
tablet
Disintegration
Soluble Disintegration test
 94

tablet
Disintegration/
Effervescent Dissolution /
tablet Dispersion
test
Bulk density /Tapped
density of powder

Powder fineness
Loss on drying
Disintegration test
Physical
Tablet friability
tests
UNITED STATES Dissolution test
applicable
PHARMACOPOEIA Drug release testing
to tablet
Uniformity of dosage
formulation
form
Container permeation
test

Labeling of inactive
ingredients

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.

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.

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
 95

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.

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.
 96

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

• Friability is official test as per USP.

• At regular interval (10 – 15minutes) during the course of manufacturing the

operator must sample specified number of tablets for testing